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Monday, 20 February 2017

A Brønsted acid catalysed enantioselective Biginelli reaction

Green Chem., 2017, Advance Article
DOI: 10.1039/C6GC03274E, Paper
Margherita Barbero, Silvano Cadamuro, Stefano Dughera
A chiral derivative of 1,2-benzenedisulfonimide, namely (-)-4,5-dimethyl-3,6-bis(o-tolyl)-1,2-benzenedisulfonimide is herein proven to be an efficient chiral catalyst in a one pot three-component Biginelli reaction.

A Brønsted acid catalysed enantioselective Biginelli reaction

*Corresponding authors
aDipartimento di Chimica, Università di Torino, C.so Massimo d'Azeglio 48, 10125 Torino, Italy
E-mail: stefano.dughera@unito.it
Green Chem., 2017, Advance Article
A chiral derivative of 1,2-benzenedisulfonimide, namely (−)-4,5-dimethyl-3,6-bis(o-tolyl)-1,2-benzenedisulfonimide is herein proven to be an efficient chiral catalyst in a one pot three-component Biginelli reaction. In fact the yields of the target dihydropyrimidines were very high (25 examples; average 91%) and enantiomeric excesses were always excellent (14 examples; average 97%). Ultimately, we herein propose a procedure that displays a number of benefits and advantages including the total absence of solvents, mild reaction conditions, relatively short reaction times and stoichiometric reagent ratios. Target dihydropyrimidines are obtained in adequate purity, making further chromatographic purification unnecessary. Moreover, the chiral catalyst was easily recovered from the reaction mixture and reused, without the loss of catalytic activity.
(R)-(-)-Ethyl 6-methyl-4-phenyl-2-thioxo-3,4-dihydropyrimidine-5-carboxylate (5a): pale grey solid (135 mg, 98% yield); mp 201–202 °C ( from EtOH; lit17 200–202 °C). 96.4% Ee (GC connected to a J&W Scientific Cyclosil-B column; stationary phase: 30% heptakis (2,3-di-Omethyl-6-O-t-butyldimethylsilyl)-β-cyclodextrin in DB-1701), tR= 12.11 min (major), tR= 12.54 min (minor); [a]D -65.4 (c 0.1 in MeOH).
1H NMR (200 MHz, DMSO-d6): δ = 10.24 (br s, 1H), 9.55 (br s, 1H), 7.31–7.12 (m, 5H), 5.09 (d, J = 3.9 Hz, 1H), 3.92 (q, J = 7.0 Hz, 2H), 2.21 (s, 3H), 1.01 (t, J = 7.0 Hz, 3H);
13C NMR (50 MHz, DMSO-d6): δ = 174.9, 165.8, 145.7, 129.3, 128.3, 127.0, 101.3, 60.2, 54.7, 17.8, 14.7.
MS (m/z, EI): 276 [M+ ] (45), 247 (40), 199 (100). IR (neat) ν (cm−1): 3311 (NH), 3112 (NH), 1665 (CO), 1195 (CS).
USES
Image result for Biginelli reaction
Image result for Biginelli reaction
Image result for Biginelli reaction
////////////Bronsted acid,  catalysed, enantioselective, Biginelli reaction

Thursday, 16 February 2017

AZD 7762

Image result for AZD 7762

AZD7762

CAS 860352-01-8

AZD7762; 860352-01-8; AZD-7762; AZD 7762; (S)-5-(3-Fluorophenyl)-N-(piperidin-3-yl)-3-ureidothiophene-2-carboxamide; UNII-5D822Y3L1H
3-(carbamoylamino)-5-(3-fluorophenyl)-N-[(3S)-piperidin-3-yl]thiophene-2-carboxamide
Potent and selective ATP-competitive inhibitor of Chk1 and Chk2 (IC50 vales are 5 nM for both kinases); displays at least >10 fold selectivity over a panel of 164 kinases. Potentiates cytotoxicity of DNA-damaging agents
HCL; SALT, Technical Data
M.Wt:398.88, Formula:C17H19FN4O2S.HCl
Solubility:Soluble to 100 mM in water and to 100 mM in DMSO, CAS No:1246094-78-9
 
