Catalyst- and additive-free Baeyer–Villiger-type oxidation of α-iodocyclopentenones to α-pyrones: using air as the oxidant

An efficient synthetic approach for the synthesis of α-pyrones via Baeyer–Villiger-type oxidation of α-iodocyclopentenones through a catalyst- and additive-free system using air as an environmentally benign oxidant is described. The reaction exhibits excellent functional group compatibility and provides a simple and efficient protocol for the construction of highly functionalized α-pyrones under mild reaction conditions.

Catalyst- and additive-free Baeyer–Villiger-type oxidation of α-iodocyclopentenones to α-pyrones: using air as the oxidant†

Yuanyuan Zhou,^a   Xianxiao Chen,^a   Xiangxiang Ling^a  and  Weidong Rao  *^a  

 Author affiliations

*Corresponding authors

^aJiangsu Key Laboratory of Biomass-based Green Fuels and Chemicals, College of Chemical Engineering, Nanjing Forestry University, Nanjing 210037, China
E-mail:weidong@njfu.edu.cn

6-Cyclohexyl-4-phenyl-2H-pyran-2-one (2e)[S3]

Product 2e was obtained as a pale-yellow solid in 68% yield (52 mg) following the general procedure, mp 96-97 °C;

1H NMR (600 MHz, CDCl3) δ 7.58-7.56 (m, 2H), 7.48-7.46 (m, 3H), 6.34 (d, J = 1.3 Hz, 1H), 6.26 (d, J = 0.8 Hz, 1H), 2.48 (tt, J = 11.8, 3.3 Hz, 1H), 2.04-2.01 (m, 2H), 1.87-1.84 (m, 2H), 1.47 (qd, J = 12.5, 3.0 Hz, 2H), 1.39-1.32 (m, 2H), 1.28-1.23 (m, 2H);

13C NMR (150 MHz, CDCl3) δ 169.8, 163.6, 155.6, 136.2, 130.5, 129.1, 126.7, 108.4, 100.9, 42.5, 30.6, 25.9, 25.8

http://www.rsc.org/suppdata/c9/gc/c9gc02725d/c9gc02725d1.pdf

 

/////////https://pubs.rsc.org/en/Content/ArticleLanding/2019/GC/C9GC02725D?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2FGC+%28RSC+-+Green+Chem.+latest+articles%29#!divAbstract

Ethyl 4-(4-cyclopropyl-2-oxo-2H-pyran-6-yl)butanoate

Catalyst- and Additive-Free Baeyer−Villiger-type Oxidation of α-Iodocyclopentenones to α-Pyrones: Using Air as the Oxidant

Yuanyuan Zhou,  Xianxiao Chen,  Xiangxiang Ling  and  Weidong Rao 

Abstract

An efficient synthetic approach for the synthesis of α-pyrones via Baeyer−Villiger-type oxidation of α-iodocyclopentenones through a catalyst- and additive-free system using air as an environmentally benign oxidant is described. The reaction exhibits excellent functional group compatibility and provides a simple and efficient protocol for the construction of highly functionalized α-pyrones under mild reaction conditions.

Ethyl 4-(4-cyclopropyl-2-oxo-2H-pyran-6-yl)butanoate (2aa) Product 2aa was obtained as yellow oil in 50% yield (38 mg) following the general procedure; 1H NMR (600 MHz, CDCl3) δ 5.84 (s, 1H), 5.61 (s, 1H), 4.13-4.09 (m, 2H), 2.48 (t, J = 7.3 Hz, 2H), 2.33 (td, J = 7.3, 2.3 Hz, 2H), 1.97-1.94 (m, 2H), 1.66-1.63 (m, 1H), 1.26-1.22 (m, 3H), 1.07-1.05 (m, 2H), 0.80-0.79 (m, 2H); 13C NMR (150 MHz, CDCl3) δ 172.8, 163.9, 163.0, 162.8, 106.7, 102.1, 60.5, 33.2, 33.0, 22.1, 15.4, 14.2, 10.0; HRMS (ESI) calcd. for C14H18O4Na [M+Na]+ : 273.1097, found: 273.1101

