(4-(3-(methylsulfinyl)phenyl)-l-propyl-l,2,3,6- tetrahydropyridine)

Example 7 - Preparation Of Compound 7 (4-(3-(methylsulfinyl)phenyl)-l-propyl-l,2,3,6- tetrahydropyridine)

4-(3-(methylsulfinyl)phenyl)-1-propyl- 1 ,2,3,6-tetrahydropyridin-1-ium chloride Sulfuric acid (42.23g, 0.43 lmol, leq) was added to a mixture of 4-hydroxy-4-(3- (methylsulfonyl)phenyl)-l-propylpiperidin-l-ium chloride (130g, 0.431 mo, leq) and toluene (650mL) at room temperature. The resulting two-phase solution was refluxed for lhour and HPLC showed that the product reached 95% area. The reaction mixture was cooled down to 20°C and the toluene phase was decanted to give viscous residue that was diluted with water (600mL) and neutralized with 2N NaOH to pH~4.2. Hydrogen peroxide (50%, 32.21g, 0.474mol, l.leq) was added dropwise to the water phase and the mixture was stirred at 60°C for lh after which the product reached 96% area (HPLC).

Toluene (600mL) was added to the reaction mixture and made basic first with 25% NaOH (60g) and finally with 10% NaOH up to pH 12. The phases were separated and the water phase was re-extracted with toluene (2xl00mL). The combined toluene phases were washed with 5% sodium sulfite (150mL), brine (150mL) and water (150mL). The toluene phase was then concentrated under vacuum on a rotavapor to give 111.3g oil (HPLC area: 96.6%). Methanol (50mL) was added to the residue and it was filtered and cooled down on ice batch. Dry HC1 in ethyl acetate was added up to pH 1-2 (120mL) and lOOmL of ethyl ether were added to give two phases mixture. The mixture was seeded with the product and precipitation started. The reaction mixture was stirred on ice bath (2-5°C) for additional lh, filtered and washed with 1/3 ethyl acetate/ether mixture (lOOmL) to give 140g of very hygroscopic light yellow solid that was dried on a rotavapor for 2h and stored under nitrogen in deep freeze. The dry 4-(3-(methylsulfinyl)phenyl)-l-propyl-l,2,3,6-tetrahydropyridine-HCl is slightly yellowish solid (94.1g, 79% yield, HPLC (254nm): 96.3% area, 1H-NMR assay: 97.5%).

NMR Identity Analysis of Compound 7

Compound 7: 

The following data in Tables 14 and 15 was determined using a sample of Compound 7, a solvent of CDCb, and the instruments were a Bruker AMX500 and Avance III 800 MHz instrument.

Table 14: Assignment of ¾ NMR"

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

bafter addition of small amount of CeDe

Table 15: Assignment of 13C NMRa*

a Spectra is calibrated by a solvent peak (77.0 ppm)

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(l-(3,3-bis(3-(methylsulfonyI)phenyl)propyl)-4-(3- (methylsulfonyl) phenyl)piperidine)

Example 2 - Preparation Of Compound 2 (l-(3,3-bis(3-(methylsulfonyI)phenyl)propyl)-4-(3- (methylsulfonyl) phenyl)piperidine)

Preparation of ethyl 3-(4-oxopiperidin-l-yl)-propanoate (starting material for Compound 2)

3-(4-oxopiperidin-1-yl)-propanoate

Ethanol (1550mL) was poured into a 4 L three-necked round-bottom flask equipped with over-head stirring followed by the addition of 125g (814mmol, leq) 4-piperidone monohydrate hydrochloride and 225g (1628mmol, 2eq) potassium carbonate. Ethyl 3-chloropropanoate (l l lg, leq) was added and the reaction mixture was stirred for 3h after which HPLC showed that the product reached only 10% area. Another 0.5eq of K2CO3 was added (56.2g) and stirring continued at 24°C. After total of 45h the product reached 86% area (HPLC). Another 0.2eq of K2CO3 was added and the reaction mixture was stirred for additional 4.5h at 35°C after which HPLC showed 96% area of the product. The mixture was filtered through a sintered glass filter, washed with 200 ml ethanol and concentrated on vacuum to 156g yellow colored oil that was distilled under vacuum of 2mmHg in 156°C bath. The main fraction distilled at 120°C to yield 97.8g (60%) of 99.3% area (HPLC).

