1. Procedure
2. Notes
1.
The following reagents and solvents in Step A were used as received: (
Sa)-(–)-1,1'-binaphthyl-2,2'
-diamine (Sigma-Aldrich, 99%),
dichloromethane (Fisher, ACS reagent, 99.5%),
EtOAc (Fisher, ACS reagent, 99%),
pyridine (Sigma-Aldrich, 99%), and
p-TsCl (Acros, 99%).
2.
The internal temperature was monitored using a J-Kem Gemini digital thermometer with a Teflon-coated T-Type thermocouple probe (12-inch length, 1/8 inch outer diameter, temperature range -200 to +250 °C).
There was no exotherm on addition of
p-TsCl.
3.
The reaction was monitored by thin layer chromatography on silica gel (EMD, silica gel, grade 60, F
254) with 1:1 EtOAc:hexanes as the eluent and visualization with UV.
The diamine starting material has R
f = 0.5 (blue fluorescence) and the tosyl product has R
f = 0.6.
The bis-tosyl by-product co-elutes with the mono-tosylate product.
The mono- and bis-tosyl products can be separated by TLC by using an eluent of 1:6 EtOAc:hexanes and 3 elutions (bis-Ts, R
f = 0.45; mono-Ts, R
f = 0.40).
4.
The acid wash removes unreacted (
Sa)-(–)-1,1'-binaphthyl-2,2'-diamine, which can be recovered as follows.
The combined acidic washes are neutralized with 2.5N NaOH until pH 8-10 and then are extracted with
dichloromethane (3 × 30 mL).
The combined organic layers are washed with brine, dried over sodium sulfate and concentrated by rotary evaporation (40 °C, 20 mmHg) to give 0.30 g (10%) of (
Sa)-Binam.
5.
The mono-tosylate
1 is approximately 82% pure (80% yield), containing 7 wt% EtOAc and 11 wt% of the bis-tosylate by-product as determined by
1H NMR analysis of the Ts methyl groups of the mono- and bis-tosylated species:
1H NMR (400 MHz, CDCl
3); mono-tosylate
1: δ: 2.32; bis-tosylate: δ: 2.40.
This bis-tosylate by-product is difficult to separate by standard column chromatography due to overlap of the peaks using a more polar eluent and tailing of the early eluting bis-tosylate into the mono-tosylate peak using a less polar eluent.
The submitters reported preparation of a purified sample by column chromatography on silica gel eluting with hexane/EtOAc, 6:1, following a literature report.
4 The checker purified a 100 mg crude sample by reverse-phase preparative HPLC using the following conditions: column, YMC-pack ODS-AQ, 5um, 150×20 mm I.D; mobile phase, linear gradient elution: 25% MeCN/75% water to 55% MeCN/45% water over 15 min; flow rate, 25mL/min; sample dissolved in MeCN at 10mg/mL;1 mL per injection.
Fractions eluting between 7-9 min were concentrated by rotary evaporation to remove the organic phase (bath temperature 35 °C, 10 mmHg).
The remaining aqueous layer was lyophilized, affording 24 mg of mono-tosylate
1.
6.
Mono-tosylate
1 has the following spectroscopic properties:
1H NMR
pdf(400 MHz, CDCl
3) δ: 2.32 (s, 3 H, CH
3), 3.29 (br s, 2 H, NH
2), 6.42 (d,
J = 8.4 Hz, 1 H), 6.67 (s, 1 H, NH), 6.94-7.09 (m, 5 H), 7.20-7.25 (m, 2 H), 7.37-7.43 (m, 3 H), 7.78 (d,
J = 8.0 Hz, 1 H), 7.84 (t,
J = 8.7 Hz, 1 H), 7.87 (d,
J = 8.0 Hz, 1 H), 7.96 (d,
J = 9.0 Hz, 1 H), 8.13 (d,
J = 9.0 Hz, 1 H);
13C NMR
pdf(100 MHz, CDCl
3) δ: 21.7, 109.9, 118.2, 119.7, 121.8, 122.7, 123.6, 125.6, 125.9, 127.35, 127.37, 127.5, 128.37, 128.39, 129.7, 129.9, 130.9, 131.5, 133.0, 133.8, 133.9, 136.5, 142.9, 143.8; LC-MS calcd for [M + H]
+ 439.5; found, 439.2.