 
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https://pubs.rsc.org/en/Content/ArticleLanding/2019/GC/C9GC02725D?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2FGC+%28RSC+-+Green+Chem.+latest+articles%29#!divAbstract

http://www.rsc.org/suppdata/c9/gc/c9gc02725d/c9gc02725d1.pdf

4-(trifluoromethoxy)benzyl trichloroacetimidate:

4-(Trifluoromethoxy)benzyl Trichloroacetimidate

To a stirred suspension of NaH (60%, 127 mg, 3.45 mmol) in t-BuOMe (100 mL) was added 4-(trifluoromethoxy)benzyl alcohol 11 (5 mL, 34.5 mmol) dropwise by syringe at room temperature. After H2 evolution had ceased (about 5 min), the clear mixture was cooled to 0 °C. Cl3CCN (3.46 mL, 34.5 mmol) was added dropwise by syringe, and the resulting solution was stirred for 1 h. After warming to room temperature, the solution was concentrated in vacuo, and the residue was resuspended in heptane (100 mL) containing MeOH (0.14 mL, 3.45 mmol). After 10 min of stirring, the suspension was filtered through a thin bed of silica and washed with heptane. Concentration in vacuo affords the title compound as a yellow-orange liquid (11.4 g, 98%) that was used directly without further purification. Rf 0.3 (5% EtOAc/hexanes);

 1H NMR (501 MHz, CDCl3) δ 8.43 (s, 1H), 7.48 (d, J = 8.2 Hz, 2H), 7.24 (d, J = 8.2 Hz, 2H), 5.35 (s, 2H); 

13C NMR (126 MHz, CDCl3) δ 162.6, 149.3, 134.3, 129.4, 121.6, 121.3, 119.6, 69.9; 

IR [CH2Cl2 solution] νmax (cm−1) 3345, 2954, 1667, 1511, 1261, 1221, 1166, 1077, 998, 828, 797, 649; 

HRMS (ESI-TOF) calcd for C10H7Cl3F3NO2 334.95, found C8H6F3O 174.03.

(R)-3-Chloro-2-hydroxypropyl-4-methoxybenzoate

(R)-3-Chloro-2-hydroxypropyl-4-methoxybenzoate 10

To a stirred solution of (R)-3-chloro-1,2-propanediol (6.61 g, 59.8 mmol) in CH2Cl2 (120 mL) was added imidazole (4.07 g, 59.8 mmol). After the reaction mixture had cooled to 0 °C, p-methoxybenzoyl chloride (10.2 g, 59.8 mmol) in CH2Cl2 (10 mL) was added dropwise via addition funnel. The resulting solution was allowed to warm to room temperature and stirred until complete consumption of starting material by thin layer chromatography (TLC). The mixture was poured into saturated aq NH4Cl (150 mL), and the aqueous layer was extracted with CH2Cl2 (3 × 100 mL). The combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo to provide chlorohydrin 10as a clear, viscous oil (11.43 g, 78%) that was used without further purification. Rf 0.3 (20% EtOAc/hexanes); ee >99% as determined by chiral SFC (see the Supporting Information); 

1H NMR (500 MHz, CDCl3) δ 8.07−7.94 (m, 2H), 7.00−6.88 (m, 2H), 4.46 (d, J = 5.1 Hz, 2H), 4.22 (dd, J = 10.6, 5.3 Hz, 1H), 3.88 (s, 3H), 3.78−3.64 (m, 2H), 2.73 (d, J = 5.6 Hz, 1H); 

13C NMR (126 MHz, CDCl3) δ 166.7, 163.9, 132.1, 121.9, 114.0, 70.1, 65.7, 55.7, 46.3; 