Preparation of l -('3-hvdroxy-3,3-bis(3-(methylthio)phenyl')propyl)-4-(3-(methylthio) phenyl)piperidin-4-ol (Compound 2, 1st intermediate)

- - me y t o pheny p peri n-4-ol

3-Bromothioanisole (170.3g; 0.84mol, 3.2eq) and THF (700mL) were charged to a 2L flask, stirred under nitrogen and cooled on dry ice/acetone bath to -74°C. A solution of n-hexyllithium in hexane (2.3M; 237.4g; 0.77mol, 3.0eq) was added and the reaction mixture became slightly yellowish. Stirring continued for additional 30min at -74°C. A solution of ethyl 3-(4-oxopiperidin-l-yl)propanoate (50.2g; 0.26 mol, leq) in THF (lOOmL) was added during lhl5min to the reaction mixture and the stirring continued for additional 30min at -74°C to give a yellow clear solution. The cooling stopped and the reaction warmed to -40°C. A solution of HC1 (33%; 90g, 0.82mol, 3. leq) in water (lOOmL) was added dropwise for 20min to give a light yellow emulsion in +8°C. The light yellow organic phase was separated, washed with water (3x200mL) and extracted twice with aqueous HC1 (33%HC1 40g/300mL water) to give lower yellow phase (234g). The organic upper light yellow phase was evaporated up to 159g solution and the precipitate formed during concentration was filtered to give 19. lg yellow sticky precipitate. The precipitate was combined with the lower yellow phase, methanol (50mL) and THF (200mL) were added and distilled (67°C, 248g distilled). Heptane (200mL was added, the two liquid phase was stirred for 20min at 40°C and cooled to RT. The upper heptane phase was discarded and water (200mL) was added to the viscous yellow residue water. After stirring stopped the colorless water was decanted to leave 182g of very viscous light yellow residue (HPLC: 82% area).

Preparation of l-(3,3-bis(3-(methylthio)phenyl)allyl)-4-(3-(methylthio)phenyl)-l,2,3.6-tetrahydropyridine (Compound 2, 2nd intermediate')

Into the viscous light yellow residue was added 2-propanol (200mL) and the reaction mixture was distilled at atmospheric pressure to give 200mL of azeotropic distillate, leaving dark yellow oil into which methanol (50mL), 2-propanol (350mL) and cone, sulfuric acid (36.5g, 0.35mol. 1.35eq) were added. The reaction mixture was heated for 26 hours (mixture temperature 81-84°C, vapor temperature 79°C) and about 440mL of distillate were collected. At the end the temperature reached 87°C and the reaction mixture was foaming. After cooling was added toluene (lOOmL) and water (200mL) and the reaction mixture was heated to reflux (87°C). The heating stopped and after cooling three phases were formed. The lower oily phase was washed with water (2x200mL) and concentrated by vacuum distillation to give dark yellow viscous residue. Water (300mL) was added and the mixture was refluxed then cooled to 40°C and water phase was decanted to leave about 200g orange turbid liquid (HPLC: 82% area) which was used in the next step.

Preparation of l-(3.3-bis(3-(methylsulfonyl)phenyl')allyl)-4-(3-(methylsulfonyl) phenyl)- 1,2,3,6-tetrahydropyridine (Compound 2, 3rd intermediate)

To the 200g orange turbid liquid from the previous stage was added 500mL water, sodium tungstate dihydrate (2g, 6mmol) and concentrated sulfuric acid (20mL). The mixture was heated to 35°C and

33%¾θ2 was added drop-wise in lh during which the yellow viscous mass on the bottom of the flask dissolved slowly and the temperature rose up to 55°C then decreased slowly to 42°C. The reaction mixture was heated to 50°C for 2hr and additional 32g of 33%¾θ2 were added. The reaction continued for another 4h at 50°C and additional 20g of 33%¾θ2 were added. After 2h the reaction mixture was cooled down (25°C) and alkalized to pH12 by 50%NaOH solution. Water (300mL) was added and after 20min of mechanical stirring was discarded. Another 200mL of water were added, stirred mechanically for 20min and discarded to give 158.2g highly viscous yellow mass (HPLC: 75.4% area). This mass was heated for 30min 4 times with butanol (200mL@95°C, 200mL@ 100°C, 400mL@ 100°C and 700mL@ 114°C) and twice with acetic acid (8mL and 250mL@95°C) to give light brown oil that was used in the next step (114.9g, HPLC: 89% area).