5-(3′-Fluorophenyl)-3-ureidothiophene-2-carboxylic Acid (S)-Piperidin-3″-ylamide (AZD7762)
1H NMR (400 MHz, DMSO-d6, 353 K): 9.88 (br. s, 1H), 8.22 (s, 1H), 7.52–7.36 (m, 4H), 7.19 (m, 1H), 6.35 (br. s, 2H), 3.81 (m, 1H), 2.95 (m, 1H), 2.76 (m, 1H), 2.44–2.56 (m, 2H), 1.82 (m, 1H), 1.67–1.34 (m, 3H).
13C NMR (100 MHz, DMSO-d6, 353 K): 163.3 (s), 163.1 (d, J = 243 Hz), 155.5 (s), 145.2 (s), 142.0 (d, J = 3 Hz), 136.0 (d, J = 3 Hz), 131.8 (d, J = 9), 122.2 (d, J = 3 Hz), 120.1 (s), 115.8 (d, J = 21 Hz), 112.6 (d, J = 23 Hz), 111.0 (s), 51.6 (s), 47.4 (s), 46.3 (s), 30.9 (s), 25.5 (s).
LC-HRMS Calcd for [M + H] C17H20FN4O2S: 363.1286; found [M + H]+: 363.1277.

An Improved Convergent Synthesis of AZD7762: A One-Pot Construction of a Highly Substituted Thiophene at the Multikilogram Scale
Pharmaceutical Technology and Development, AstraZeneca, Silk Road Business Park, Macclesfield, Cheshire, SK10 2NA, United Kingdom
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.6b00364
 
Abstract Image
A multikilogram synthesis of AZD7762 has been achieved using a highly convergent route employing two efficient telescoped sequences to generate the key intermediates. Aminothiophene 11 is formed in a four-step, one-pot addition–elimination–cyclization sequence from cinnamonitrile 9, constructing the trisubstituted thiophene ring with the desired API substitution pattern in place. Cinnamonitrile 9 is derived by elaboration of 3-fluoroacetophenone. Generation of the urea function, followed by deprotection, affords AZD7762 in 49% yield over 5 isolated stages from chiral piperidine 5, a 5-fold increase in yield versus the first generation route, reducing the starting material burden and eliminating the previous requirement for metal-mediated couplings and chromatography.
Patent
formula I
I or a pharmaceutically acceptable salt thereof, comprising the following steps:

Example 1:
Synthesis of (Z)-3-Chloro-3-(3-fluorophenyl)-acrylonitrile from 3'-Fluoroacetophenone.
To a solution of 3'-fluoroacetophenone (80.0 g, 0.579 mol) in 7V,N-dimethyl formamide (560 ml) at about 400C was added phosphoryl chloride (92.50 ml, 1.01 mol) dropwise, maintaining the temperature at about 39-410C during the addition. The resulting reaction mixture was stirred at about 400C overnight before sampling for conversion to 2 by HPLC.
To the resulting reaction mixture was added a solution of hydroxylamine hydrochloride (45.17 g, 0.637 mol) in 7V,N-dimethyl formamide (240 ml) dropwise, maintaining the temperature at about 39-45°C during the addition, followed by a line -wash of JV,Λ/-dimethyl formamide (40 ml). After stirring at about 400C for 15 min, the reaction mixture was sampled for conversion to 4 before cooling to about 15-200C and addition of water (800 ml) dropwise, maintaining the temperature between about 17 to about 210C. The reaction mixture was then cooled to about 5°C and held at this temperature for a further 20 min before filtration of the solid, displacement washing with two separate portions of water (2 x 240 ml) and drying at about 400C overnight to afford the title compound as a pale yellow solid (74.24 g, 71% yield).
IH NMR (400MHz, DMSO-d6) δ: 7.72-7.65 (m, 2H), 7.63-7.56 (m, IH), 7.49-7.42 (m, IH),
7.03 (s, IH).
13C NMR (400MHz, DMSO-d6) δ: 162.0 (d, J = 245 Hz), 149.3 (d, J = 3 Hz), 135.6 (d, J= 8
Hz), 131.1 (d, J = 9 Hz), 123.3 (d, J = 3 Hz), 118.8 (d, J = 21 Hz), 115.8, 113.8 (d, J = 24 Hz),
89.3.
Example 2:
Synthesis of tert-buty\ (3S)-3-({[3-amino-5-(3-fluorophenyl)thiophen-2-yl]carbonyl}amino)piperidine-l-carboxylate from (S)-l-Boc-3-aminopiperidine and compound 4.