IR [CH2Cl2 solution] νmax (cm−1) 3454, 2959, 2889, 1713, 1606, 1512, 1259, 1170, 1104, 1028, 848, 770, 697, 614; 

HRMS (ESI-TOF) calcd for C11H13ClO4 (M)+244.0573, found 244.0501.

https://pubs.acs.org/doi/full/10.1021/jo1015807
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https://pubs.acs.org/doi/suppl/10.1021/jo1015807/suppl_file/jo1015807_si_001.pdf

Pretomanid

Pretomanid

read syn  https://newdrugapprovals.org/2019/09/04/pretomanid-%e3%83%97%e3%83%ac%e3%83%88%e3%83%9e%e3%83%8b%e3%83%89/

The combined organic extracts were washed with brine, dried (Na2SO4), filtered, and concentrated. Chromatography (75% EtOAc/hexanes) followed by recrystallization (i-PrOH/hexanes) affords PA-824 (1) (2.41 g, 62%) as a crystalline solid. Mp 150−151 °C (lit.(11a) mp 149−150); Rf 0.2 (75% EtOAc/hexanes); ee >99.9% as determined by chiral SFC (see the Supporting Information);

 1H NMR (500 MHz, d6-DMSO) δ 8.09 (s, 1H), 7.48 (d, J = 8.6 Hz, 2H), 7.39 (d, J = 8.2 Hz, 2H), 4.81−4.62 (m, 3H), 4.51 (d, J = 11.9 Hz, 1H), 4.39−4.19 (m, 3H);

 13C NMR (126 MHz, d6-DMSO) δ 148.7, 148.1, 143.0, 138.3, 130.4, 122.0, 120.0, 119.8, 69.7, 68.8, 67.51, 47.73;

IR [CH2Cl2 solution] νmax (cm−1) 2877, 1580, 1543, 1509, 1475, 1404, 1380, 1342, 1281, 1221, 1162, 1116, 1053, 991, 904, 831, 740;

HRMS (ESI-TOF) calcd for C14H12F3N3O5 359.0729, found 359.0728.

https://pubs.acs.org/doi/full/10.1021/jo1015807

Verubecestat Impurity 10

Verubecestat

Verubecestat Impurity 10

1H NMR (600 MHz, Acetonitrile-d3) δ 9.86 (s, 1H), 8.21 (d, J = 3.0 Hz, 1H), 8.02 (dd, J = 7.5, 2.8 Hz, 1H), 7.96 (d, J = 8.9 Hz, 1H), 7.81 (ddd, J = 8.7, 4.2, 2.7 Hz, 1H), 7.24 (dd, J = 8.9, 3.0 Hz, 1H), 7.19 (d, J = 8.7 Hz, 2H), 7.07 (dd, J = 12.0, 8.7 Hz, 1H), 6.88 (d, J = 8.7 Hz, 2H), 4.06 (d, J = 14.6 Hz, 1H), 3.92 (d, J = 14.6 Hz, 1H), 3.81 (d, J = 14.2 Hz, 1H), 3.75 (s, 3H), 3.65 (ddd, J = 11.7, 9.8, 3.9 Hz, 1H), 3.39 (d, J = 14.3 Hz, 1H), 2.86 (s, 3H), 2.59 (td, J = 10.3, 4.0 Hz, 1H), 2.55 (s, 3H), 2.28 (s, 3H), 2.22 – 2.09 (m, 1H), 1.78 – 1.71 (m, 2H), 1.69 – 1.64 (m, 1H), 1.61 – 1.54 (m, 4H), 1.41 (qt, J = 13.7, 3.9 Hz, 1H), 1.28 (qt, J = 13.3, 3.8 Hz, 1H), 1.17 – 1.07 (m, 1H).

