SUPORTING INFORMATION SECTION · 1 SUPORTING INFORMATION SECTION The Total Synthesis of Calcium Atorvastatin Luiz C. Dias a, Adriano S. Vieira and Eliezer J. Barreirob aInstituto

1

SUPORTING INFORMATION SECTION

The Total Synthesis of Calcium Atorvastatin

Luiz C. Diasa, Adriano S. Vieiraa and Eliezer J. Barreirob

aInstituto de Química, Universidade Estadual de Campinas, UNICAMP, P.O. Box 6154, 13084-

971 Campinas, SP, Brazil

Tel.: +55 19 35213097; fax: +55 19 35213023.

bLaboratório de Avaliação e Síntese de Substâncias Bioativas, Universidade Federal do Rio de

Janeiro, P.O. Box 68024, 21944-971 Rio de Janeiro, RJ, Brazil.

Tel.: +55 21 25626644; fax: +55 21 25626478.

Table of contents

Contents Page

1- General Experimental 2

2- Preparation of aldehyde 3 2

3- Preparation of methyl ketone 4 5

4- Experimental 7

5- Appendix – Copies of 1H and 13C NMR data 12

Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry.This journal is © The Royal Society of Chemistry 2016

2

1. General Experimental

The air-sensitive and/or water-sensitive reactions were performed under nitrogen

atmosphere with dry solvents under anhydrous conditions. Standard syringe techniques were

applied for the transfer of dry solvents and air-sensitive reagents. The reactions were monitored

by TLC performed on Merck silica gel (60 F254) using UV light as the visualizing agent and 5%

vanillin in 10% H2SO4 and heat as developing agents. Merck silica gel (particle size 0.040-0.063

mm) was used for flash chromatography. Dry THF and Et2O were distilled from

sodium/benzophenone under nitrogen prior to use. Some reagents and solvents were

commercially available and were used without further purification. All of the yields were

calculated as gross yields. 1H (250 and 500 MHz) and 13C (62.5 and 125 MHz) NMR spectra

were recorded on Bruker DPX250 and INOVA 500 MHz spectrometers in CDCl3, acetone-d6,

C6D6, MeOD or DMSO-d6 using tetramethylsilane (TMS) as internal standards.

2. Preparation of aldehyde 3

4-Methyl-3-oxo-N-phenylpentanamide (10) was prepared from the inexpensive and

commercially available 4-methyl-3-oxo-methylpentanoate (9) and aniline (Scheme 1).1,4,13 Many

reaction conditions were evaluated, and improvements were made to the original Pfizer route.1

Among the several reaction conditions tested, the best result was obtained using NaOH (2 mol%)

as the catalyst in the absence of solvent followed by the removal of methanol at 135 °C (92%

yield). N-phenylpentanamide (10) was obtained as a viscous yellow oil in a pure form.

3

O

O

Me

Me

FPh

OHN 12

Ph

O

Me

MeOCH3

O

+

NH2 O

Me

MeN

O

H

NaOH cat.

135 oC, 12 h, 92%

CH3OH+9 10

PhCHOO

Me

MeN

O

HCH3CO2H

4-aminophenol

hexanes, reflux, 24 h, 94%11

4-F-C6H4CHO, Et3N

75 oC, 16 h

85%

N

S

Me

HO

Et

Br

Scheme 1. Preparation of 1,4-diketone (12).

In the next step, to obtain 2-benzylidene-4-methyl-3-oxo-N-phenylpentanamide (11), 4-methyl-

3-oxo-N-phenylpentanamide (10) was subjected to a reaction with benzaldehyde in the presence

of acid catalysts in hexanes as the solvent (Scheme 1).13 Among the several reaction conditions

evaluated, we obtained the best results using 4-aminophenol (20 mol%) and acetic acid (20

mol%) as catalysts in refluxing hexanes for 24 h. Under these conditions, Z+E-2-benzylidene-4-

methyl-3-oxo-N-phenylpentanamide (11) was obtained in 94% isolated yield. 2-Benzylidene-4-

methyl-3-oxo-N-phenylpentanamide (11) is a white solid and was purified by washing with hot

hexanes (60 °C) to remove the remaining benzaldehyde, followed by washing with distilled

water to remove catalyst residues.

The synthesis of 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-N-

phenylpentanamide (12) was performed via the Stetter reaction, according to the work of Sagyan

and coworkers (Scheme 1).14c N-phenylpentanamide (11) was subjected to a reaction with 4-

fluorobenzaldehyde in the presence of triethylamine as the base and 3-ethyl-5-(2-hydroxyethyl)-

4-methyl-3-thiazolium bromide as the catalyst (20 mol%) in anhydrous ethanol, according to the

reported procedure.4b,13 Using this protocol, 1,4-diketone (12) was obtained in only 39% yield

after recrystallization. Considering this result, we decided to test the reaction in the absence of

4

solvent at 75 °C for 16 h. To our delight, these conditions afforded 2-[2-(4-fluorophenyl)-2-oxo-

1-phenylethyl]-4-methyl-3-oxo-N-phenylpentanamide (12) in 85% isolated yield (Scheme 1).

Then, pyrrolic aldehyde (3) was prepared by a Pall-Knorr reaction.1b,15 This process is composed

of the reaction between 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-N-

phenylpentanamide (12) (previously prepared) with 3-aminopropan-1-ol and the subsequent

oxidation of the resulting pyrrolic alcohol (13) (Scheme 2). For this purpose, 1,4-diketone (12)

was treated with 1.5 equiv of 3-aminopropan-1-ol under pivalic acid catalysis in a mixture of

toluene-heptane-tetrahydrofuran (1:4:1) under reflux with azeotropic removal of water for 24 h.

Thus, 5-(4-fluorophenyl)-1-(3-hydroxypropyl)-2-isopropyl-N,4-diphenyl-1H-pyrrole-3-

carboxamide (13) was obtained as a pale yellow solid in 73% isolated yield after purification by

passing through a plug of silica gel. In the next step, pyrrolic alcohol (13) was subjected to

oxidation under Swern conditions16 to give the corresponding pyrrolic aldehyde (3) in 84% yield,

which was used in the next step without further purification.1b

O

O

Me

Me

FPh

OHN 12

Ph

N

Ph

OH

F

MeMe

N

O

Ph

13

H2N(CH2)3OH

t-BuCO2H

toluene/heptane/THF(1:4:1)

reflux 24 h, 73%

N

Ph

H

O

F

MeMe

N

O

Ph

1) DMSO, (ClCO)2CH2Cl2, 50 oC, 1 h

2) Et3N, rt, 1 h, 84%

3

H

H

Scheme 2. Preparation of pyrrolic aldehyde (3)

3. Preparation of methylketone 4

The preparation of (S)-1-(2,2-dimethyl-1,3-dioxolan-4-yl)propan-2-one (4) was easily performed

in four steps from inexpensive L-(S)-malic acid (14), according to the procedure described in the

literature17 (Scheme 3). In the first step, L-(S)-malic acid (14) was converted to its corresponding

methyl ester (15) by a Fischer esterification reaction with methanol in the presence of catalytic

amounts of sulfuric acid. Importantly, the product (S)-dimethylmalate (15) does not require

5

purification and can be used directly in the next step. In the next step, (S)-dimethyl malate (15)

was converted to acetonide methyl ester (17) via Moriwake’s regioselective reduction reaction18

employing BH3.SMe2 and NaBH4 (78% isolated yield). In this reaction, the intermediate 1,2-diol

ester (16) was not isolated and was submitted directly to the ketalization reaction with 2,2-

dimethoxy propane in the presence of catalytic amounts of p-TsOH (Scheme 3).