Preparation of l-(3.3-bis(3-(methylsulfonyl)phenyl)propyl)-4-("3-(methylsulfonyl) phenvDpiperidine (Compound 2)

The light brown oil from the previous stage (114.9g, HPLC: 89% area) was added into a 2L autoclave with 550mL acetic acid and 10%Pd/C catalyst (25g, 23.5mmol). Hydrogen was introduced (120psi) and the reaction was heated to 90°C for 16h. After cooling, the catalyst was filtered, washed with acetic acid (50ml) and the clear yellowish filtrate was concentrated in vacuum to give 134g brown viscous residue (HPLC: 82% area). Water (300ml) was added, made alkaline (40% NaOH, pH>12) and extracted with 120mL dichloromethane that after concentration gave 77.2g brown sticky mass (HPLC: 83% area). The residue was treated with butanol (5xl00mL, 95°C), cooled down and the butanol phase over an oily phase was filtered. A total of 74.9g solid phase was resulted which was dissolved in 200mL acetone and the clear yellow solution was evaporated to give 70. lg dark yellow clear viscous residue. The residue was treated with heptane (2xl00mL, 95°C) which was cooled and decanted. After evaporation in a rotavapor a pale yellow foamy solid was obtained (65. lg, HPLC: 84% area). The solid was dissolved in 200mL dichloromethane, 85g silica was added and the mixture was evaporated and loaded on 1.32Kg silica gel column which was eluted by dichloromethane with 0.5-3.0% methanol and 0.5% triethylamine. Compound 2 was isolated to give 25.8g, HPLC: 93.2% area, lH-NMR assay: 91.2%.

NMR Identity Analysis of Compound 2

Compound 2: 

The following data in Tables 4 and 5 was determined using a sample of 62.03 mg Compound 2, a solvent of 0.6 ml CDC13, 99.8 atom%D, and the instrument was a Bruker Avance III 400 MHz.

Table 4: Assignment of ¾ NMRa-c

a 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 (7.28 ppm).

Table 5: 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 (77.16 ppm)

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((3R,4S)-4-(3-(methylsulfonyl)phenyl)-l-propylpiperidin-3-ol)

Example 4 - Preparation Of Compound 4 ((3R,4S)-4-(3-(methylsulfonyl)phenyl)-l-propylpiperidin-3-ol)

Preparation of dS,6S)-6-(3-(methylsulfonvnphenyl)-3-propyl-7-oxa-3-azabicyclo [4.1.Olheptane

(1S,6S)-6-(3-(methylsulfonyl)p enyl)

-3-propyl-7-oxa-3-azabicyclo

[4.1.0]heptane

Into a 4L reactor was added at room temperature Compound 8 (229g, 820mmol, leq) and 2N sulfuric acid (1147mL, 112g sulfuric acid, 1.147mol, 1.4eq). The reaction light yellow mixture was stirred and sodium bromate (126g, 836mmol, 1.02eq) was added. The mixture became yellow and the temperature dropped (endothermic dissolution). After 30min the reaction temperature reached 35°C and heated further to 40°C for 6h to give dark yellow solution with precipitate in the bottom of reactor. Toluene (2L) and NaOH (24%, 546g, 131g NaOH, 3.28mol, 4.0eq) were added and the reaction mixture was vigorously stirred for 1 hour at 42°C. The reaction mixture was then poured into a 4 L separation funnel. The dark water phase was discarded and the dark red organic phase was washed with 1.1L 5% sodium sulphite solution and 1L 20% brine. The organic phase was then concentrated on a rotavapor (50°C, 90-65 mbar, finally at 45mbar) to give l l lg dark red oil with crystals in the flask. A GC analysis (5mg red oil dissolved in 0.6 ml toluene) showed 53% area product, 29% and 5.2% area unknown peaks and 0.4% Compound 8. The product goes to the reduction in the next stage.

Preparation of (3S,4R -4-(3-(methylsulfonyl phenyl)-l-propylpiperidin-3-ol (Compound 4)

(3S,4R)-4-(3-(methylsulfonyl)

phenyl)-1 -propylpiperidin-3-ol

The epoxide from the previous stage (11 lg of 53% GC purity, 62.0g, 210mmol, leq) was dissolved in ethanol (1.2L) for lh. The red colored mixture was potired into 2L Parr reactor and a solution of 10% Pd/C (I4.6g, dry) in ethanol (50mL) was added. The mixture was reacted with hydrogen (4bar) at 30°C for lOhr. Pd/C was filtered through a Celite and the filtrate was concentrated in the rotavapor to give 108g red oil (65% area product by GC). The product was added to 200g silica gel, 0.5% triethylamine in dichloromethane were added and the mixture was concentrated and loaded on a column with 620g silica gel. The purification was done with 0.5% triethylamine in dichloromethane to give 28g hard residue (97.0% area by GC). The residue was heated to reflux in 34mL dichloromethane until complete dissolution to give clear red solution which was cooled slowly with parallel removal of some solvent by nitrogen flow over the solvent. The precipitation was filtered and washed with dichloromethane (5mL) to give 20g white solid, HPLC: 99.0% area, 1H-NMR assay: 99.4%.

