Pridopidine OXIDE

Pridopidine OXIDE
Example 5 – Preparation Of Compound 5 (4-(3-(methylsulfonyl)phenyl)-l-propylpiperidine 1-oxide)

Pridopidine (50.0g, 178mmol, leq) was dissolved in methanol (250mL) and 33% hydrogen peroxide (20mL, 213mmol, 1.2eq). The reaction mixture was heated and kept at 40°C for 20h. The reaction mixture was then concentrated in a rotavapor to give 71g light-yellow oil. Water (400mL) was added and the suspension was extracted with isopropyl acetate (150mL) which after separation contains unreacted pridopidine while water phase contains 91% area of Compound 5 (HPLC). The product was then washed with dichloromethane (400mL) after adjusting the water phase pH to 9 by sodium hydroxide. After phase separation the water phase was washed again with dichloromethane (200mL) to give 100% area of Compound 5 in the water phase (HPLC). The product was then extracted from the water phase into butanol (lx400mL, 3x200ml) and the butanol phases were combined and concentrated in a rotavapor to give 80g yellow oil (HPLC: 100% area of Compound 5). The oil was washed with water (150mL) to remove salts and the water was extracted with butanol. The organic phases were combined and concentrated in a rotavapor to give 43g of white solid which was suspended in MTBE for lhr, filtered and dried to give 33g solid that was melted when standing on air. After high vacuum drying (2mbar, 60°C, 2.5h) 32.23g pure Compound 5 were obtained (HPLC: 99.5% area, 1H-NMR assay: 97.4%).
NMR Identity Analysis of Compound 5
Compound 5:
The following data in Tables 10 and 11 was determined using a sample of 63.06 mg Compound 5, a solvent of 1.2 ml DMSO-D6, 99.9 atom%D, and the instrument was a Bruker Avance ΙΠ 400 MHz.
Table 10: Assignment of ¾ NMR<sup>a,c

a</sup> The assignment is based on the coupling pattern of the signals, coupling constants and chemical shifts.
^b Weak signal.
^c Spectra is calibrated by the solvent residual peak (2.5 ppm).
Table 11: Assignment of ¹³C NMR<sup>a,b

a</sup> 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)
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016003919&recNum=5&docAn=US2015038349&queryString=EN_ALL:nmr%20AND%20PA:(teva%20pharmaceutical)&maxRec=677#H3

2,2′-(1-(tert-Butoxycarbonyl)pyrrolidine-3,4-diyl)diacetic Acid

2,2′-(1-(tert-Butoxycarbonyl)pyrrolidine-3,4-diyl)diacetic Acid

    

2,2′-(1-(tert-Butoxycarbonyl)pyrrolidine-3,4-diyl)diacetic Acid 

as a white solid. Mp: 162–163 °C, % purity: 94.09% (HPLC);

 

¹H NMR (DMSO-d₆, 400 MHz) δ: 1.38 (s, 9H), 2.10–2.18 (m, 2H), 2.28–2.32 (m, 2H), 2.49–2.50 (m, 2H, merged with DMSO peak), 2.97–3.03 (m, 2H), 3.33–3.40 (m, 2H), 12.23 (bs, 2H); ¹H NMR (CD₃OD, 400 MHz) δ: 1.46 (s, 9H), 2.26 (ddd, J₁ = 2.8 Hz, J₂ = 9.2 Hz, J₃ = 16.0 Hz, 2H), 2.43 (dd, J₁ = 5.2 Hz, J₂ = 16.0 Hz, 2H), 2.69 (m, 2H), 3.16 (dd, J₁ = 5.2 Hz, J₂ = 10.8 Hz, 2H), 3.49–3.54 (m, 2H);

 

¹³C NMR (DMSO-d₆, 100 MHz) δ: 28.49, 32.97, 36.49, 37.31, 50.10, 50.20, 78.67, 154.05, 173.96;

 

IR (KBr): ν = 871, 933, 1143, 1166, 1292, 1411, 1689, 1708, 2881, 2929, 2980, 3001 cm^–1;

 

TOFMS: [C₁₃H₂₁NO₆ – H⁺]: calculated 286.1296, found 286.1031(100%).

