(±)-trans-ethyl 2-(3,4-difluorophenyl)Cyclopropanecarboxylate

  

(±)-trans-ethyl 2-(3,4-difluorophenyl)Cyclopropanecarboxylate

C12H12F2O2

GC-MS (EI) m/z: [M]+ calc. for C12H12F2O2 + : 226.08; found: 226.08.

δH (400 MHz, CDCl3): 1.25 (1H, ddd, 3 J 8.4 Hz, 3 J 6.4 Hz, 2 J 4.5 Hz , 3-H); 1.28 (3H, t 3 J 6.4 Hz CH3Ethyl) 1.57-1.62 (2H, m, 3 J 9.2 Hz, 3 J 5.2 Hz, 2 J 4.5 Hz, 3-H + H2O), 1.84 (1H, ddd, 3 J 8.5 Hz, 3 J 5.3 Hz, 3 J 4.3 Hz , 2-H), 2.47 (1H, ddd, 3 J 9.5 Hz, 3 J 6.4 Hz, 3 J 4.2 Hz , 1-H), 4.17 (2H, q, 3 J 6.3 Hz, CH2Ethyl) 6.81-6.87 (1H, m, 3 J 8.5 Hz, 4 J 7.6 Hz, 4 J 2.4 Hz, 6-H’ ), 6.88 (1H, ddd, 3 J 11.5 Hz, 4 J 7.6 Hz, 4 J 2.2 Hz, 2-H’) 7.06 (1H, dt, 3 J 10.3 Hz, 3 J 8.2 Hz. 5-H’).

δc (400 MHz, CDCl3): 14.27 (CH3Ethyl), 16.84 (3-C) 24.04 (1-C), 25.14 (d, 4 J 1.4, 2-C), 60.71 (CH2Ethyl), 114.74 (d, 2 J 19 Hz, 2-C’), 117.09 (d, 2 J 18 Hz, 5-C’), 122.25 (dd, 3 J 6.1 Hz, 4 J 3.4 Hz, 6- C’), 137.06 (dd, 3 J 6.1 Hz, 4 J 3.4 Hz, 1- C’), 149.2 (dd, 1 J 248 Hz, 2 J 13 Hz, 4-C’) 151.32 (dd, 1 J 249 Hz, 2 J 12.5 Hz, 3-C’) 172.87 (Ccarbonyl).

[ ] 20 a D = -381.9 (c 1.0 in EtOH) for (1R,2R)-3, ee = 95%

In this study a batch reactor process is compared to a flow chemistry approach for lipase-catalyzed resolution of the cyclopropanecarboxylate ester (±)-3. (1R,2R)-3 is a precursor of the amine (1R,2S)-2 which is a key building block of the API ticagrelor. For both flow and batch operation, the biocatalyst could be recycled several times, whereas in the case of the flow process the reaction time was significantly reduced.

Comparison of a Batch and Flow Approach for the Lipase-Catalyzed Resolution of a Cyclopropanecarboxylate Ester, A Key Building Block for the Synthesis of Ticagrelor

Katharina G. Hugentobler^†, Marcello Rasparini^‡, Lisa A. Thompson^§, Katherine E. Jolley^§, A. John Blacker^§, and Nicholas J. Turner^*† 

^† School of Chemistry, University of Manchester, Manchester Institute of Biotechnology, 131 Princess Street, Manchester M1 7DN, United Kingdom

^‡ Chemessentia, SRL - Via G. Bovio, 6-28100 Novara, Italy

^§ Institute of Process Research and Development, School of Chemistry, University of Leeds, Woodhouse Lane, Leeds, LS2 9JT, United Kingdom

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.6b00346

Publication Date (Web): December 22, 2016

Copyright © 2016 American Chemical Society

*E-mail: Nicholas.Turner@manchester.ac.uk.

http://pubs.acs.org/doi/suppl/10.1021/acs.oprd.6b00346

“ALL FOR DRUGS” CATERS TO EDUCATION GLOBALLY, No commercial exploits are done or advertisements added by me. This article 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

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

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.