l-Boc-3-(S)-aminopiperidine (120.0 g, 0.599 mol) was dissolved in 2-methyltetrahydrofuran (540 ml). Pyridine (58.14 ml, 0.719 mol) was added, followed by a line-wash of 2-methyltetrahydrofuran (60 ml). Chloroacetyl chloride (55.32 ml, 0.689 mol) was added dropwise, maintaining the temperature at about 21-25°C, followed by a line wash of 2-methyltetrahydrofuran (60 ml). After 2.5 h at ambient temperature, the reaction mixture was sampled for conversion to 6 by HPLC before the addition of a 16% w/w aqueous solution of sodium chloride (360 ml). The mixture was stirred for 30 min before separating off the aqueous phase.
To the organic phase was added a filtered solution of potassium thioacetate (102.65 g, 0.899 mol) in water (204 ml), followed by a line-wash of water (36 ml), maintaining the temperature at about 19-26°C throughout. After stirring overnight at ambient temperature, the organic phase was sampled for conversion to 7 by HPLC before separating off the aqueous phase.
To the organic phase was added 4 (97.93 g, 0.539 mol) before dropwise addition of a solution of sodium methoxide in methanol (202 ml @ 25% w/w, 0.899 mol), maintaining the temperature at about 21-24°C. This was followed by a line wash of methanol (36 ml). After stirring for 1 h 50 min at ambient temperature, the reaction mixture was sampled by HPLC for conversion to 9 before heating to about 33°C, followed by dropwise addition of water (600 ml). After stirring for 10 min, the aqueous phase was separated off.
To the organic phase was added isohexane (960 ml) dropwise before removing a small sample of the reaction mixture, allowing it to cool and returning it to the bulk mixture to seed crystallisation. Dropwise addition of a second portion of isohexane (480 ml), followed by a ramped cool to about 3°C over 1 h and a subsequent hold at this temperature overnight caused crystallisation of the product. Filtration, displacement washing the solid with ice-cold tert-butyi acetate (240 ml) and 2 x ice-cold mixed solvent system of tert-butyl acetate and isohexane (1 :1, 2 x 240 ml) and drying at about 400C over 3 days afforded 9 as a pale yellow solid (192.69 g, 77% yield based on l-Boc-3-(S)-aminopiperidine).
IH NMR (400MHz, DMSO-d6, 8O0C) δ: 7.49-7.32 (m, 3H), 7.19-7.12 (m, IH), 7.01 (s, IH), 6.91 (d, IH), 6.29 (br, s, IH), 3.91-3.64 (m, 3H), 2.96-2.77 (m, 2H), 1.92-1.77 (m, IH), 1.74-1.30 (m, 12H). Mass Spectrum: 420 [MH]+ and 364 [M-Φu]+.
Example 3:
Synthesis of tert-butγ\ (3S)-3-({[5-(3-fluorophenyl)-3- { [(trichloroacetyljcarbamoyl] amino}thiophen-2-yl] carbonyl}amino)piperidine-l-carboxylate from compound 9 and trichloroacetyl isocyanate.
To a solution of 9 (73.12 g, 0.174 mol) in tetrahydrofuran (800 ml) was added trichloroacetyl isocyanate (23.23 ml, 0.196 mol), maintaining the temperature at about 20-300C during the addition. After 2.5 h at ambient temperature, the mixture was sampled for conversion to 10 before addition of isohexane (1120 ml) dropwise over 1 hour. After stirring for a further 1 h, the reaction mixture was filtered, the solid washed with isohexane (160 ml) and dried at about 400C to afford 10 as a pale peach solid (103.54 g, 98% yield).
IH NMR (400MHz, DMSO-d6, 702C) δ: 11.70 (s, IH), 11.49 (br. s, IH), 8.24 (s, IH), 7.80 (d, IH), 7.57-7.40 (m, 3H), 7.26-7.18 (m, IH), 3.97-3.67 (m, 3H), 2.95-2.78 (m, 2H), 1.97-1.84 (m, IH), 1.78-1.53 (m, 2H), 1.51-1.33 (m, 10H).
13C NMR (400MHz, DMSO-d6) δ: 162.3 (d, J = 245 Hz), 161.7, 160.3, 153.7, 148.5, 141.9 (d, J = 3 Hz), 140.5, 134.6 (d, J = 8 Hz), 131.1 (d, J = 9), 121.4 (d, J = 3 Hz), 119.5, 115.3 (d, J = 21 Hz), 114.7, 112.0 (d, J = 23 Hz), 91.8, 78.4, 47.4, 45.7, 43.2, 29.2, 27.7, 23.2.
Example 4:
Synthesis of tert-butγ\ (3S)-3-({[3-(ureido)-5-(3-fluorophenyl)thiophen-2-yl]carbonyl}amino)piperidine-l-carboxylate via deprotection of compound 10.