HPLC conditions were as follows for compound ; Agilent 1100 series, column: YMC J’SPHERE C18 (150 mm X 4.6 mm) 4µm with mobile phases A (0.05% TFA in water) and B (acetonitrile). Detection was at 210 nm, flow was set at 1.0 mL/min, and the temperature was 30 °C (Run time: 45 min). Gradient: 0 min, A = 90%, B = 10%; 5.0 min, A = 90%, B = 10%; 25 min, A = 0%, B = 100%; 30 min, A = 0%, B = 100%, 35 min, A = 90%, B = 10%; 45 min, A = 90%, B = 10%.

 

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.6b00399

http://pubs.acs.org/doi/full/10.1021/acs.oprd.6b00399

 

/////////

Dimethyl 4,4′-(Benzylazanediyl)(2E,2′E)-bis(but-2-enoate)

Dimethyl 4,4′-(Benzylazanediyl)(2E,2′E)-bis(but-2-enoate)

IR (CHCl₃): ν = 758, 1215, 1278, 1437, 1660, 1720, 2806, 2953, 3020, 3421 cm^–1;

¹³C NMR (CDCl₃, 100 MHz) δ: 51.53, 53.42, 58.37, 122.66, 127.28, 128.41, 128.55, 128.76, 138.24, 145.84, 166.58;

¹H NMR (CDCl₃, 400 MHz) δ: 3.23 (dd, J₁ = 1.6 Hz, J₂ = 6.0 Hz, 4H), 3.62 (s, 2H), 3.75 (s, 6H), 6.07 (dt, J₁ = 1.6 Hz, J₂ = 16.0 Hz, 2H), 6.97 (dt, J₁ = 6.0 Hz, J₂ = 16.0 Hz, 2H), 7.25–7.34 (m, 5H-merged with CDCl₃ proton);

TOFMS: [C₁₇H₂₁NO₄ + H⁺]: calculated 304.1543, found 304.1703(100%).

UPLC conditions were as follows for compound 11; Acquity Waters, column: BEH C18 (2.1 mm X 100 mm) 1.7 µm with mobile phases A (0.05% TFA in water) and B (acetonitrile). Detection was at 220 nm, flow was set at 0.4 mL/min, and the temperature was 30 °C (Run time: 9 min). Gradient: 0 min, A = 90%, B = 10%; 0.5 min, A = 90%, B = 10%; 6.0 min, A = 0%, B = 100%; 7.5 min, A = 0%, B = 100%; 7.6 min, A = 90%, B = 10%; 9.0 min, A = 90%, B = 10%.

Dimethyl 4,4′-(Benzylazanediyl)(2E,2′E)-bis(but-2-enoate) (11)

as a yellow oil. % purity: 93.4% (UPLC);

 

¹H NMR (CDCl₃, 400 MHz) δ: 3.23 (dd, J₁ = 1.6 Hz, J₂ = 6.0 Hz, 4H), 3.62 (s, 2H), 3.75 (s, 6H), 6.07 (dt, J₁ = 1.6 Hz, J₂ = 16.0 Hz, 2H), 6.97 (dt, J₁ = 6.0 Hz, J₂ = 16.0 Hz, 2H), 7.25–7.34 (m, 5H-merged with CDCl₃ proton);

 

¹³C NMR (CDCl₃, 100 MHz) δ: 51.53, 53.42, 58.37, 122.66, 127.28, 128.41, 128.55, 128.76, 138.24, 145.84, 166.58;

 

IR (CHCl₃): ν = 758, 1215, 1278, 1437, 1660, 1720, 2806, 2953, 3020, 3421 cm^–1;

 

TOFMS: [C₁₇H₂₁NO₄ + H⁺]: calculated 304.1543, found 304.1703(100%).

 

 

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.6b00399

http://pubs.acs.org/doi/full/10.1021/acs.oprd.6b00399

//////

3,6−bis([1,1'−biphenyl]−4−ylmethyl)−1,2,4,5−tetra zine

3,6−bis([1,1'−biphenyl]−4−ylmethyl)−1,2,4,5−tetra zine

Synthesis of tetrazines from gem-difluoroalkenes under aerobic conditions at room temperature

Green Chem., 2017, Advance Article
DOI: 10.1039/C6GC03494B, Paper

Zheng Fang, Wen-Li Hu, De-Yong Liu, Chu-Yi Yu, Xiang-Guo Hu
A procedure for the synthesis of tetrazines from gem-difluoroalkenes under aerobic conditions has been developed.