7.
The following reagents and solvents in Step B were purchased from Sigma-Aldrich and used as received:
N-(
t-butoxycarbonyl)-
L-proline (>99%),
triethylamine (99.5%), THF (ACS reagent, >99%, inhibited with 250 ppm BHT), and
ethyl chloroformate (97%).
8.
Addition of ethyl chloroformate results in a slight exotherm from 3 °C to 5 °C.
9.
The progress of the reaction can be monitored by TLC (EMD, silica gel, grade 60, F
254) with 1:1 EtOAc:hexanes and visualization with UV (starting material
1 has R
f = 0.45 and the Boc-proline product
2 has R
f = 0.3); however, the end of reaction cannot be determined by TLC since the unreactive bis-tosylate carried forward from step A co-elutes with the mono-tosylate.
NMR of the crude reaction mixture is uninformative due to broad peaks caused by Boc rotamers.
Therefore, the end of reaction was assessed by deprotecting the Boc group and determining the amount of mono-tosylate that remained unreacted by
1H NMR.
A ~20 mg aliquot of the reaction mixture was evaporated then dissolved in 0.5 mL of CDCl
3 followed by addition of 0.2 mL of TFA.
The sample was reacted for 15 min at room temperature then analyzed by
1H NMR.
The Ts-methyl group was diagnostic for assessing reaction completion: bis-tosylate, d 2.42; product
3, d 2.45; mono-Ts
1, d 2.52.
10.
Given the broad peaks in the
1H NMR spectrum
(Note 12) the purity of the crude material from step B could not be estimated by NMR.
The rough purity and yield estimates are based on the 65% recovery of material when subjected to flash chromatography in a separate experiment
(Note 11).
11.
Compound
2 (2.33 g crude weight) can be purified by column chromatography using 85 g silica gel (Fisher, 230-400 mesh, 60 Å) packed as a slurry with 2:1 hexanes: EtOAc, and eluted with 2:1 hexanes: EtOAc (600 mL), 1:1 hexanes:EtOAc (200 mL), and 1:2 hexanes: EtOAc (200 mL), taking 40 mL fractions.
The desired product is obtained in fractions 16-23, (R
f = 0.3, 1:1 hexanes:EtOAc), which are combined and concentrated by rotary evaporation (40 °C, 20 mmHg) to give, after vacuum drying at room temperature to constant weight, 1.68 g of
2 (~90% purity, 65% recovery) as a pink foam.
12.
At ambient temperature compound
2 is a mixture of 2 rotamers that cause broad peaks in the
1H NMR and
13C NMR spectra.
The following NMR data were collected at 360 K where the rotamers had partially coalesced.
1H NMR
pdf(600 MHz, 360 K, DMSO-d
6) δ: 0.76 (br s, 1 H), 1.06 (br s, 1 H), 1.32 (s, 9 H, C(CH
3)
3], 1.39 (br s, 1 H), 1.67-1.73 (m, 1 H), 2.38 (s, 3 H, CH
3), 2.74 (br s, 1 H), 3.08 (app q,
J = 8.3 Hz, 1 H), 4.00 (dd,
J = 8.9, 3.0, 1 H), 6.70 (d,
J = 8.5 Hz, 1 H,), 6.88 (d,
J = 8.5 Hz, 1 H), 7.13-7.16 (m, 1 H), 7.20-7.25 (m, 3 H), 7.37 (d,
J = 9.0 Hz, 1 H), 7.43-7.46 (m, 2 H), 7.48 (d,
J = 8.3 Hz, 2 H), 7.88 (br d,
J = 8.6 Hz, 1 H), 7.94 (d,
J = 8.2 Hz, 1 H), 7.96-7.99 (m, 2 H), 8.08 (d,
J = 8.8 Hz, 1 H), 8.52 (br s, 1 H, NH), 8.78 (br s, 1 H, NH).