To a suspension of 10 (101.45 g, 0.169 mol) in methanol (516 ml) was added triethylamine (58.15 ml, 0.417 mol). After a further 2.5 h at ambient temperature, the mixture was sampled for conversion to 11 before addition of water (206 ml) over 10 min. After stirring overnight at ambient temperature, the reaction mixture was heated to about 45°C for 15 min before addition of a second portion of water (1083 ml) over 2 h. After a further 1 h at about 45°C, the reaction mixture was allowed to cool to about 200C and held at this temperature for 1 h. The reaction mixture was filtered and the solid washed with water (206 ml) before drying at about 400C overnight to afford 10 as a white solid (77.10 g, 99% yield).
IH NMR (400MHz, DMSO-d6, 8O0C) δ: 9.86 (s, IH), 8.24 (s, IH), 7.60-7.41 (m, 3H), 7.41-7.33 (m, IH), 7.22-7.15 (m, IH), 6.36 (br, s, 2H), 3.94-3.68 (m, 3H), 2.97-2.79 (m, 2H), 1.94-1.84 (m, IH), 1.76-1.55 (m, 2H), 1.47-1.34 (m, 10H) Mass Spectrum: 486 [MNa]+.
Example 5:
Synthesis of 5-(3-Fluorophenyl)-3-ureidothiophene-2-carboxylic acid (S)-piperidin-3-ylamide via deprotection of compound 11.
11 12
To a suspension of 11 (75.3 g, 0.163 mol) in methanol (383 ml) was added an aqueous solution of hydrochloric acid (40.78 ml @ 37% w/w in water, 0.488 mol) dropwise, maintaining the temperature at about 20-300C. The resulting reaction mixture was then heated at about 500C for 4 h before sampling for conversion to 12. Triethylamine (85.10 ml, 0.610 mol) was added dropwise before addition of water (345 ml). A small sample of the reaction mixture was then removed, allowing it to cool before returning to the bulk mixture to seed crystallisation with stirring for 30 min. Further water (613 ml) was added over 1.5 h before holding at about 500C for a further 30 min and allowing to cool to about 200C with stirring overnight. The reaction mixture was filtered and the solid washed with water (153 ml) before drying at about 400C overnight to afford 12 as a white solid (57.26 g, 97% yield).
IH NMR (400MHz, DMSO-d6, 8O0C) δ: 9.88 (br. s, IH), 8.22 (s, IH), 7.52-7.36 (m, 4H), 7.19 (m, IH), 6.35 (br. s, 2H), 3.81 (m, IH), 2.95 (m, IH), 2.76 (m, IH), 2.44-2.56 (m, 2H), 1.82 (m, IH), 1.67-1.34 (m, 3H). Mass Spectrum: 363 [MH]+.
Example 6:
Purification of 5-(3-Fluorophenyl)-3-ureidothiophene-2-carboxylic acid (S)-piperidin-3-ylamide (compound 12).
A suspension of 12 (50.0 g, 0.138 mol) in methanol (650 ml) was heated to about 300C for 30 min before filtering the resulting hazy suspension through a 1.6 micron glass microfibre filter paper into a second vessel, followed by a line-wash with methanol (100 ml), discarding the solid residue. The resulting solution was cooled to about 100C before addition of water (250 ml), dropwise over 20 min, maintaining the temperature at about 10-150C. To seed crystallisation, a sample of purified 12 was then added (150 mg, 0.3% wt/wt), and the contents of the vessel allowed to stir at about 100C for 30 min. Addition of a second portion of water (500 ml) over 1 h 30 min, maintaining the temperature at about 10-130C, followed by stirring for 20 h at about 100C, resulted in complete crystallisation. Filtration, washing the solid with water (2 x 100 ml), sucking dry for 30 min before drying under vacuum at about 400C overnight, afforded purified 12 as a white solid (46.91 g, 92% yield).
IH NMR (400MHz, DMSO-d6) δ: 10.04 (s, IH), 8.29 (s, IH), 7.77 (d, IH), 7.55 - 7.42 (m, 3H), 7.24 (m, IH), 6.67 (br. s, 2H), 3.79 (m, IH), 2.94 (m, IH), 2.78 (m, IH), 2.49 - 2.37 (m, 2H), 1.82 (m, IH), 1.65 - 1.34 (m, 3H). Mass Spectrum: 363 [MH]+.
Example 7:
Synthesis of 5-(3-Fluorophenyl)-3-ureidothiophene-2-carboxylic acid (S)-piperidin-3-ylamide fumarate salt (compound 12 Fumarate salt).