OH

MeO2C OMe

O15

OH

MeO2C OH

1) BH3.SMe2

NaBH4 (5 mol%), THF

2) CH3OH

25 oC, 2 h

O

MeO

OO

MeMe(CH3)2C(OCH3)2

acetone, p-TsOH

25 oC, 4 h

78%17

CO2H

OH

HO2CCH3OH

H2SO4 (cat)14

ref lux, 12 h

94%

16 THF, MeMgCl

10 oC to r.t., 8 h

92%

MeN(OMe)H.HCl

O

Me

OO

MeMe

4

Scheme 3. Synthesis of methyl ketone (4) from L-(S)-malic acid (14)

The acetonide methyl ester (17) was easily purified by distillation under reduced pressure. Then,

acetonide methyl ester (17) was submitted to a reaction with CH3MgCl in THF in the presence of

N-methyl-N-methoxy amine hydrochloride to produce the corresponding methyl ketone (4) via

Weinreb’s amide (Scheme 3).19 The product (S)-1-(2,2-dimethyl-1,3-dioxolan-4-yl)propan-2-one

(4) can be easily purified by vacuum distillation and was obtained in 62% overall yield from the

4-step sequence.

6

4. Experimental

4-methyl-3-oxo-N-phenylpentanamide (10). To a mixture of 4-methyl-3-oxo methyl

pentanoate (9) (100.0 g, 700 mmol) and NaOH (0.5 g) was added aniline (68.4 g, 730.5 mmol) at

135 °C, with simultaneous removal of methanol over 2 h. The reaction mixture was maintained

for another 12 h at 135 °C and was monitored by thin layer chromatography. The reaction was

cooled to room temperature and was slowly added to a 0 °C 5% aqueous HCl solution (until pH

= 6) followed by water (300 mL). The reaction mixture was extracted with ethyl acetate (3 x 300

mL), and the organic phase was washed with water (3 x 300 mL). The organic phase was dried

with anhydrous magnesium sulfate and then concentrated under vacuum to provide 4-methyl-3-

oxo-N-phenylpentanamide (10) as a viscous yellow oil in 92% yield (130.5 g) in pure form (bp

262-263 °C). 1H NMR (250 MHz, DMSO-d6) δ 1.03 (d, J = 7.0 Hz, 6H), 2.77-2.83 (m, 1H), 3.61

(s, 2H); 7.04 (t, J = 8.1 Hz, 1H), 7.30 (t, J = 8.1 Hz, 2H), 7.58 (d, J = 8.1 Hz, 2H); 10.07 (s, 1H).

13C NMR (62.5 MHz, DMSO-d6) δ 17.5, 40.3, 49.4, 118.9, 123.3, 128.6, 138.8, 165.1, 208.2. IR

(KBr, cm1): 3298, 3044, 1729, 1658.

2-benzylidene-4-methyl-3-oxo-N-phenylpentanamide (11). A mixture of 4-methyl-3-oxo-N-

phenylpentanamide (10) (100.0 g, 480 mmol), 4-aminophenol (10.4 g, 96.0 mmol),

benzaldehyde (53.0 g, 504.0 mmol) and acetic acid (5.7 g, 96.0 mmol) in hexanes (1 L) was

refluxed for 24 h with azeotropic removal of water. The remaining solid was filtered, washed

with hexanes (1 L) followed by distilled water (1.5 L) and dried under high vacuum (12 h) to

give 2-benzylidene-4-methyl-3-oxo-N-phenylpentanamide (11) in 94% yield (131.0 g) as a white

solid, mp 191-192 °C. 1H NMR (250 MHz, DMSO-d6) δ 1.12 (d, J = 7.1 Hz, 6H), 3.30-3.47 (m,

1H), 7.08 (t, J = 8.0 Hz, 1H), 7.30-7.41 (m, 5H), 7.66-7.70 (m, 5H), 9.61 (s, 1H). 13C NMR (62.5

MHz, DMSO-d6) δ 18.3, 36.0, 121.1, 124.2, 128.3, 129.5, 130.3, 132.7, 135.1, 136.0, 137.3,

140.2, 165.3, 202.8. IR (KBr, cm1): 3312, 3049, 1728, 1663.

2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-N-phenylpentanamide (12)

(diketone of Atorvastatin). A mixture of 2-benzylidene-4-methyl-3-oxo-N-phenylpentanamide

(11) (130.0 g, 443.1 mmol), 3-ethyl-5-(2-hydroxyethyl)-4-methyl-3-thiazolium bromide (22.3 g,

88.6 mmol), triethylamine (135.8 mL, 974.8 mmol) and 4-fluorobenzaldehyde (60.5 g, 487.4

mmol) was heated at 75 °C under argon atmosphere with vigorous stirring for 16 h. The reaction

7

was monitored by thin layer chromatography (TLC) until consumption of N-phenylpentanamide

(11) was achieved. Isopropyl alcohol (650 mL) was added, and the reaction mixture was

maintained at 25 °C for 4 h under stirring. The remaining solid was vacuum filtered and washed

with 700 mL of water followed by 500 mL of isopropyl alcohol. The product 2-[2-(4-

fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-N-phenylpentanamide (12) was dried under

high vacuum for 4 h, affording a white crystalline solid (mp 205-209 °C, Lit.4b 206-209 °C) in

85% yield (167.2 g). 1H NMR (250 MHz, DMSO-d6) δ 0.92 (d, J = 6.5 Hz, 3H), 1.15 (d, J = 7.5

Hz, 3H), 2.83-2.94 (m, 1H), 4.87 (d, J = 11.0 Hz, 1H), 5.42 (d, J = 11.0 Hz, 1H), 6.97-7.40 (m,

12H), 8.13 (d, J = 8.2 Hz, 2H), 10.18 (s, 1H). 13C NMR (62.5 MHz, DMSO-d6) δ 18.1, 18.6,

40.9, 54.1, 64.1, 115.6 (d, JC-F = 22.0 Hz), 120.6, 124.7, 128.0, 128.6, 129.4, 131.5, 131.6 (d, JC-F

= 9.4 Hz) , 132.2 (d, JC-F = 2.5 Hz), 135.2, 136.7, 165.5, 165.6 (d, JC-F = 255.3 Hz), 196.4, 209.6.

IR (KBr, cm1): 3296, 1720, 1684, 1598.

5-(4-fluorophenyl)-1-(3-hydroxypropyl)-2-isopropyl-N,4-diphenyl-1H-pyrrole-3-

carboxamide (13). To a solution of 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-

oxo-N-phenylpentanamide (12) (140.0 g, 335.3 mmol) and 3-aminopropan-1-ol (37.8 g, 502.9

mmol) in toluene-heptane-tetrahydrofuran (1:4:1) (1 L) was added pivalic acid (6.8 g, 67.0

mmol) under nitrogen atmosphere. The reaction mixture was refluxed for 24 h with azeotropic

removal of water, monitored by thin layer chromatography (TLC), cooled to room temperature

and extracted with ethyl acetate (3 x 700 mL). The organic phase was washed with brine (500

mL). The solvent was removed under vacuum, and pyrrolic alcohol (13) was obtained as a pale

yellow solid in 73% yield (113.8 g, 251.4 mmol) after purification by passing through a plug of

silica. Alternatively, pyrrolic alcohol (13) can be purified by recrystallization from hexane-

isopropyl alcohol. Mp 175-178 oC. 1H NMR (500 MHz, CDCl3) δ 1.53 (d, J = 7.0 Hz, 6H), 1.71-

1.82 (m, 2H), 3.46-3.61 (m, 3H), 3.99 (t, J = 7.7 Hz, 2H), 6.87 (s, 1H), 6.95-7.21 (m, 14H). 13C

NMR (125 MHz, CDCl3) δ 21.7 (2C), 26.1, 34.3, 41.7, 59.8, 115.4 (d, JC-F = 21.3 Hz), 119.6,

121.8, 123.5, 126.5, 128.2 (d, JC-F = 2.5 Hz), 128.3, 128.6, 128.8, 130.4, 133.1 (d, JC-F = 8.8 Hz),

133.2, 134.6, 138.3, 141.4, 162.2 (d, JC-F = 247.6 Hz), 164.8. IR (KBr, cm1): 3335, 3367, 1669.