NMR Identity Analysis of Compound 4

Compound 4:

The following data in Tables 8 and 9 was determined using a sample of 54.06 mg Compound 4, a solvent of 0.55 ml DMSO-D6, 99.9 atom%D, and the instrument was a Bruker Avance III 400 MHz.

Table 8: Assignment of ¾ 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 9: 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)

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(l-(2-methylpentyl)-4-(3-(methylsulfonyl)phenyl)piperidine)

Example 6 - Preparation Of Compound (l-(2-methylpentyl)-4-(3-(methylsulfonyl)phenyl)piperidine)

1-(2-methylpentyl)-4-(3- (methylsulfonyl)phenyl)piperidine

Into a 1L autoclave was added KI (28.4g, 171mmol leq) and potassium carbonate (47.4g, 343mmol, 2eq). 4-(3-(methylsulfonyl)phenyl)piperidine (41g, 171mmol, leq) was dissolved in acetonitrile (420mL) and the mixture was added into the autoclave followed by l-chloro-2-methylpentane (25.8mL, 188mmol, l .leq). The autoclave was closed and the reaction mixture was heated under nitrogen atmosphere to 120°C for 30hr. The reaction mixture was cooled down and filtered. The cake was washed with acetonitrile and the filtrate was concentrated in vacuum to give 70g crude product with the following HPLC areas: 60% of Compound 6, 1% of 4-(3-(methylsulfonyl)phenyl)piperidine and 10% of a by-product. The crude product was dissolved in toluene (350ml) and about 20g solid material was filtered. The toluene phase was washed with water (200mL) and concentrated in a rotavapor to give 35.5g (73% area of product by HPLC). The residue was then dissolved in ethyl acetate (180mL) and cooled on ice bath. Into the reaction mixture was then added 33mL of 18% HC1 solution in ethyl acetate in lhr and the mixture was stirred for an additional lh. The precipitate that was formed was then filtered, washed with ethyl acetate and dried to give 36.3g white solid (HPLC: 94% area. The product was recrystallized by dissolving in methanol (290mL), heating to 70°C, adding ethyl acetate (400mL) and cooling to room temperature. The precipitate was filtered, washed with ethyl acetate (60mL) and dried in vacuum at 50°C to give 28.3g Compound 6 (HPLC: 99.5% area, 1H-NMR assay: 99.6%).

NMR Identity Analysis of Compound 6

Compound 6: 

The following data in Tables 12 and 13 was determined using a sample of 33.93 mg Compound 6, a solvent of 8 ml DMSO-D6, 99.9 atom%D, and the instrument was a Bruker Avance ΓΠ 400 MHz. Two conformers (ca 10: 1) at room temperature are observed. Due to the overlap of proton signals of the major and minor conformers and relatively weak signal of the minor isomer in 2D speactra only some of the peaks of minor isomer on 1 H spectra and corresponding 1 H-l H COSY cross peaks are given. Due to the low solubility of the material in D6-DMSO some of the expected HMBC signals are masked by background noise.

Table 12: Assignment of ¾ NMRa'c

a 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 13: 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)

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tert-butyl(3aR,6aS)-5-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

tert-butyl(3aR,6aS)-5-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

   

tert-Butyl (3aR,6aS)-5-Oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (1)

pure compound 1 (1.051 kg, 67%) as a white solid. Mp: 70–71 °C (uncorrected); [α]²⁵_D +0.40° (c 1.00 CHCl₃); % purity: 98.5% (HPLC);

 

¹H NMR (CDCl₃, 400 MHz) δ: 1.46 (s, 9H), 2.15 (dd, J₁ = 4.8 Hz, J₂ = 19.6 Hz, 2H), 2.47 (dd, J₁ = 7.4 Hz, J₂ = 19.6 Hz, 2H), 2.93 (bs, 2H), 3.16–3.28 (m, 2H), 3.65–3.67 (m, 2H).;

 

¹³C NMR (CDCl₃, 100 MHz) δ: 38.49, 39.36, 42.32, 50.51, 50.77, 79.49, 154.39, 217.65; IR (KBr): ν = 638, 771, 877, 1118, 1166, 1247, 1367, 1402, 1691, 1741, 2877, 2910, 2958, 2976, 3005 cm^–1;

 

TOFMS: [C₁₂H₁₉NO₃ + H⁺]: calculated 226.1438, found 152.0663 (M-OtBu)⁺ (100%), 170.0755 (M-tBu + H)⁺ (40%), 248.1166 (M + Na)⁺ (5%).

 

Anal. Calcd for C₁₂H₁₉NO₃: C, 63.98; H, 8.50; N, 6.22. Found: C, 63.89; H, 8.27; N, 5.97.

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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(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).

“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

(±)-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