12 Fumarate salt To a mixture of 12 (1.00 g, 2.8 mmol) and fumaric acid (160 mg, 1.4 mmol) was added acetone (3.0 ml) and water (1.9 ml). The resulting hazy solution was filtered through a syringe filter, before adding it dropwise to a second vessel containing a solution of fumaric acid (160 mg, 1.4 mmol) in acetone (18.5 ml) and water (0.5 ml), and a seed crystal of 12 Fumarate salt. The solution addition took place at ambient temperature over 1 h and was followed by a line -wash with acetone (1.0 ml) and water (0.1 ml). Gradual crystallisation of the product occurred, and after stirring the resulting slurry at ambient temperature for 1 h 30 min, the solid was filtered and washed with acetone (2 x 2.0 ml), sucking dry for 30 min before drying under vacuum at about 400C overnight to afford 12 Fumarate salt as a white solid (0.96 g, 96% yield).
IH NMR (400MHz, DMSO-d6) δ: 10.00 (s, IH), 8.29 (s, IH), 8.24 (d, IH), 7.54 - 7.42 (m, 3H), 7.24 (m, IH), 6.67 (br. s, 2H), 6.52 (s, 2H [2 H Fumaric acid]), 4.16 (br. m, IH), 3.22 (m, IH), 3.09 (m, IH), 2.91 - 2.76 (m, 2H), 1.86 (m, 2H), 1.65 (m, 2H). Mass Spectrum: 363 [MH]+.
Example 8:
Synthesis of 5-(3-Fluorophenyl)-3-ureidothiophene-2-carboxylic acid (S)-piperidin-3-ylamide fumarate salt (compound 12 Hemi-Fumarate salt).
12 12 Hemi-Fumarate salt
To a solution of 12 (2.0 g, 5.6 mmol) in methanol (33.7 ml) was added fumaric acid (327 mg, 2.8 mmol) and the resulting solution was stirred for 30 min at about 18°C. After seeding the solution with 12 Hemi-Fumarate salt (5 mg, 0.006 mmol) and stirring for 5 h at about 18-19°C, the reaction mixture was cooled to about 5°C, stirring was ceased and the reaction was held at this temperature overnight. Filtration of the resulting solid, washing with methanol (1 x 2 ml) and sucking dry on the filter afforded 12 Hemi-Fumarate salt as a white solid (1.90 g, 80%).
IH NMR (400MHz, DMSO-d6) δ: 10.02 (s, IH), 8.28 (s, IH), 8.08 (d, IH), 7.54 - 7.42 (m, 3H), 7.24 (m, IH), 6.66 (br s., 2H), 6.47 (s, IH [2 H Fumaric acid]), 4.02 (br. m, IH), 3.11 (m, IH), 2.96 (m,lH), 2.75 - 2.60 (m, 2H), 1.85 (m, IH), 1.76 (m, IH), 1.58 (m, 2H). Mass Spectrum: 363 [MH]+.
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Patent IDPatent TitleSubmitted DateGranted Date
US2016252530AGENT FOR PREVENTING OR TREATING SPINOCEREBELLAR ATAXIA2014-10-102016-09-01
US2016220537COMPOSITIONS TO IMPROVE THE THERAPEUTIC BENEFIT OF BISANTRENE AND ANALOGS AND DERIVATIVES THEREOF2014-07-252016-08-04
US2016176882TRIAZOLOPYRIMIDINE COMPOUNDS AND USES THEREOF2015-12-212016-06-23
US2016166546COMBINATORIAL METHODS TO IMPROVE THE THERAPEUTIC BENEFIT OF BISANTRENE AND ANALOGS AND DERIVATIVES THEREOF2014-07-252016-06-16
US2016137730ANTIBODY DRUG CONJUGATES2015-11-132016-05-19
US2016046711ANTI-CDH6 ANTIBODY DRUG CONJUGATES2015-08-072016-02-18
US2016030594ANTIBODY DRUG CONJUGATES2014-03-122016-02-04
US2016022720COMPOSITIONS AND METHODS FOR TREATING DISEASE STATES ASSOCIATED WITH ACTIVATED T CELLS AND/OR B CELLS2014-08-012016-01-28
US2015320880ANTIBODY DRUG CONJUGATES2015-05-202015-11-12
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US2014301946ANTIBODY DRUG CONJUGATES2014-03-112014-10-09
US2014271688ANTIBODY DRUG CONJUGATES2014-03-122014-09-18
US2014194388COMBINATION THERAPY OF HSP90 INHIBITORY COMPOUNDS WITH CHK INHIBITORS2012-05-252014-07-10
US2013184342METHODS AND COMPOSITIONS FOR TREATMENT OF CANCER AND AUTOIMMUNE DISEASE2013-03-132013-07-18
US2011112144METHODS OF PREPARING SUBSTITUTED HETEROCYCLES2011-05-12 
US2007010556Thiophene derivatives as chk 1 inhibitors2007-01-11
//////////AZD 7762
C1CC(CNC1)NC(=O)C2=C(C=C(S2)C3=CC(=CC=C3)F)NC(=O)N