8

5-(4-fluorophenyl)-2-isopropyl-1-(3-oxopropyl)-N,4-diphenyl-1H-pyrrole-3-carboxamide

(3). To a solution of oxalyl chloride (33.3 g, 262.8 mmol) in CH2Cl2 (800 mL) under an

atmosphere of dry argon at 50 °C was added DMSO (34.2 g, 438 mmol) over 30 min. After 20

min at 50 °C, pyrrolic alcohol (13) (100.0 g, 219.0 mmol) dissolved in CH2Cl2 (200 mL) was

slowly added over 30 min. The reaction mixture was maintained at 0 oC for 1 h, and Et3N was

added (88.4 g, 876 mmol, 4.0 eq.). The reaction was continued for 1 h at room temperature and

was extracted with ethyl acetate (3 x 500 mL). Pyrrolic aldehyde (3) was purified by passing

through a plug of silica and eluted with hexane/acetate (9:1 mixture) to obtain a pale yellow solid

in 84% yield (84.2 g, 186.1 mmol). Mp 160-163 oC. Lit.1b mp 164-165 oC. 1H NMR (500 MHz,

CDCl3) δ 1.51 (d, J = 7.0 Hz, 6H), 2.67 (t, J = 7.5 Hz, 2H), 3.61 (quint, J = 7.0 Hz, 1H), 4.25 (t,

J = 7.5 Hz, 2H), 6.85 (s, 1H), 6.95-7.21 (m, 14H), 9.58 (s 1H). 13C NMR (125 MHz, CDCl3) δ

21.6 (2C), 25.9, 37.6, 45.2, 115.7 (d, JC-F = 21.4 Hz), 119.5, 122.1, 123.5, 126.7, 127.6, 127.7 (d,

JC-F = 3.8 Hz), 128.5, 128.6, 130.5, 133.0 (d, JC-F = 8.7 Hz), 133.4, 134.7, 138.5, 141.5, 162.3 (d,

JC-F = 248.8 Hz), 164.4, 198.5. IR (KBr, cm1): 3402, 2965, 1722, 1674, 1596, 1510.

(S)-dimethylmalate (15). To a mixture of L-(S)-malic acid (14) (100.0 g, 745.7 mmol) in

anhydrous methanol (600 mL) was added sulfuric acid (3.65 g, 2 mL), and the resulting mixture

was refluxed for 12 h. Methanol was distilled off to obtain a final volume of approximately 100

mL. To the mixture was added a saturated aqueous NaHCO3 solution until reaching pH = 8.0

(100 mL). The reaction was extracted with ethyl acetate (3 x 500 mL), and the organic phase was

collected and dried with anhydrous Na2SO4. The solvent was removed in a rotary evaporator (40

°C/100 mmHg), and the remaining solvent was removed under high vacuum (1 mmHg) for 5 h.

(S)-Dimethyl malate (15) was obtained in 94% yield (113.9 g) as a pale yellow oil and was used

in the next step without purification. 1H NMR (250 MHz, CDCl3) δ 2.67 (dd, J = 15.1 Hz, 7.4

Hz, 1H), 2.71 (s, 1H), 2.78 (dd, J = 15.1 Hz, 7.4 Hz, 1H), 3.69 (s, 3H), 3.70 (s, 3H), 4.50 (t, J =

7.3 Hz, 1H). 13C NMR (62.5 MHz, CDCl3) δ 38.2, 51.6, 51.8, 68.9, 172.1, 172.3. IR (thin film,

cm1): 3368, 2964, 1740.

(S)-methyl 2-(2,2-dimethyl-1,3-dioxolan-4-yl)acetate (17). To a solution of (S)-dimethyl

malate (15) (110.0 g, 678.7 mmol) in anhydrous THF (1.0 L) at 20 °C under argon atmosphere

was added BH3.SMe2 (10 M) (60.5 mL, 605.0 mmol) over 40 min. The solution was stirred for

9

30 min at 20 °C until the hydrogen evolution ceased. The reaction temperature was reduced to 10

°C, and the solution was maintained for 10 min at this temperature. Then, NaBH4 was added in

portions (0.23 g in 5 portions) (1.15 g, 28.6 mmol) over 50 min. The reaction mixture was

maintained under intense agitation for 1 h at 20 °C. The reaction was monitored by thin layer

chromatography until total consumption of (S)-dimethyl malate (15) was achieved. Next,

anhydrous methanol (500 mL) was slowly added to the reaction at 0 °C, and the mixture was

stirred for 30 min at 20 °C. The solvent was removed completely on a rotary evaporator and then

under high vacuum for 4 h. The viscous oil residue containing 16 was dissolved in a mixture of

acetone (600 mL) and 2,2-dimethoxypropane (200 mL). To this mixture was added p-TsOH

(4.95 g), and the reaction was stirred for 4 h at 20 °C. The mixture was extracted with ethyl

acetate (3 x 500 mL), and the residue was subjected to distillation under reduced pressure (bp 74-

75 °C/6 mbar). The product (17) was obtained as a colorless liquid in 78% yield (92.2 g, 529.3

mmol). 1H NMR (250 MHz, CDCl3) δ 1.35 (s, 3H), 1.41 (s, 3H), 2.52 (dd, J = 15.0 Hz, 7.5 Hz,

1H); 2.72 (dd, J = 15.0 Hz, 7.5 Hz, 1H), 3.65 (dd, J = 10.0 Hz, 7.5 Hz, 1H), 3.70 (s, 3H); 4.15

(dd, J = 8.7 Hz, 7.5 Hz, 1H), 4.47 (quint, J = 7.5 Hz, 1H). 13C NMR (62.5 MHz, CDCl3) δ 25.4,

26.8, 38.7, 51.7, 69.1, 72.0, 109.2, 171.0. IR (thin film, cm1): 2966, 1738, 1230.

(S)-1-(2,2-dimethyl-1,3-dioxolan-4-yl)propan-2-one (4). To a slurry of (S)-methyl 2-(2,2-

dimethyl-1,3-dioxolan-4-yl)acetate (17) (90.0 g, 516.7 mmol) and CH3(OCH3)NH.HCl (57.6 g,

593.8 mmol) in anhydrous THF (1.0 L) at 10 °C was slowly added a solution of CH3MgCl (3.0

M in THF) (689.0 mL, 2.06 mol) over 1 h. After 1 h at 5 °C, the reaction mixture was warmed

to 25 °C over 1 h, aged for 8 h then quenched into 1 M HCl (pH = 7.0). The layers were

separated, and the THF solution was concentrated to 100 mL. The crude mixture was extracted

with ethyl acetate (3 x 400 mL) and washed with brine (300 mL), and the residue was subjected

to distillation under reduced pressure (bp 68-69 °C/7 mmHg). The product (S)-1-(2,2-dimethyl-

1,3-dioxolan-4-yl)propan-2-one (4) was obtained as a light yellow liquid in 92% yield (75.2 g,

475.3 mmol). 1H NMR (250 MHz, CDCl3) δ 1.34 (s, 3H), 1.40 (s, 3H), 2.19 (s, 3H), 2.60 (dd, J

= 17.5 Hz, 7.0 Hz, 1H), 2.89 (dd, J = 17.5 Hz, 6.0 Hz, 1H), 3.53 (dd, J = 7.5 Hz, 6.7 Hz, 1H); 4

17 (dd, J = 7.5 Hz, 6.7 Hz, 1H), 4.45 (quint, J = 6.7 Hz, 1H). 13C NMR (62.5 MHz, CDCl3) δ

25.3, 26.8, 30.5, 47.7, 69.3, 71.6, 108.7, 206.2. IR (thin film, cm1): 2960, 1732, 1235.