13C NMR (151 MHz, Acetonitrile-d3) δ 163.79, 160.26, 156.68, 149.74, 137.95, 136.00 (d, J = 2.3Hz), 134.69 (d, J = 13.7 Hz), 134.15, 130.58, 129.35, 123.67, 120.82 (d, J = 8.7 Hz), 120.51 (d, J = 4.3 Hz), 119.60, 116.85, 114.82, 63.09, 60.77, 60.31 (d, J = 5.5 Hz), 55.84, 54.27 (d, J = 3.4 Hz), 53.30, 34.11, 33.75, 31.85, 30.96, 30.23 (d, J = 3.3 Hz), 28.91, 26.13, 25.25.

19F NMR (564 MHz, Acetonitrile-d3) δ -119.08. HRMS [M+H] (C32H43FN6O4S) calc. 627.3123, obs. 627.3151.

Improved Process for a Copper-Catalyzed C–N Coupling in the Synthesis of Verubecestat

Eric M. Phillips*

Cite This:Org. Process Res. Dev.2019XXXXXXXXXX-XXX

Publication Date:July 23, 2019

 

https://doi.org/10.1021/acs.oprd.9b00192

Verubecestat is a β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitor which was previously evaluated for the treatment of Alzheimer’s disease. The synthesis of verubecestat relies on a Cu-catalyzed carbon–nitrogen coupling. During process development, observations of impurity formation led to a more robust understanding of the catalyst. The transformation was discovered to be highly dependent on the ratio of ligand to substrate concentration during the course of the reaction. In-depth studies aimed at attaining mechanistic understanding provided an explanation of experimental findings and ultimately led to the identification of conditions that resulted in a more robust process.

//////////////https://pubs.acs.org/doi/suppl/10.1021/acs.oprd.9b00192/suppl_file/op9b00192_si_001.pdf

https://pubs.acs.org/doi/10.1021/acs.oprd.9b00192

///////////Verubecestat,  Impurity 10

AB 680 « New Drug Approvals

AB 680 « New Drug Approvals: AB 680 C20H24ClFN4O9P2, 580.827 g/mol Cas 2105904-82-1 1H-Pyrazolo[3,4-b]pyridin-4-amine, 6-chloro-N-[(1S)-1-(2-fluorophenyl)ethyl]-1-[5-O-[hydroxy(phosphonomethyl)phosphinyl]-β-D-ribofuranosyl]- […

RISDIPLAM , リスジプラム « New Drug Approvals

RISDIPLAM , リスジプラム « New Drug Approvals

Taselisib

TASELISIB

SYNTHESIS........https://newdrugapprovals.org/2018/06/15/rg-7604taselisib/

CLIP

Manufacture of the PI3K β-Sparing Inhibitor Taselisib. Part 2: Development of a Highly Efficient and Regioselective Late-Stage Process

Frédéric St-Jean*† , Travis Remarchuk†, Rémy Angelaud*†, Diane E. Carrera†, Danial Beaudry†, Sushant Malhotra†, Andrew McClory†, Archana Kumar†, Gerd Ohlenbusch‡, Andreas M. Schuster‡, and Francis Gosselin†

† Department of Small Molecule Process Chemistry, Genentech Inc., 1 DNA Way, South San Francisco, California 94080, United States

‡ Small Molecules Technical Development PTDC-C, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, 4070 Basel, Switzerland

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.9b00050

*E-mail: stjean.frederic@gene.com. (F.St.-J.), *E-mail: angelaud.remy@gene.com. (R.A.)

A highly efficient and regioselective manufacturing route for the phosphoinositide 3-kinase β-sparing inhibitor taselisib was developed. Highlights of the synthesis include: (1) magnesium-mediated formation of a challenging cyclic amidine; (2) regioselective imidazole construction via alkylation/condensation with bromopyruvic acid; and (3) triazole formation with 2-isopropyl acetamidrazone to generate the key bromobenzoxazepine core intermediate. Subsequent highly efficient one-pot palladium-catalyzed Miyaura borylation/Suzuki cross-coupling/saponification, followed by a 1,1′-carbonyldiimidazole-mediated coupling with ammonia, led to the pentacyclic taselisib. This new synthetic approach provides a more efficient route to taselisib with a significant decrease in process mass intensity compared to the previous early development routes to the bromobenzoxazepine core. Finally, implementation of a controlled crystallization provided the active pharmaceutical ingredient with the desired polymorphic form.