An efficient and green procedure for the synthesis of tetrazines has been developed based on an old chemistry reported by Carboni in 1958. Both symmetric and asymmetric 3,6-disubstituted 1,2,4,5-tetrazines can be obtained in moderate to high yields from the corresponding gem-difluoroalkenes under aerobic conditions at room temperature. This work represents a rare example that ambient air is utilized as an oxidant for the synthesis of tetrazines.

Synthesis of tetrazines from gem-difluoroalkenes under aerobic conditions at room temperature

Zheng Fang,^a   Wen-Li Hu,^a   De-Yong Liu,^a  Chu-Yi Yu^ab and   Xiang-Guo Hu*^a  

Hide Affiliations

*

Corresponding authors

^a

National Engineering Research Center for Carbohydrate Synthesis, Jiangxi Normal University, Nanchang 330022, P. R. China
 E-mail: huxiangg@iccas.ac.cn

^b

Beijing National Laboratory for Molecular Science (BNLMS), CAS Key Laboratory of Molecular Recognition and Function, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China

Green Chem., 2017, Advance Article

DOI: 10.1039/C6GC03494B

http://pubs.rsc.org/en/Content/ArticleLanding/2017/GC/C6GC03494B?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2FGC+%28RSC+-+Green+Chem.+latest+articles%29#!divAbstract

3,6−bis([1,1'−biphenyl]−4−ylmethyl)−1,2,4,5−tetra zine (3a). (41 mg, 83%). purple solid;

m.p. 200−202°C;

IR(KBr) nmax/cm−1 2924, 2850, 1488, 1451, 1432, 1388, 851, 750;

1 H NMR (400 MHz, CDCl3) 7.55−7.33 (m, 18H), 4.65 (s, 4H).

 13C NMR (100 MHz, CDCl3) δ 169.2, 140.6, 140.4, 134.8, 129.7, 128.8, 127.6, 127.4, 127.1, 40.9;

HRMS (ESI): calcd. for C28H22N4 [M+H]+ 415.19172, found 415.19124.



///////

1-Bromo-4-fluoro-2-((2-iodobenzyl)oxy)benzene

1-Bromo-4-fluoro-2-((2-iodobenzyl)oxy)benzene

CAS 1161931-51-6

 

Mp 89.8–92.3 °C.

IR (neat, ATR): 3072 (w), 1482 (s), 1451 (s), 1294 (s), 1294 (s) cm^–1.

¹H NMR (399 MHz, DMSO-d₆) δ 5.12 (s, 2H), 6.81 (td, J = 8.49, 2.77 Hz, 1H), 7.14 (td, J = 7.64, 1.65 Hz, 1H), 7.18 (dd, J = 10.90, 2.82 Hz, 1H), 7.46 (td, J = 7.52, 0.92 Hz, 1H), 7.60 (dd, J = 7.64, 1.41 Hz, 1H), 7.62 (dd, J = 8.66, 6.23 Hz, 1H), 7.92 (dd, J = 7.83, 0.83 Hz, 1H).

¹³C NMR (100 MHz, DMSO-d₆) δ 74.5, 99.2, 102.4 (d, J = 27.1 Hz), 105.8 (d, J = 3.4 Hz), 108.9 (d, J = 22.5 Hz), 128.5, 129.8, 130.3, 133.6 (d, J = 9.9 Hz), 138.0, 139.2, 155.4 (d, J = 10.7 Hz), 162.2 (d, J = 244.3 Hz).

GCMS: m/z [M]⁺ calcd for C₁₃H₉BrFIO: 405.88600; found: 405.88620.

1H AND 13C NMR PREDICT

   

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.6b00368

 

////////////

Brc2ccc(F)cc2OCc1ccccc1I

2,6-diphenyl-5-methylpyrimidinone

Metal-free radical C-H methylation of pyrimidinones and pyridinones with dicumyl peroxide

Green Chem., 2017, Advance Article
DOI: 10.1039/C6GC03355E, Communication

Pei-Zhi Zhang, Jian-An Li, Ling Zhang, Adedamola Shoberu, Jian-Ping Zou, Wei Zhang
A method for free radical methylation of pyrimidinones and pyridinones with dicumyl peroxide under metal-free conditions is introduced. A 50 g-scale reaction could be performed safely. The product was separated by crystallization and the byproducts were recovery by distillation

http://pubs.rsc.org/en/Content/ArticleLanding/2017/GC/C6GC03355E?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2FGC+%28RSC+-+Green+Chem.+latest+articles%29#!divAbstract