10

5. Appendix – Copies of 1H and 13C NMR data

1H NMR spectrum of 4-methyl-3-oxo-N-phenylpentanamide (10) in DMSO-d6 at 250 MHz

11 10 9 8 7 6 5 4 3 2 1 ppm

1.111

2.353

2.381

2.408

2.486

2.493

2.500

2.507

2.515

2.680

2.695

2.707

2.722

2.750

2.778

2.805

3.416

3.576

3.614

3.669

4.750

5.218

7.013

7.018

7.023

7.048

7.072

7.077

7.081

7.270

7.277

7.304

7.326

7.334

7.556

7.560

7.582

7.590

7.595

9.966

10.071

6.1

0

1.0

0

2.0

9

1.1

4

2.3

5

2.2

2

0.9

4Current Data Parameters

NAME out28asvH1EXPNO 1

PROCNO 1

F2 - Acquisition ParametersDate_ 20091028

Time 12.57INSTRUM spect

PROBHD 5 mm QNP 1H/13PULPROG zg30

TD 32768

SOLVENT DMSONS 16

DS 0

SWH 5175.983 Hz

FIDRES 0.157958 HzAQ 3.1653888 sec

RG 228.1DW 96.600 usec

DE 6.00 usecTE 300.0 K

D1 1.00000000 secTD0 1

======== CHANNEL f1 ========NUC1 1H

P1 13.00 usecPL1 -6.00 dB

SFO1 250.1315447 MHz

F2 - Processing parametersSI 32768

SF 250.1299986 MHz

WDW EM

SSB 0

LB 0.30 HzGB 0

PC 1.00

13C NMR spectrum of 4-methyl-3-oxo-N-phenylpentanamide (10) in DMSO-d6 at 62.5 MHz

200 180 160 140 120 100 80 60 40 20 0 ppm

18.18

20.01

33.58

38.89

39.22

39.55

39.89

40.22

40.55

40.74

40.89

49.92

119.46

123.81

129.18

139.36

165.64

208.77

Current Data Parameters

NAME out29asvC

EXPNO 1PROCNO 1

F2 - Acquisition Parameters

Date_ 20091029Time 19.25

INSTRUM spectPROBHD 5 mm QNP 1H/13

PULPROG zgpg30

TD 16384SOLVENT DMSO

NS 67DS 0

SWH 15060.241 HzFIDRES 0.919204 Hz

AQ 0.5439488 secRG 406.4

DW 33.200 usecDE 6.00 usec

TE 300.0 K

D1 2.00000000 secd11 0.03000000 sec

DELTA 1.89999998 secTD0 1

SFO1 62.9015280 MHzNUC1 13C

P1 10.00 usecPLW1 -1.00000000 W

SFO2 250.1310005 MHzNUC2 1H

CPDPRG[2 waltz16

PCPD2 100.00 usecPLW2 -1.00000000 W

PLW12 -1.00000000 WPLW13 -1.00000000 W

F2 - Processing parameters

SI 32768

SF 62.8952390 MHz

WDW EM

SSB 0

LB 1.00 Hz

GB 0

PC 1.40

O

N

O

H3C

CH3 H

OH

N

O

H3C

CH3 H

10

O

N

O

H3C

CH3 H

OH

N

O

H3C

CH3 H

10

11

1H NMR spectrum of (Z)-2-benzylidene-4-methyl-3-oxo-N-phenylpentanamide (11) in acetone-

d6 at 250 MHz

11 10 9 8 7 6 5 4 3 2 1 ppm

1.129

1.156

2.032

2.041

2.050

2.059

2.068

2.901

3.337

3.364

3.391

3.418

3.445

7.080

7.084

7.089

7.107

7.114

7.120

7.139

7.144

7.148

7.296

7.304

7.311

7.337

7.359

7.367

7.376

7.385

7.418

7.665

7.666

7.672

7.696

7.705

7.710

9.616

6.1

2

1.1

4

1.0

2

1.0

6

5.1

3

5.0

0

0.7

0


NAME nov11asvH

EXPNO 1PROCNO 1


Date_ 20091111Time 12.30


PULPROG zg30TD 32768

SOLVENT CD3CN

NS 16

DS 0

SWH 5175.983 HzFIDRES 0.157958 Hz

AQ 3.1653888 secRG 512


TE 300.0 KD1 1.00000000 sec

TD0 1

======== CHANNEL f1 ========

NUC1 1H

P1 13.00 usec

PL1 -6.00 dBSFO1 250.1315447 MHz


SI 32768SF 250.1299715 MHz

WDW EMSSB 0

LB 0.30 HzGB 0

PC 1.00

13C NMR spectrum of (Z)-2-benzylidene-4-methyl-3-oxo-N-phenylpentanamide (11) in acetone-