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 Yuab and   Xiang-Guo Hu*a  

 

*Corresponding authors

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

bBeijing 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

 

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 symmetric 3,6-dialkyl-1,2,4,5−tetrazine(3a−3h)

 

To a solution of 1,1−difluoroalkenes (1a, 50 mg, 0.27 mmol) in N,N-dimethylformide (DMF,5 mL) was added hydrazine (80%, 35 mg, 1.35 mmol). After stirring at room temperature for 4−6 hours, saturated ammonium chloride (20 mL) was added and the reaction mixture was extracted with dichloromethane (10 mL×3). The organic layer was combined, dried with anhydrous sodium sulfate. The solvent was concentrated and the crude product was dissolved in a suspension of Ethyl Acetate(5 mL) and 10% potassium carbonate solution(wt%, 5 mL) and stirred at room temperature for 24h under air atomerspere until the organic layer turned into amaranth obviously. The organic layer was collected, dried with anhydrous sodium sulfate. The crude product was purified by flash column chromatography[silica gel(#100–200), toluene] to afford the pure 1,2,4,5−tetrazines(3a−3h).

 

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.

 

 

 

///////tetrazines,  gem-difluoroalkenes, aerobic conditions, room temperature

N-((1-(tert-butyl)-1H-tetrazol-5-yl)(4-chlorophenyl)methyl)aniline

Endogenous water-triggered and ultrasound accelerated synthesis of 1,5-disubstituted tetrazoles via a solvent and catalyst-free Ugi-azide reaction

Green Chem., 2017, Advance Article
DOI: 10.1039/C6GC03324E, Communication

Shrikant G. Pharande, Alma Rosa Corrales Escobosa, Rocio Gamez-Montano
An ultrasound accelerated, environmentally benign Ugi-azide based method was developed for the synthesis of 1,5-disubstituted tetrazoles under solvent and catalyst-free conditions.

Endogenous water-triggered and ultrasound accelerated synthesis of 1,5-disubstituted tetrazoles via a solvent and catalyst-free Ugi-azide reaction

Shrikant G. Pharande,^a  Alma Rosa Corrales Escobosa^a and  Rocío Gámez-Montaño*^a  

 *Corresponding authors

^aDepartamento de Química, División de Ciencias Naturales y Exactas, Universidad de Guanajuato, Noria Alta S/N, Col. Noria Alta, Guanajuato, México
E-mail: rociogm@ugto.mx

Green Chem., 2017, Advance Article

DOI: 10.1039/C6GC03324E,  http://pubs.rsc.org/en/Content/ArticleLanding/2017/GC/C6GC03324E?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2FGC+%28RSC+-+Green+Chem.+latest+articles%29#!divAbstract

A novel, sustainable, endogenous water-triggered, environmentally friendly, high substrate scope, efficient, solvent-free and catalyst-free Ugi-azide based method for the synthesis of 1,5-disubstituted tetrazoles is described.

Shrikant Pharande

Doctoral student

Universidad de Guanajuato, Guanajuato · Department of Chemistry

Research experience 

• Apr 2014–Jun 2014, Research chemist
  TCG Lifesciences · pune
• Mar 2012–Dec 2013, project assistant
  CSIR - National Chemical Laboratory, Pune · Organic Chemistry Division (NCL)

Shrikant Pharande

Doctoral student

Universidad de Guanajuato, Guanajuato · Department of Chemistry

Research experience 

• Apr 2014–Jun 2014, Research chemist
  TCG Lifesciences · pune
• Mar 2012–Dec 2013, project assistant
  CSIR - National Chemical Laboratory, Pune · Organic Chemistry Division (NCL)

N-((1-(tert-butyl)-1H-tetrazol-5-yl)(4-chlorophenyl)methyl)aniline (4a)

Based on GP, 100 mg 4-Chlorobenzaldehyde (0.71 mmol), 0.065 cm3 aniline (0.71 mmol), 0.080 cm3 ter. Butyl isocyanide (0.71 mmol), and 0.093 cm3 TMS-azide (0.71 mmol) were reacted together to afford 237 mg (97%) as a white solid.

Melting range 144-145oC,

Rf = 0.45 (Hexane-AcOEt = 7/3 V/V),

1H NMR (500 MHz, CDCl3) δ 7.34 – 7.29 (m, 4H), 7.18 – 7.13 (m, 2H), 6.79 – 6.75 (m, 1H), 6.65 (d, J = 7.6 Hz, 2H), 6.11 (d, J = 6.2 Hz, 1H), 4.78 (d, J = 5.6 Hz, 1H), 1.71 (s, 9H);

13C NMR (126 MHz, CDCl3) δ 155.03, 145.54, 136.81, 134.71, 129.62, 129.43, 129.19, 119.64, 114.42, 61.95, 53.93, 30.29;

FT-IR (ATR) νmax/cm-1 3330.5, 3052.5, 2940.9, 1603.6, 1284.1;

HRMS (ESI+): m/z calcd. for C18H20ClN5 + 342.1480, found 342.1474

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1 (4-(3-(methylsulfonyl)phenyl)-l-propylpiperidin-4-ol)