(Z)-3-Chloro-3-(3′-fluorophenyl)-acrylonitrile

str1
cas 1192875-03-8, 181.59
C9 H5 Cl F N
2-Propenenitrile, 3-chloro-3-(3-fluorophenyl)-, (2Z)-
 
WO 2009133389
IV V VI II
Example 1:
Synthesis of (Z)-3-Chloro-3-(3-fluorophenyl)-acrylonitrile from 3'-Fluoroacetophenone.
To a solution of 3'-fluoroacetophenone (80.0 g, 0.579 mol) in 7V,N-dimethyl formamide (560 ml) at about 400C was added phosphoryl chloride (92.50 ml, 1.01 mol) dropwise, maintaining the temperature at about 39-410C during the addition. The resulting reaction mixture was stirred at about 400C overnight before sampling for conversion to 2 by HPLC.
To the resulting reaction mixture was added a solution of hydroxylamine hydrochloride (45.17 g, 0.637 mol) in 7V,N-dimethyl formamide (240 ml) dropwise, maintaining the temperature at about 39-45°C during the addition, followed by a line -wash of JV,Λ/-dimethyl formamide (40 ml). After stirring at about 400C for 15 min, the reaction mixture was sampled for conversion to 4 before cooling to about 15-200C and addition of water (800 ml) dropwise, maintaining the temperature between about 17 to about 210C. The reaction mixture was then cooled to about 5°C and held at this temperature for a further 20 min before filtration of the solid, displacement washing with two separate portions of water (2 x 240 ml) and drying at about 400C overnight to afford the title compound as a pale yellow solid (74.24 g, 71% yield).
IH NMR (400MHz, DMSO-d6) δ: 7.72-7.65 (m, 2H), 7.63-7.56 (m, IH), 7.49-7.42 (m, IH),
7.03 (s, IH).
13C NMR (400MHz, DMSO-d6) δ: 162.0 (d, J = 245 Hz), 149.3 (d, J = 3 Hz), 135.6 (d, J= 8
Hz), 131.1 (d, J = 9 Hz), 123.3 (d, J = 3 Hz), 118.8 (d, J = 21 Hz), 115.8, 113.8 (d, J = 24 Hz),
89.3.
paper
(Z)-3-Chloro-3-(3′-fluorophenyl)-acrylonitrile (9)
 
1H NMR (400 MHz, DMSO-d6, 300 K): 7.72–7.65 (m, 2H), 7.63–7.56 (m, 1H), 7.49–7.42 (m, 1H), 7.03 (s, 1H). 13C NMR (100 MHz, DMSO-d6, 300 K): 162.0 (d, J = 245 Hz), 149.3 (d, J = 3 Hz), 135.6 (d, J = 8 Hz), 131.1 (d, J = 9 Hz), 123.3 (d, J = 3 Hz), 118.8 (d, J = 21 Hz), 115.8 (s), 113.8 (d, J = 24 Hz), 99.3 (s). GC-HRMS Calcd for [M] C9H5NFCl: 181.0095; found [M]+: 181.0090.
 
 
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Monday, 13 February 2017

(5-Chloro-2-methoxyphenyl)[3-fluoro-5-(trifluoromethyl)phenyl]methanone

str1
Cas 329941-92-6
(5-Chloro-2-methoxyphenyl)[3-fluoro-5-(trifluoromethyl)phenyl]methanone (7)
7 as white crystals
 
mp 93–95 °C;
 
1H NMR (500 MHz, CDCl3) 7.82 (s, 1H), 7.66 (d, J = 8.5 Hz, 1H), 7.53 (d, J =7.5 Hz, 1H), 7.49 (d, J = 9.0 Hz, 1H), 7.42 (s, 1H), 6.97 (d, J = 9.0 Hz, 1H), 3.71 (s, 3H);
 
13C NMR (500 MHz, CDCl3) 192.1, 162.4 (d, J = 249.3 Hz), 156.0, 140.4 (d, J = 6.4 Hz), 132.8, 132.7 (dq, J = 7.5, 33.6 Hz), 129.7, 128.4, 126.3, 122.9 (q, J = 272.3), 122.1 (m), 119.5 (d, J = 22.4), 116.9 (m), 113.3, 55.3;
 
HRMS calculated for C15H9ClF4O2 [M + H]+: 333.0299, Found: 333.0306.
 