d6 at 62.5 MHz

200 180 160 140 120 100 80 60 40 20 0 ppm

18.37

19.41

28.87

29.18

29.49

29.80

30.10

30.41

30.72

36.34

120.40

120.49

120.76

124.83

129.54

129.58

130.12

130.67

130.74

131.08

134.56

137.74

139.45

139.79

166.84

202.07

206.25

Current Data ParametersNAME nov12asvC

EXPNO 1PROCNO 1


Date_ 20091112Time 18.48


PULPROG zgpg30

TD 16384

SOLVENT Acetone

NS 226DS 0

SWH 15060.241 HzFIDRES 0.919204 Hz

AQ 0.5439488 sec

RG 456.1DW 33.200 usec


D1 2.00000000 secd11 0.03000000 sec

DELTA 1.89999998 sec

TD0 1SFO1 62.9015280 MHz

NUC1 13CP1 10.00 usec

PLW1 -1.00000000 WSFO2 250.1310005 MHz

NUC2 1HCPDPRG[2 waltz16

PCPD2 100.00 usec

PLW2 -1.00000000 WPLW12 -1.00000000 W

PLW13 -1.00000000 W


SF 62.8951897 MHz

WDW EM

SSB 0

LB 1.00 Hz

GB 0

PC 1.40

O

CH3

H3CN

O

H

11

O

CH3

H3CN

O

H

11

12

1H NMR spectrum of 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-N-

phenylpentanamide (12) in CDCl3 at 250 MHz

10 9 8 7 6 5 4 3 2 1 ppm

0.000

1.116

1.143

1.195

1.222

2.949

2.976

3.004

3.031

4.622

4.665

5.397

5.441

6.965

6.999

7.025

7.034

7.052

7.086

7.118

7.124

7.169

7.177

7.198

7.233

7.251

7.257

7.305

7.311

7.335

7.343

7.618

7.957

7.965

7.986

7.992

6.3

1

1.0

2

1.0

0

1.0

1

13.1

5

1.0

1

2.0

8

Current Data ParametersNAME jul08asvH1

EXPNO 1

PROCNO 1




TD 32768SOLVENT CDCl3

NS 16DS 0

SWH 5175.983 Hz

FIDRES 0.157958 HzAQ 3.1653888 sec

RG 256DW 96.600 usec


D1 1.00000000 sec

TD0 1

======== CHANNEL f1 ========

NUC1 1H

P1 13.00 usecPL1 -6.00 dB

SFO1 250.1315447 MHz


SI 32768SF 250.1300024 MHz

WDW EMSSB 0

LB 0.30 HzGB 0

PC 1.00

13C NMR spectrum of 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-N-

phenylpentanamide (12) in CDCl3 at 62.5 MHz

200 180 160 140 120 100 80 60 40 20 ppm

18.12

18.65

40.93

54.16

64.12

76.55

77.06

77.56

115.48

115.83

120.64

124.97

128.09

128.56

128.84

129.42

131.59

131.74

132.18

132.22

135.28

136.78

163.61

165.58

167.67

196.45

209.61


NAME jul12asvC1EXPNO 1

PROCNO 1



PROBHD 5 mm QNP 1H/13PULPROG zgpg30

TD 16384

SOLVENT CDCl3NS 782

DS 0SWH 15060.241 Hz

FIDRES 0.919204 HzAQ 0.5439488 sec

RG 456.1DW 33.200 usec


D1 2.00000000 sec

d11 0.03000000 secDELTA 1.89999998 sec

TD0 1SFO1 62.9015280 MHz


PLW1 -1.00000000 WSFO2 250.1310005 MHz


PCPD2 100.00 usec

PLW2 -1.00000000 WPLW12 -1.00000000 W

PLW13 -1.00000000 W


SI 32768

SF 62.8952425 MHz

WDW EM

SSB 0

LB 1.00 Hz

GB 0

PC 1.40

O

H3C

H3C

Ph

O

F

NHO

12

O

H3C

H3C

Ph

O

F

NHO

12

13

1H NMR spectrum of [5-(4-fluorophenyl)-1-(3-hydroxypropyl]-2-isopropyl-N,4-diphenyl-1H-

pyrrole-3-carboxamide (13) in CDCl3 at 500 MHz.

10 9 8 7 6 5 4 3 2 1 ppm

-0.000

1.528

1.542

1.741

1.753

1.765

1.772

1.784

1.796

3.479

3.491

3.503

3.524

3.538

3.552

3.567

3.581

3.982

3.998

4.014

6.875

6.964

6.971

6.978

6.988

7.005

7.049

7.064

7.141

7.157

7.168

7.173

7.178

7.185

7.195

7.252

0.9

0

6.4

8

2.3

2

3.1

7

2.0

5

1.1

3

3.2

2

2.1

1

10.0

0

Current Data ParametersNAME jun24lcdH2

EXPNO 1PROCNO 1


Date_ 20140624Time 15.11

INSTRUM spectPROBHD 5 mm PABBO BB/

PULPROG zg30


NS 16DS 2

SWH 10000.000 HzFIDRES 0.305176 Hz

AQ 1.6384000 secRG 57


TE 298.2 KD1 1.00000000 sec

TD0 1

======== CHANNEL f1 ========

SFO1 499.8730869 MHz

NUC1 1H

P1 11.75 usecPLW1 25.00000000 W


SI 65536SF 499.8700208 MHz

WDW EMSSB 0

LB 0.30 Hz

GB 0PC 1.00

13C NMR spectrum of [5-(4-fluorophenyl) -1-(3-hydroxypropyl]-2-isopropyl-N,4-diphenyl-1H-

pyrrole-3-carboxamide (13) in CDCl3 at 125 MHz

200 180 160 140 120 100 80 60 40 20 ppm

-0.05

21.68

26.14

34.26

41.69

59.78

76.74

77.00

77.25

115.32

115.49

119.59

121.81

123.53

126.55

128.22

128.24

128.31

128.63

128.78

130.43

133.08

133.15

134.55

138.28

141.43

161.22

163.19

164.81


NAME jun24lcdH2EXPNO 2

PROCNO 1


Time 15.37


PULPROG zgpg30TD 32768

SOLVENT CDCl3NS 640

DS 4SWH 29761.904 Hz

FIDRES 0.908261 HzAQ 0.5505024 sec

RG 2050DW 16.800 usec

DE 6.50 usec

TE 298.2 KD1 2.00000000 sec

D11 0.03000000 secTD0 1

======== CHANNEL f1 ========

SFO1 125.7049801 MHz

NUC1 13C

P1 10.00 usecPLW1 91.00000000 W

======== CHANNEL f2 ========SFO2 499.8719995 MHz


PCPD2 80.00 usecPLW2 26.85300064 W

PLW12 0.57928002 W

PLW13 0.37074000 W


SI 32768

SF 125.6924211 MHz

WDW EM

SSB 0

LB 1.00 Hz

GB 0

PC 1.40

N

i-Pr

Ph

F

NO

OH

13

H

N

i-Pr

Ph

F

NO

OH

13

H

14

1H NMR spectrum of 5-(4-fluorophenyl)-2-isopropyl-1-(3-oxopropyl)-N,4-diphenyl-1H-pyrrole-

3-carboxamide (3) in CDCl3 at 500 MHz

10 9 8 7 6 5 4 3 2 1 0 ppm

-0.000

1.504

1.518

2.654

2.670

2.685

2.693

3.585

3.599

3.613

3.627

3.642

4.232

4.248

4.263

6.855

6.984

6.998

7.002

7.019

7.053

7.068

7.140

7.156

7.161

7.166

7.173

7.178

7.183

7.190

7.204

7.217

7.255

9.573

6.0

3

2.3

1

1.1

0

2.3

3

1.2

0

5.7

1

10.2

0

1.0

0


NAME jun24lcdH1EXPNO 1

PROCNO 1


Time 13.37



SOLVENT CDCl3

NS 16

DS 2SWH 10000.000 Hz

FIDRES 0.305176 HzAQ 1.6384000 sec

RG 57


TE 298.2 KD1 1.00000000 sec

TD0 1

======== CHANNEL f1 ========SFO1 499.8730869 MHz

NUC1 1HP1 11.75 usec

PLW1 25.00000000 W


SI 65536SF 499.8700196 MHz

WDW EMSSB 0

LB 0.30 HzGB 0

PC 1.00

13C NMR spectrum of 5-(4-fluorophenyl)-2-isopropyl-1-(3-oxopropyl)-N,4-diphenyl-1H-

pyrrole-3-carboxamide (3) in CDCl3 at 125 MHz.

200 180 160 140 120 100 80 60 40 20 ppm

-0.04

21.67

25.97

37.68

45.21

76.75

77.00

77.26

115.60

115.74

115.77

119.54

122.19

123.59

126.74

127.69

127.72

128.39

128.66

128.79

130.39

132.93

133.00

134.24

138.21

141.29

161.36

163.34

164.46

198.55


NAME jun24lcdH1

EXPNO 2PROCNO 1


Date_ 20140624Time 13.45


PULPROG zgpg30

TD 32768

SOLVENT CDCl3

NS 256DS 4

SWH 29761.904 HzFIDRES 0.908261 Hz

AQ 0.5505024 secRG 2050

DW 16.800 usec

DE 6.50 usec

TE 298.1 K

D1 2.00000000 secD11 0.03000000 sec

TD0 1

======== CHANNEL f1 ========

SFO1 125.7049801 MHzNUC1 13C

P1 10.00 usec

PLW1 91.00000000 W

======== CHANNEL f2 ========SFO2 499.8719995 MHz


PCPD2 80.00 usecPLW2 26.85300064 W

PLW12 0.57928002 WPLW13 0.37074000 W


SI 32768

SF 125.6924203 MHz

WDW EM

SSB 0

LB 1.00 Hz

GB 0

PC 1.40

N

i-Pr

Ph

F

NO

H

H

O

3

N

i-Pr

Ph

F

NO

H

H

O

3

15

1H NMR spectrum of (S)-1-(2,2-dimethyl-1,3-dioxolan-4-yl)propan-2-one (4) in CDCl3 at 250