1 (4-(3-(methylsulfonyl)phenyl)-l-propylpiperidin-4-ol)

Examples

Example 1 - Preparation Of Compound 1 (4-(3-(methylsulfonyl)phenyl)-l-propylpiperidin-4-ol)

4-(3-(methylthio)phenyl)-1 - 4-(3-(methylsulfonyl)phenyl)- propylpiperidin-4-ol 1 -propylpiperidin-4-ol

To a suspension of 4-hydroxy-4-(3-(methylthio)phenyl)-l-propylpiperidin-l-ium chloride (140g, 348mmol) in 710mL water were added 1.5g sodium tungstate dihydrate, and the mixture was heated to 45°C. 102mL of 33%H202 were added in 20min at 45-55°C. The suspension dissolved after 20mL addition. The solution was then stirred at 48-51°C for 30min after which HPLC showed no more starting material and two new peaks, one at RT 2.68min (82.3%) and the other at RT 3.66min (11.8%). After additional stirring for 2hr and 45min HPLC showed that the peak at RT 2.68min decreases to 7.5% and the peak at RT 3.66min increases to 88.5%. After another 45min the mixture was cooled to 20°C and into the reaction mixture were added 500mL toluene and 150mL ~5M NaOH. After stirring for 5min the mixture was poured into separator funnel. The solubility of the product in toluene is low. Majority of the product settled as very viscous liquid layer in the bottom. The water phase (and most of the product) was separated, toluene phase was washed successively with 5% Na2S03 solution and with brine and dried on MgSC>4. The water phase was extracted with 500mL DCM. The organic phase was washed successively with 5% Na2S03 solution and water and was dried on MgSC>4. Both extracts were concentrated on a rotavapor. 500mL of heptanes were added to both residues, and the suspensions were stirred at room temperature for 2 hrs. The precipitates were filtered, washed with heptane and dried. From the DCM extract were obtained 83.8g of white powder, purity by HPLC 98.8%, IH-NMR assay 97.9%. (From the toluene extract were obtained 13.7g of white powder, purity by HPLC 98.0%).

NMR Identity Analysis of Compound 1

Compound 1 : 

The following data in Tables 2 and 3 was determined using a sample of 78.95 mg Compound 1, a solvent of 0.55 ml DMSO-D6, 99.9 atom%D, and the instrument was a Bruker Avance ΙΠ 400 MHz.

Table 2: Assignment of 'H NMRa-c

a The assignment is based on the coupling pattern of the signals, coupling constants and chemical shifts.

b Weak signal.

0 Spectra is calibrated by the solvent residual peak (2.5 ppm).

Table 3: Assignment of 13C NMRa'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)

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

tert-Butyl 3a,4,7,7a-Tetrahydro-1H-isoindole-2(3H)-carboxylate

tert-Butyl 3a,4,7,7a-Tetrahydro-1H-isoindole-2(3H)-carboxylate

    

tert-Butyl 3a,4,7,7a-Tetrahydro-1H-isoindole-2(3H)-carboxylate 

 as a brown oil. % Purity: 93.72% (GC);

 

¹H NMR (CDCl₃, 400 MHz) δ: 1.47 (s, 9H), 1.89–194 (m, 2H), 2.20–2.33 (m, 4H), 3.08 (dd, J₁ = 6.2 Hz, J₂= 10.2 Hz, 1H), 3.17 (dd, J₁ = 4.8 Hz, J₂ = 10.4 Hz, 1H), 3.37–3.43 (m, 2H), 5.65 (s, 2H);

 

¹³C NMR (CDCl₃, 100 MHz) δ: 24.63, 24.68, 28.49, 33.35, 34.23, 50.86, 50.92, 78.88, 124.19, 124.50, 155.22;

 

IR (CHCl₃): ν = 756, 1128, 1170, 1217, 1411, 1685, 2937, 2978, 3009 cm^–1;

 

TOFMS: [C₁₃H₂₁NO₂ + H⁺]: calculated 224.1645, found 168.0958 (M-tBu + H)⁺ (100%), 246.1382 (M + Na)⁺ (5%).

 

GC conditions were as follows for compound 4; Agilent GC-FID 7890A, column: ZB-5MSi (30 m X 0.32 mm, 0.25 µm) with injector temperature 250 ºC and detector temperature 280 ºC, diluent was Methanol, Oven temperature was at 70 ºC isocratic for 3 min. then raised up to 250 ºC @ 20 ºC/min then 15 min. hold.

 

 

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.6b00399

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

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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

 

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