13C NMR
pdf(150 MHz, 360K, DMSO-d
6) δ: 20.4, 22.1, 27.6, 29.4, 45.8, 60.0, 78.5, 122.4, 123.7, 124.5, 124.7, 124.8, 125.3, 125.93, 125.95, 126.3, 127.4, 127.5, 128.3, 128.7, 128.9, 130.9, 131.0, 131.9, 132.1, 133.3, 134,5, 137.7, 142.5, 153 (br), 171.2.
13.
The following reagents and solvents in Step C were used as received:
trifluoroacetic acid (Sigma-Aldrich, >99%),
dichloromethane (Fisher, ACS reagent, 99.5%), silica gel (Fisher, 230-400 mesh, 60 Å), EtOAc (Fisher, ACS reagent, 99%), and
hexanes (Fisher, ACS reagent, >98.5%).
14.
During the TFA addition, the temperature decreases from 22 °C to 19 °C.
15.
Reaction progress can be monitored by TLC using 2:1 EtOAc:hexanes as eluent and visualized by UV.
An aliquot of the reaction mixture is quenched into a mixture of 0.5 mL of 2N NaOH and 0.5 mL of dichloromethane with the bottom organic layer sampled for TLC.
R
f product
3, 0.3; R
f starting material,
2, 0.8; R
f bis-tosylate, 0.9.
16.
Addition of NaOH is exothermic and should be added at a rate to keep the internal temperature below 35 °C to prevent boiling of dichloromethane.
17.
At the end of the NaOH addition, the pH is checked by pH paper and should be 8-10.
If below 8, additional NaOH is added.
18.
The organic layer is hazy due to the retention of a second phase water that is not completely removed upon drying with sodium sulfate.
19.
A 6-cm diameter glass column is slurry-packed (2:1 EtOAc:hexanes) with
silica gel (200 g).
Crude product
3 co-mixed with silica is slurried in 2:1 EtOAc:hexanes and added to the top of the column.
The column is topped with 0.5 cm of sand, then eluted with 2:1
EtOAc:hexanes (500 mL), 3:1 EtOAc:hexanes (500 mL), and EtOAc (1 L), taking 100 mL fractions.
The chromatography is monitored by TLC (EtOAc, R
f 0.5).
The product elutes in fractions 9-15, which are combined and concentrated by rotary evaporation (40 °C water bath, 20 mmHg) in a 1-L flask, then transferred to a 250-mL round-bottomed flask for the final concentration.
The white solid is dried under vacuum (20 mmHg) at room temperature for 28 h to constant weight (3.9 - 4.1 g).
20.
(
Sa,
S)-
N-[2´-(4-Methylphenylsulfonamido)-1,1´-binaphthyl-2-yl-pyrrolidine-2-carboxamide (
3) exhibits the following physical and spectroscopic properties: R
f 0.5 (EtOAc); [α]
D25 -95 (
c 1.0, CHCl
3); mp 196-197 °C, Lit
7d 191-192 °C;
1H NMR
pdf(400 MHz, CDCl
3) δ: 0.64-0.73 (m, 1 H), 1.15-1.28 (m, 2 H), 1.57-1.64 (m, 1 H), 1.74-1.84 (m, 1 H), 2.20-2.26 (m, 1 H), 2.35 (s, 3 H), 3.32 (dd,
J = 4.0, 9.5 Hz, 1 H), 6.35 (br s, 1 H), 6.86 (d,
J = 8.4 Hz, 1 H), 6.94 (d,
J = 8.5 Hz, 1 H), 7.12 (d,
J = 8.1, 2 H), 7.16-7.22 (m, 2 H), 7.37-7.46 (m, 4 H), 7.87 (d,
J = 7.9 Hz, 1 H), 7.95 (d,
J = 8.2 Hz, 1 H), 8.00 (d,
J = 9.1 Hz, 1 H), 8.06 (d,
J = 9.0, 1 H), 8.19 (d,
J = 9.0 Hz, 1 H), 8.82 (d,
J = 9.0 Hz, 1 H), 9.31 (br s, 1 H);
13C NMR
pdf(100 MHz, CDCl
3) δ: 21.7, 25.4, 30.7, 46.3, 60.7, 117.0, 119.4, 119.6, 120.8, 124.3, 125.3, 125.4, 125.8, 127.6, 127.8, 128.3, 128.8, 129.7, 130.3, 130.7, 130.9, 131.4, 132.3, 132.7, 133.9, 135.9. 136.7, 144.1, 173.5; Anal.
calcd.
for C
32H
29N
3O
3S: C, 71.75; H, 5.46; N, 7.84; Found: C, 71.41; H, 5.15; N, 7.73.