MHz

10 9 8 7 6 5 4 3 2 1 0 ppm

-0.000

1.347

1.403

2.190

2.555

2.583

2.623

2.651

2.855

2.879

2.922

2.947

3.506

3.533

3.539

3.566

4.145

4.170

4.178

4.203

4.404

4.430

4.456

4.481

4.507

6.1

0

3.1

0

1.0

6

1.0

4

1.0

4

1.0

4

1.0

0

Current Data ParametersNAME set22asvH1

EXPNO 1PROCNO 1


Date_ 20100922




NS 16

DS 0SWH 5175.983 Hz

FIDRES 0.157958 Hz

AQ 3.1653888 sec

RG 161.3


TE 298.2 KD1 1.00000000 sec

TD0 1

======== CHANNEL f1 ========NUC1 1H

P1 13.00 usec

PL1 -6.00 dBSFO1 250.1315447 MHz


SI 32768SF 250.1299849 MHz

WDW EMSSB 0

LB 0.30 HzGB 0

PC 1.00

13C NMR spectrum of (S)-1-(2,2-dimethyl-1,3-dioxolan-4-yl)propan-2-one (4) in CDCl3 at 62.5

MHz

200 180 160 140 120 100 80 60 40 20 0 ppm

25.33

26.75

30.46

47.70

69.25

71.56

76.49

77.00

77.51

108.71

206.22

Current Data ParametersNAME set22asvC1

EXPNO 1PROCNO 1


Date_ 20100922Time 13.03

INSTRUM spect

PROBHD 5 mm QNP 1H/13PULPROG zgpg30


NS 474DS 0

SWH 15060.241 HzFIDRES 0.919204 Hz

AQ 0.5439488 secRG 645.1


TE 298.2 K

D1 2.00000000 secd11 0.03000000 sec

DELTA 1.89999998 secTD0 1

SFO1 62.9015280 MHz

NUC1 13C

P1 10.00 usecPLW1 -1.00000000 W

SFO2 250.1310005 MHz


PCPD2 100.00 usecPLW2 -1.00000000 W

PLW12 -1.00000000 WPLW13 -1.00000000 W


SF 62.8952422 MHz

WDW EM

SSB 0

LB 1.00 Hz

GB 0

PC 1.40

H3C

OO

O

H3CCH3

4

H3C

OO

O

H3CCH3

4

16

1H NMR spectrum of 1-[(R)-6-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-3-hydroxy-5-oxohexyl]-5-

(4-fluorophenyl)-2-isopropyl-N,4-diphenyl-1H-pyrrole-3-carboxamide (5) in C6D6 at 250 MHz

10 9 8 7 6 5 4 3 2 1 ppm

1.334

1.431

1.608

1.783

1.793

1.830

1.844

1.858

1.870

1.928

1.953

1.977

1.994

2.013

2.313

2.340

2.944

3.319

3.347

3.379

3.737

3.764

3.792

3.942

3.967

3.999

4.292

4.318

6.779

6.814

6.848

6.873

6.904

6.933

6.964

6.988

7.018

7.105

7.116

7.137

7.168

7.246

7.292

7.316

7.443

7.474

9.0

4

7.0

2

2.0

6

1.0

0

0.9

3

1.0

1

1.9

2

2.0

6

2.0

1

7.2

4

4.1

6

4.0

6


NAME ago24asvHEXPNO 1

PROCNO 1




TD 32768

SOLVENT C6D6NS 16

DS 0SWH 5175.983 Hz

FIDRES 0.157958 HzAQ 3.1653888 sec

RG 256DW 96.600 usec


D1 1.00000000 sec

TD0 1

======== CHANNEL f1 ========NUC1 1H

P1 13.00 usecPL1 -6.00 dB

SFO1 250.1315447 MHz


SF 250.1300000 MHzWDW no

SSB 0

LB 0 HzGB 0

PC 1.00

13C NMR spectrum of 1-[(R)-6-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-3-hydroxy-5-oxohexyl]-5-


200 180 160 140 120 100 80 60 40 20 0 ppm

21.93

22.15

25.55

26.76

27.04

38.28

41.47

47.24

49.45

64.88

69.32

71.72

109.05

115.57

115.74

116.89

119.42

122.47

123.53

126.75

127.81

127.91

128.00

128.10

128.19

128.29

128.67

128.87

128.91

128.98

133.49

133.56

135.24

139.53

141.81

161.60

163.57

164.72

208.28

Current Data ParametersNAME jun24lcdH3

EXPNO 2PROCNO 1


Date_ 20140624Time 15.59


PULPROG zgpg30

TD 32768

SOLVENT CDCl3

NS 512DS 4

SWH 29761.904 HzFIDRES 0.908261 Hz

AQ 0.5505024 secRG 2050

DW 16.800 usec


D1 2.00000000 secD11 0.03000000 sec

TD0 1

======== CHANNEL f1 ========SFO1 125.7049801 MHz


PLW1 91.00000000 W

======== CHANNEL f2 ========

SFO2 499.8719995 MHzNUC2 1H

CPDPRG[2 waltz16PCPD2 80.00 usec

PLW2 26.85300064 W

PLW12 0.57928002 W

PLW13 0.37074000 W


SI 32768

SF 125.6923843 MHz

WDW EM

SSB 0

LB 1.00 Hz

GB 0

PC 1.40

N

i-Pr

Ph

F

NO

OH OO

O

H3CCH3

5

H

N

i-Pr

Ph

F

NO

OH OO

O

H3CCH3

5

H

17

1H NMR spectrum of 1-[(3R,5R)-6-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-3,5-dihydroxyhexyl]-5-


10 9 8 7 6 5 4 3 2 1 0 ppm

-0.000

0.899

0.927

1.209

1.262

1.282

1.290

1.296

1.299

1.305

1.310

1.314

1.318

1.335

1.771

1.785

3.294

3.310

3.325

3.743

3.755

3.759

3.771

3.936

6.702

6.719

6.736

6.808

6.822

6.837

6.884

6.899

6.922

6.938

6.952

6.954

7.037

7.054

7.066

7.069

7.072

7.079

7.083

7.162

7.224

7.238

7.355

7.371

1.2

2

10.4

5

2.6

1

6.0

0

1.0

7

1.1

1

1.2

1

3.3

1

3.1

4

1.0

6

2.1

3

1.2

4

4.2

7

4.1

0

2.1

2

2.0

0


NAME abr06lcdH1EXPNO 1

PROCNO 1


Time 9.36



SOLVENT C6D6

NS 16

DS 2SWH 10000.000 Hz

FIDRES 0.305176 HzAQ 1.6384000 sec

RG 32


TE 298.1 KD1 1.00000000 sec

TD0 1

======== CHANNEL f1 ========SFO1 499.8730869 MHz

NUC1 1HP1 11.75 usec

PLW1 25.00000000 W


SI 65536SF 499.8700000 MHz

WDW EMSSB 0

LB 0.30 HzGB 0

PC 1.00

13C NMR spectrum of 1-[(3R,5R)-6-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-3,5-dihydroxyhexyl]-

5-(4-fluorophenyl)-2-isopropyl-N,4-diphenyl-1H-pyrrole-3-carboxamide (6) in C6D6 at 125 MHz