Metal-free radical C–H methylation of pyrimidinones and pyridinones with dicumyl peroxide

Pei-Zhi Zhang,^a   Jian-An Li,^a   Ling Zhang,^a  Adedamola Shoberu,^a   Jian-Ping Zou*^a and  Wei Zhang*^b  

*

Corresponding authors

^a

Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry and Chemical Engineering, Soochow University, 199 Renai Street, Suzhou, China
 E-mail: jpzou@suda.edu.cn

^b

Centre for Green Chemistry and Department of Chemistry, University of Massachusetts Boston, 100 Morrissey Boulevard, Boston, USA
 E-mail: wei2.zhang@umb.edu

Green Chem., 2017, Advance Article

DOI: 10.1039/C6GC03355E

A new method for free radical methylation of pyrimidinones and pyridinones with dicumyl peroxide (DCP) under metal-free conditions is introduced. A 50 g-scale reaction could be performed safely at the desired concentration. The reaction solvent and DCP derivative were readily recovered by distillation. The product was purified by crystallization to minimize the amount of waste.


2,6-diphenyl-5-methylpyrimidinone

Colorless solid, mp 258−260 °C, 73% yield (191 mg).

1H NMR (400 MHz, DMSO-d6): δ 12.85 (s, 1H), 8.17 (d, J = 7.1 Hz, 2H), 7.68 (d, J = 6.6 Hz, 2H), 7.53 (dd, J = 14.3, 6.8 Hz, 6H), 2.10 (s, 3H).

13C NMR (101 MHz, CDCl3): δ 161.15, 152.97, 138.68, 132.26, 131.62, 129.11, 129.02, 128.86, 128.15, 127.45, 119.09, 12.65.

 HRMS (ESI-TOF) m/z: (M+H)+ Calcd for C17H15N2O 263.1184, found 263.1194.





///////////

(3R)-4-[2-chloro-6-[[(R)-methylsulfinyl]methyl]pyrimidin-4-yl]-3-methyl-morpholine

(3R)-4-[2-chloro-6-[[(R)-methylsulfinyl]methyl]pyrimidin-4-yl]-3-methyl-morpholine

 

Synthesis of (3R)-4-[2-chloro-6-[[(R)-methylsulfinyl]methyl]pyrimidin-4-yl]-3-methyl-morpholine (10)

off-white solid (53.9 kg, 68.3% yield). 1H NMR (400 MHz, DMSO-d6, δ): 1.20 (d, J = 6.8 Hz, 3 H), 2.52 (m, 1 H), 2.63 (s, 3 H), 3.21 (m, 1 H), 3.44 (m, 1 H), 3.58 (dd, J = 11.6, 3.1 Hz, 1 H), 3.72 (d, J = 11.5 Hz, 1 H), 3.92 (m, 3 H), 4.07 (d, J = 12.4 Hz, 1 H), 6.80 (s, 1 H); Assay (HPLC) 99%; Assay (QNMR) 100%; Chiral purity (HPLC) (R,R)-diastereoisomer 99.6%, (R,S)-diastereoisomer 0.4%.

A Baeyer–Villiger monooxygenase enzyme has been used to manufacture a chiral sulfoxide drug intermediate on a kilogram scale. This paper describes the evolution of the biocatalytic manufacturing process from the initial enzyme screen, development of a kilo lab process, to further optimization for plant scale manufacture. Efficient gas–liquid mass transfer of oxygen is key to obtaining a high yield.

Development and Scale-up of a Biocatalytic Process To Form a Chiral Sulfoxide

William R. F. Goundry^* , Bradley Adams, Helen Benson, Julie Demeritt†∥, Steven McKown, Keith Mulholland, Amy Robertson, Paul Siedlecki, Paula Tomlin, and Kevin Vare

The Departments of Pharmaceutical Sciences and 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.6b00391

Publication Date (Web): January 4, 2017

Copyright © 2017 American Chemical Society

*Tel: +44 (0)1625-519149. E-mail: william.goundry@astrazeneca.com.

http://pubs.acs.org/doi/full/10.1021/acs.oprd.6b00391

 

 

Examples of biologically active molecules containing a sulfoxide or sulfoximine: esomeprazole (3), aprikalim (4), oxisurane (5), OPC-29030 (6), ZD3638 (7), buthionine sulfoximine (8), and AZD6738 (9).