Abstract Image
A convergent synthesis of NNRTI 1 is described. The key step involves a direct coupling of acid chloride 4 with Grignard reagent 11 in the presence of bis[2-(N,N-dimethylamino)ethyl] ether that moderates the reactivity of the Grignard reagent to give benzophenone 7. An efficient 2-step process for the preparation of 2-fluoro-3-methyl-4-aminobenzoic acid (3) is also described.

Practical Synthesis of A Benzophenone-Based NNRT Inhibitor of HIV-1

 Chemical Development, Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, Connecticut 06877, United States
 Boehringer Ingelheim (Canada) Ltd., Research and Development, 2100 Cunard Street, Laval, Québec H7S 2G5, Canada
Org. Process Res. Dev.201216 (4), pp 561–566
DOI: 10.1021/op200301h
 
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Thursday, 9 February 2017

(l,4-bis((3-(l-propylpiperidin-4' yl)phenyI)sulfonyl)butane)


Example 3 - Preparation Of Compound 3 (l,4-bis((3-(l-propylpiperidin-4' yl)phenyI)sulfonyl)butane)
Preparation of 1.4-bis((3-bromophenyl)thio')butane (Compound 3. 1st int.)
1 ,4-bis((3-bromophenyl)thio)butane
KOH (56.2g) was added into methanol (1200mL) in 15min. The clear solution was cooled on water bath to 0°C. A solution of 3-bromo thiophenol (150.2g, 0.79mol) in methanol (200mL) was added in 50min keeping the temperature at 1-3°C. A solution of 1,4-dibromobutane (86.5g; 0.40 mol) in methanol (150 ml) was added in 40min to give a yellow turbid mixture. After additional 4 hours stirring the reaction mixture became white turbid and it was stirred for additional 20h at 25°C. The suspension was filtered and washed with water (3xl00mL) and methanol (2xl00mL) to give 239g wet white solid that was dried to 163.6g (94.6% yield, HPLC: 97.9%).
Preparation of l ,4-bis((3-bromophenyl)sulfonyl)butane ("Compound 3, 2nd intermediate)
1 ,4-bis((3-bromophenyl)sulfonyl)butane
To a solution of l,4-bis-(3-bromophenylthio)-butane (155.0g, 0.358mol) in acetic acid (1500mL) was added sodium tungstate dihydrate (2.5 g, 0.0075mol) and the suspension was heated on water-bath to 45°C. 50%¾θ2 (300 mL, 5.28 mol) was added drop-wise into the reaction mixture during 3.5h keeping the temperature at 45-55°C. The reaction mixture was kept under stirring for additional 3h at 45°C and 16h at 23°C. The off white slurry was filtered, washed with water (3x200mL) and dried on air to give 179.6g (99% crude yield, HPLC: 92.2% product, 7.1% by product). The crude product (175g) was added to toluene (1400mL) and heated to >85°C for distillation. Distillation stopped when no more water was distilled (180mL toluene and lOmL water). The clear reaction mixture was allowed to cool down and was filtered after overnight stirring at ambient temperature. The bright colorless crystals were washed (150mL toluene) and dried to give 156. lg product (86.7% yield, HPLC: product 96.0%, main by-product 3.5%).
Preparation of 1 -bis((3-(pyridin-4-yl)phenyl)sulfonyl)butane (Compound 3 3rd intermediate)
1 ,4-bis((3-(pyridin-4-yl)phenyl)sulfonyl)butane
To a solution of l,4-Bis-((3-bromophenyl)-sulfonyl)-butane (92.0g, 185mmol) and butanol (1.0L) was added 4-pyridinylboronic acid (75.0g, 610mmol), potassium carbonate (172g, 1.24mol) and the catalyst trans-dichlorobis-(triphenylphosphine) palladium (2.0g; 2.8mmol). The violet suspension was heated at stirring under nitrogen to 90-95°C within lh. The reaction mixture became brown and heating continued for more 4h. Additional 4-pyridinylboronic acid (3.5g, 28mmol) was added and the reaction mixture heated up to 100°C for lh. Heating stopped, water (600mL) was added and the temperature dropped to 60°C. The resulting dark gray suspension was stirred overnight at ambient temperature and filtered (slowly). The filter cake was washed with water (lOOmL) to give 153g wet solid which was suspended in hot acetone (2xlL, 50°C). The solid was then suspended with 0.5L water at 65°C followed by 2xlL acetone suspension. The acetone solution were combined and concentrated on a rotavapor to give 90.3g pale yellow solid (yield: 91%, HPLC: 91.8% area).
Preparation of 4,4'-((butane- 1 ,4-diyldisulfony l)bis(3 , 1 -phenylene))bis( 1 -propylpyridin- 1 -iurrOiodide (Compound 3 4th intermediate)