200 180 160 140 120 100 80 60 40 20 0 ppm

22.04

22.20

25.68

26.78

26.97

39.98

40.67

41.55

43.05

69.38

69.95

70.21

73.38

109.01

115.57

115.74

116.71

119.57

122.42

123.64

126.70

127.81

127.91

128.00

128.19

128.29

128.65

128.99

130.75

133.54

133.60

135.28

139.40

141.77

161.59

163.56

165.07

Current Data ParametersNAME abr06lcdH1

EXPNO 2PROCNO 1


Date_ 20150406Time 9.38


PULPROG zgpg30

TD 32768SOLVENT C6D6

NS 2048DS 4

SWH 29761.904 HzFIDRES 0.908261 Hz

AQ 0.5505024 secRG 2050

DW 16.800 usec


D1 2.00000000 secD11 0.03000000 sec

TD0 1

======== CHANNEL f1 ========SFO1 125.7049801 MHz

NUC1 13C

P1 10.00 usecPLW1 91.00000000 W

======== CHANNEL f2 ========

SFO2 499.8719995 MHzNUC2 1H


PLW2 26.85300064 WPLW12 0.57928002 W

PLW13 0.37074000 W


SI 32768

SF 125.6923743 MHz

WDW EM

SSB 0

LB 1.00 Hz

GB 0

PC 1.40

N

i-Pr

Ph

F

NO

OH OHO

O

H3CCH3

Ph

H

6

N

i-Pr

Ph

F

NO

OH OHO

O

H3CCH3

Ph

H

6

18

1H-NMR spectrum of 5-(4-fluorophenyl)-2-isopropyl-N,4-diphenyl-1-[(3R,5R,7S)-3,5,7,8-

tetrahydroxyoctyl]-1H-pyrrole-3-carboxamide (2) in MeOD at 500 MHz

10 9 8 7 6 5 4 3 2 1 ppm

1.373

1.405

1.410

1.473

1.484

1.487

1.498

1.501

1.542

3.307

3.310

3.313

3.349

3.372

3.386

3.401

3.454

3.467

3.476

3.483

3.486

3.498

3.508

3.846

3.901

3.909

3.918

3.927

4.875

7.019

7.032

7.046

7.052

7.070

7.087

7.103

7.141

7.156

7.191

7.207

7.223

7.228

7.239

7.245

7.256

7.298

7.314

1.9

7

7.2

2

1.1

6

2.0

0

1.0

4

2.1

1

1.0

5

3.1

2

1.0

6

6.0

8

2.1

4

4.2

7

2.1

7


NAME ago30lcdH3EXPNO 1

PROCNO 1


Date_ 20150830Time 17.17



SOLVENT MeOD

NS 8DS 0

SWH 10302.198 HzFIDRES 0.314398 Hz

AQ 1.5903403 secRG 32


TE 298.1 K

D1 1.00000000 secTD0 1

======== CHANNEL f1 ========

SFO1 499.8730869 MHzNUC1 1H

P1 11.75 usecPLW1 25.00000000 W


SI 65536

SF 499.8700149 MHzWDW EM

SSB 0LB 0.30 Hz

GB 0

PC 1.00

13C NMR spectrum of 5-(4-fluorophenyl)-2-isopropyl-N,4-diphenyl-1-[(3R,5R,7S)-3,5,7,8-

tetrahydroxyoctyl)-1H-pyrrole-3-carboxamide (2) in MeOD at 125 MHz

200 180 160 140 120 100 80 60 40 20 ppm

22.86

22.88

27.64

40.45

41.87

42.30

45.37

48.59

48.76

48.93

49.10

49.27

49.44

49.61

49.95

67.80

68.07

69.03

70.04

116.29

116.47

118.08

121.53

123.29

125.19

126.92

128.93

129.66

130.22

130.25

130.96

134.73

134.80

136.37

139.12

139.83

162.82

164.78

169.52


NAME ago30lcdH3EXPNO 2

PROCNO 1



PROBHD 5 mm PABBO BB/


SOLVENT MeOD

NS 2048

DS 0SWH 32894.738 Hz

FIDRES 1.003868 HzAQ 0.4980736 sec

RG 2050


TE 298.1 KD1 2.00000000 sec

D11 0.03000000 secTD0 1

======== CHANNEL f1 ========

SFO1 125.7062372 MHz


PLW1 91.00000000 W

======== CHANNEL f2 ========SFO2 499.8719995 MHz


PCPD2 80.00 usec

PLW2 26.85300064 WPLW12 0.57928002 W

PLW13 0.37074000 W


SI 32768

SF 125.6922379 MHz

WDW EM

SSB 0

LB 1.00 Hz

GB 0

PC 1.40

N

i-Pr

Ph

F

NO

OH OH

OH

OH

Ph

H

2

N

i-Pr

Ph

F

NO

OH OH

OH

OH

Ph

H

2

19

1H NMR spectrum of 1-[2-((2R,4R)-4,6-dihydroxytetrahydro-2H-pyran-2-yl)ethyl]-5-(4-

fluorophenyl)-2-isopropyl-N,4-diphenyl-1H-pyrrole-3-carboxamide (7) in CDCl3 at 500 MHz

10 9 8 7 6 5 4 3 2 1 ppm

-0.000

1.259

1.377

1.403

1.507

1.512

1.521

1.526

1.540

1.562

1.637

1.650

1.659

1.689

1.718

1.735

1.746

1.859

1.881

1.889

3.515

3.530

3.544

4.082

4.093

4.105

4.115

4.122

4.134

5.180

6.909

6.961

6.968

6.978

6.982

6.995

7.043

7.059

7.078

7.127

7.142

7.147

7.159

7.170

7.183

7.187

7.255

1.0

6

6.0

0

3.1

2

1.7

7

1.2

5

0.2

5

0.8

8

0.2

7

2.2

1

0.6

5

0.2

0

0.7

2

1.0

1

3.1

0

2.1

5

9.0

8

Current Data ParametersNAME set11lcdH1

EXPNO 1PROCNO 1


Date_ 20150911Time 14.21

INSTRUM spect

PROBHD 5 mm PABBO BB/PULPROG zg30


NS 16DS 0

SWH 10302.198 HzFIDRES 0.314398 Hz

AQ 1.5903403 secRG 25.4

DW 48.533 usec


D1 1.00000000 secTD0 1

======== CHANNEL f1 ========

SFO1 499.8730869 MHzNUC1 1H

P1 11.75 usecPLW1 25.00000000 W



SSB 0LB 0.30 Hz

GB 0PC 1.00

13C NMR spectrum of 1-[2-((2R,4R)-4,6-dihydroxytetrahydro-2H-pyran-2-yl)ethyl]-5-(4-

fluorophenyl)-2-isopropyl-N,4-diphenyl-1H-pyrrole-3-carboxamide (7) in CDCl3 at 125 MHz

200 180 160 140 120 100 80 60 40 20 ppm

21.63

21.77

21.88

26.11

26.16

35.04

37.29

37.33

37.39

37.66

39.51

41.11

41.40

60.47

64.58

64.98

67.68

76.75

77.00

77.21

77.26

92.13

92.58

115.24

115.41

119.68

120.15

121.73

121.80

123.65

126.49

128.14

128.16

128.29

128.62

128.70

128.79

129.75

130.34

133.04

133.11

133.17

134.51

138.13

141.28

161.20

163.17

165.08


NAME set11lcdH1

EXPNO 2PROCNO 1


Date_ 20150911Time 14.37


PULPROG zgpg30


NS 1024

DS 0

SWH 32894.738 HzFIDRES 1.003868 Hz

AQ 0.4980736 secRG 2050


TE 298.2 K

D1 2.00000000 secD11 0.03000000 sec

TD0 1

======== CHANNEL f1 ========SFO1 125.7062372 MHz

NUC1 13C

P1 10.00 usec

PLW1 91.00000000 W

======== CHANNEL f2 ========

SFO2 499.8719995 MHzNUC2 1H


PLW2 26.85300064 WPLW12 0.57928002 W

PLW13 0.37074000 W


SI 32768

SF 125.6924244 MHz

WDW EM

SSB 0

LB 1.00 Hz

GB 0

PC 1.40

N

i-Pr

Ph

F

NO

O

OH

OH

Ph

H 7

N

i-Pr

Ph

F

NO

O

OH

OH

Ph

H 7

20

1H NMR spectrum of 5-(4-fluorophenyl)-1-[2-((2R,4R)-4-hydroxy-6-oxo-tetrahydro-2H-pyran-