Taselisib was obtained in 90% yield (16.2 kg) as a white to off-white solid (>99.9 wt %; >99.9 A%) as Form B crystal.

mp (DSC): 257–258 °C.

HRMS (ESI-CID) m/z Calcd for [M + H]+ C24H29N8O2: 461.2408; found: 461.2409.

 1H NMR (600 MHz, DMSO-d6) δ ppm 8.41 (s, 1H), 8.37 (d, J = 8.4, 1H), 8.02 (s, 1H), 7.88 (m, 1H), 7.45 (dd, J = 8.4, 1.7 Hz, 1H), 7.36 (d, J = 1.7 Hz, 1H), 7.20 (br s, 1H), 6.84 (br s, 1 H), 5.83 (sept, J = 6.6 Hz, 1H), 4.53–4.51 (m, 2H), 4.52 (m, 2H), 2.26 (s, 3H), 1.75 (s, 6H), 1.47 (d, J = 6.7 Hz, 6H).

 13C NMR (DMSO-d6, 151 MHz) δ = 173.8, 158.3, 155.9, 147.3, 144.0, 136.6, 134.6, 130.3, 129.9, 126.4, 123.6, 120.4, 119.3, 116.2, 115.3, 68.3, 64.5, 49.9, 49.7, 25.5, 25.5, 22.3, 22.3, 13.8.

https://pubs.acs.org/doi/10.1021/acs.oprd.9b00050

https://pubs.acs.org/doi/suppl/10.1021/acs.oprd.9b00050/suppl_file/op9b00050_si_001.pdf

Ultraviolet/Visible Spectroscopy

Apparatus: Perkin Elmer, UV-6190, Lambda 25

Solvent: Acetonitrile/Water 1:1 (v/v)

  

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“ALL FOR DRUGS” CATERS TO EDUCATION GLOBALLY, No commercial exploits are done or advertisements added by me. This is a compilation for educational purposes only. P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent

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ANTHONY MELVIN CRASTO

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1-(4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic pivalic anhydride

 

1-(4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic pivalic anhydride (10): tan solid,

mp (DSC): onset = 172.4 °C, peak temperature = 173.0 °C;

1H NMR (400 MHz, CD3CN) δ 8.23 (d, J = 7.6 Hz, 1 H), 7.35–7.25 (m, 4 H), 6.36 (d, J = 8.0 Hz, 1 H), 2.02 (s, 3 H), 1.25 (s, 9 H);

13C NMR (100 MHz, CD3CN) 175.9 (1 C), 163.6 (d, 1 C, JCF = 245.4 Hz), 162.9 (1 C ), 161.1 (1 C), 158.2 (1 C), 148.6 (1 C), 135.7 (1 C), 131.0 (d, JCF = 8.7 Hz, 2 C), 117.7 (d, JCF = 23.2 Hz, 2 C), 116.0 (1 C), 107.1 (1 C), 40.4 (1 C), 27.0 (3 C), 22.8 (1 C);

19F NMR (376 MHz, CD3CN) δ -114.2 (m, 1 F);

IR (ATR, cm-1 ) 2966 (w), 2939 (w), 2876 (w), 1789 (vs), 1697 (s), 1682 (vs), 1554 (s), 1509 (vs);

HRMS calcd for C18H18O4NFNa (M+Na+ ) = 354.1112; found 354.1113, δ = 0.3 ppm.

//////////////https://pubs.acs.org/doi/suppl/10.1021/acs.oprd.8b00441

“ALL FOR DRUGS” CATERS TO EDUCATION GLOBALLY, No commercial exploits are done or advertisements added by me. This is a compilation for educational purposes only. P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent

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ANTHONY MELVIN CRASTO

https://newdrugapprovals.org/

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