To a solution of l,4-Bis-((3-(pyridin-4-yl)-phenyl)-sulfonyl)-butane (85.8g, 160mmol) and butanol (450mL) was added 1-iodopropane (91.7g, 540mmol). The stirring mixture was heated up to 90-95°C in nitrogen atmosphere and kept at this temperature for 6 hours. The dark yellow slurry was then cooled down to room temperature and kept at this temperature for 15h. The yellow clear solution was then decanted and butanol (300mL) was added. The mixture was heated to 70°C where it dissolved. Heating continued to 95°C and light brown slurry appeared. The heating was stopped and the mixture cooled down to 40°C. The yellow cloudy liquid was decanted and a dark yellow solid mass was filtered to give 173.5g (HPLC: 84% area) which was used as is in the next step.
Preparation of l,4-bis((3-(l -propyl- l,2,3,6-tetrahydropyridin-4-yl)phenyl)sulfonyl) butane (Compound 3, 5th intermediate)
1 ,4-bis((3-( 1 -propy 1-1 ,2,3,6-tetrahydropyridin- 4-yl)phenyl)sulfonyl)butane
To the solid crude starting material (173.5g from the previous stage) was added methanol (450mL) and the mixture was heated to reflux to give dark yellowish red clear solution which after cooling gave two phases, the lower one weigh 150g (HPLC: 88.4% area, yield corrected to area%: 13 lg, 157mmol). Methanol (400mL) was added and the mixture was cooled (0°C). Sodium borohydride (23.75g, 624mmol, 4eq) was added and the reaction mixture was allowed to warm to RT and stirred for additional 9h. The workup includes concentrating filtrates and precipitating from butanol and methanol, several slurries in butanol, extraction by hot butanol from water and finally active carbon treatment to the product dissolved in hot butanol to give 63.0g (HPLC: 85% area) which was used as is in the next step.
Preparation of l,4-bis((3-(l-propylpiperidine-4yl)phenyl)sulfonvnbutane (Compound 3)
1 ,4-bis((3-(1-propylpiperidin-4-yl)phenyl)sulfonyl)butane
The product from the previous step (60.Og, 51g as HPLC is 85% area, 87mmol) was added into an autoclave with 350mL acetic acid. A suspension of 10% Pd C catalyst (lOg, 9.4mmol) in water (80mL) was added. Air was exchange to nitrogen and then hydrogen was introduced (150psi) and the reaction was heated to 85°C for 6h. After cooling the catalyst was filtered, washed with acetic acid (2x30mL) and water (2x30mL) and concentrated under vacuum to give 98g of slightly brownish viscous residue. The residue was dissolved with water (200mL), filtered (to remove traces of charcoal) and washed with 50mL water. To the slightly brownish solution was added concentrated NaOH up to pH 13 and the mixture was stirred for 30m. The massive precipitation was filtered to give 78. lg slightly beige wet solid. The wet solid was mixed with water (lOOmL) and toluene (300mL), heated up to 87°C for 30min and the dark yellow water phase was separated. The organic phase was filtered and cooled down to 30°C. After 4h the slurry was filtered, washed with 20mL toluene and dried to give 40.8g off-white solid (HPLC: 74.4% area). The solid was then suspended in toluene (260mL) and water (40mL) and heated up to 85°C. The colorless water phase was separated and the toluene phase was filtered, cooled down to 5°C for 2hr and filtered to give after drying 38.0g off-white solid (HPLC: 81.5% area). The solid was then crystallized twice from toluene (300mL, heating to 90°C, cooled to 3°C, filtered, washed with 30mL toluene, dried) to give 31.2g, HPLC: 96.9% area, 1H-NMR assay: 93.9%.
NMR Identity Analysis of Compound 3
Compound 3:
The following data in Tables 6 and 7 was determined using a sample of 47.82 mg Compound 3, a solvent of 1.0 ml DMSO-D6, 99.9 atom%D, and the instrument was a Bruker Avance ΠΙ 400 MHz.
Table 6: Assignment of ¾ NMRa'c
a The assignment is based on the coupling pattern of the signals, coupling constants and chemical shifts. Due to the low concentration of dissolved material some expected HMBC signals were masked by background noise.
b Weak signal.
c Spectra is calibrated by the solvent residual peak (2.5 ppm).
Table 7: Assignment of 13NMRa 'b
a The assignment is based on the chemical shifts and 1H-13C couplings extracted from HSQC and HMBC experiments.
b Spectra is calibrated by a solvent peak (39.54 ppm).