2-yl)ethyl]-2-isopropyl-N,4-diphenyl-1H-pyrrole-3-carboxamide (8) in CDCl3 at 250 MHz

10 9 8 7 6 5 4 3 2 1 0 ppm

-0.000

1.497

1.511

1.526

1.539

1.587

1.598

1.692

1.748

1.762

1.791

1.815

1.831

1.850

1.869

1.888

2.545

2.564

2.583

2.892

3.499

3.528

3.556

4.014

4.037

4.051

4.075

4.138

4.159

4.178

4.198

4.245

4.481

4.515

4.527

6.910

6.964

6.990

6.998

7.032

7.061

7.115

7.150

7.198

7.207

7.259

6.4

3

4.0

6

2.0

6

0.9

1

1.0

2

3.1

4

1.0

0

6.0

4

9.0

1


NAME nov24asvHEXPNO 1

PROCNO 1


Time 12.16



SOLVENT CDCl3

NS 16

DS 0SWH 5175.983 Hz

FIDRES 0.157958 HzAQ 3.1653888 sec

RG 322.5


TE 298.2 KD1 1.00000000 sec

TD0 1

======== CHANNEL f1 ========

NUC1 1H

P1 13.00 usec

PL1 -6.00 dBSFO1 250.1315447 MHz


SI 32768SF 250.1300001 MHz

WDW EMSSB 0

LB 0.30 HzGB 0

PC 1.00

13C NMR spectrum of 5-(4-fluorophenyl)-1-[2-((2R,4R)-4-hydroxy-6-oxo-tetrahydro-2H-pyran-

2-yl)ethyl]-2-isopropyl-N,4-diphenyl-1H-pyrrole-3-carboxamide (8) in CDCl3 at 62.5 MHz

200 180 160 140 120 100 80 60 40 20 ppm

21.66

21.96

26.10

35.52

37.08

38.40

40.68

62.16

73.07

76.49

77.00

77.51

115.40

115.57

115.74

119.77

122.01

123.77

126.61

127.89

128.34

128.66

128.75

130.30

132.97

133.10

134.33

138.05

141.18

160.32

164.26

165.01

169.75


NAME nov25asvCEXPNO 1

PROCNO 1


Time 8.10



SOLVENT CDCl3NS 1024

DS 0SWH 15060.241 Hz

FIDRES 0.919204 HzAQ 0.5439488 sec

RG 724.1DW 33.200 usec


D1 2.00000000 sec

d11 0.03000000 sec

DELTA 1.89999998 sec

TD0 1SFO1 62.9015280 MHz


PLW1 -1.00000000 WSFO2 250.1310005 MHz


PCPD2 100.00 usecPLW2 -1.00000000 W

PLW12 -1.00000000 W

PLW13 -1.00000000 W


SI 32768

SF 62.8952416 MHz

WDW EM

SSB 0

LB 1.00 Hz

GB 0

PC 1.40

N

i-Pr

Ph

F

NO

O

OH

O

Ph

H

8

N

i-Pr

Ph

F

NO

O

OH

O

Ph

H

8

21

1H NMR spectrum of Calcium Atorvastatin (1) in DMSO-d6 at 500 MHz

10 9 8 7 6 5 4 3 2 1 ppm

1.226

1.236

1.253

1.361

1.375

1.405

1.419

1.518

1.540

1.621

1.720

1.940

1.956

1.970

1.986

2.082

2.106

2.113

2.497

2.500

2.503

3.172

3.218

3.232

3.246

3.362

3.541

3.778

3.787

3.953

6.963

6.978

6.986

6.994

7.003

7.012

7.067

7.076

7.163

7.180

7.198

7.214

7.231

7.242

7.260

7.508

7.524

9.804

1.2

2

7.0

2

2.1

1

1.1

1

1.0

7

1.1

3

2.0

2

1.1

7

2.1

4

1.1

1

2.2

0

4.0

0

6.5

4

2.0

4

1.0

1

Current Data ParametersNAME ago30lcdH2

EXPNO 1

PROCNO 1



PROBHD 5 mm PABBO BB/PULPROG zg30

TD 32768SOLVENT DMSO

NS 4

DS 0SWH 10302.198 Hz

FIDRES 0.314398 HzAQ 1.5903403 sec

RG 80.6DW 48.533 usec


D1 1.00000000 secTD0 1

======== CHANNEL f1 ========SFO1 499.8730869 MHz

NUC1 1H

P1 11.75 usec

PLW1 25.00000000 W



SSB 0

LB 0.30 HzGB 0

PC 1.00

13C NMR spectrum of Calcium Atorvastatin (1) in DMSO-d6 at 125 MHz

200 180 160 140 120 100 80 60 40 20 ppm

22.29

22.30

25.65

39.00

39.17

39.34

39.50

39.59

39.67

39.76

39.84

39.93

40.00

40.09

40.87

43.62

43.93

66.27

115.29

115.45

117.48

119.40

120.56

122.96

125.34

127.29

127.62

128.42

128.71

128.73

129.14

133.34

133.40

134.91

135.94

139.45

160.60

162.55

166.17

178.17


NAME ago30lcdH2

EXPNO 2PROCNO 1


Date_ 20150830Time 17.14


PULPROG zgpg30

TD 32768

SOLVENT DMSO

NS 2048DS 0

SWH 32894.738 HzFIDRES 1.003868 Hz

AQ 0.4980736 secRG 2050

DW 15.200 usec

DE 6.50 usec

TE 298.2 K

D1 2.00000000 secD11 0.03000000 sec

TD0 1

======== CHANNEL f1 ========

SFO1 125.7062372 MHzNUC1 13C

P1 10.00 usecPLW1 91.00000000 W

======== CHANNEL f2 ========

SFO2 499.8719995 MHz


PCPD2 80.00 usec

PLW2 26.85300064 W

PLW12 0.57928002 WPLW13 0.37074000 W


SI 32768

SF 125.6924729 MHz

WDW EM

SSB 0

LB 1.00 Hz

GB 0

PC 1.40

22

Amorphous Calcium Atorvastatin (1) XR Diffractogram

Measurement Condition

X-ray tube

target = Cu

voltage = 40.0 (kV)

current = 20.0 (mA)

Slits

divergence slit = 1.00000 (deg)

scatter slit = 1.00000 (deg)

receiving slit = 0.30000 (mm)

Scanning

drive axis = Theta-2Theta

scan range = 2.000 - 37.000

scan mode = Continuous Scan

scan speed = 2.0000 (deg/min)

sampling pitch = 0.0200 (deg)

preset time = 0.60 (sec)

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36

0

500

1000

1500

2000

2500

CP

S

O

23

24

25

26

27

Documents

SUPORTING INFORMATION SECTION · 1 SUPORTING INFORMATION SECTION The Total Synthesis of Calcium Atorvastatin Luiz C. Dias a, Adriano S. Vieira and Eliezer J. Barreirob aInstituto