21.
The checkers determined the enantiomeric purity by SFC using a Lux-4 column (150 x 4.6mm, 5um particle size); isocratic elution, 40% MeOH with 25 mM
i-butylamine/60% CO
2; 3.0 mL/min flow; detection at 210 nm; 200 bar pressure; t
r (
S,S)= 4.5 min; t
r (
R,R)= 5.5 min; none of the enantiomer was detectable (ee >99%).
The submitters determined enantiomeric purity by HPLC analysis at 254 nm using a Chiralpak AD-H column; isocratic elution, 80:20 hexanes:
i-PrOH; 1mL/min: t
r (
R,R)= 51 min, t
r (
S,S)= 105 min.
The (
R,R)-enantiomer was prepared by the same procedure using (
Ra)-(–)-1,1'-binaphthyl-2,2'-diamine and Boc-
D-proline and exhibited the following physical properties: mp 195-197 °C; [α]
D25 +93 (
c 1.0, CHCl
3).
22.
The diastereomeric purity (de) was determined to be >99% by
1H NMR analysis in comparison to the (
Sa,
R)-diastereomer, which was prepared via the same procedure except that Boc-
D-proline was used instead of Boc-
L-proline.
One aromatic proton in the (
Sa,
R)-diastereomer is upfield (6.54 ppm doublet) relative to the (
Sa,
S)-diastereomer (6.86 ppm doublet).
The 6.54 ppm doublet was undetectible (<0.5%) in the (
Sa,
S)-diastereomer.
The diastereomer (
Sa,
R)-
N-[2´-(4-methylphenylsulfonamido)-1,1´-binaphthyl-2-yl-pyrrolidine-2-carboxamide exhibits the following physical and spectroscopic properties: mp 134-137 °C, Lit
7d 152-155 °C; [α]
D25 + 6 (
c 1.0, CHCl
3);
1H NMR
pdf(400 MHz, CDCl
3) δ: 1.50-1.55 (m, 2 H), 1.86-2.00 (m, 2 H), 2.30-2.34 (m, 1 H), 2.34 (s, 3 H), 2.57-2.62 (m, 1 H), 3.51 (dd,
J = 4.5, 9.5 Hz, 1 H), 6.54 (d,
J = 8.4 Hz, 1 H), 6.91 (d,
J = 8.5 Hz, 1 H), 6.98 (dt,
J = 1.1, 7.7 Hz, 1 H), 7.01 (d,
J = 8.0 Hz, 2 H), 7.20-7.23 (m, 1 H), 7.34-7.41 (m, 4 H), 7.89 (dd,
J = 8.3, 11.0 Hz, 2 H), 7.99 (d,
J = 9.0 Hz, 1 H), 8.06 (d,
J = 9.0 Hz, 1 H), 8.15 (d,
J = 9.0 Hz, 1 H), 8.80 (d,
J = 9.0 Hz, 1 H), 9.65 (br s, 1 H, NH);
13C NMR
pdf(100 MHz, CDCl
3) δ: 21.7, 26.1, 30.9, 47.0, 61.0, 117.6, 118.9, 120.0, 120.3, 124.7, 124.9, 125.6, 127.2, 127.3, 127.6, 128.3, 128.5, 129.8, 130.2, 130.7, 130.9, 131.2, 132.5, 132.9, 134.0, 135.8, 136.4, 144.0, 174.1.
Safety and Waste Disposal Information
All hazardous materials should be handled and disposed of in accordance with "Prudent Practices in the Laboratory"; National Academy Press; Washington, DC, 1995.
3. Discussion
1) Minimal purification steps: only the final product needs to be purified by chromatography.
2) The amide bond formation is efficiently accomplished using ethyl chloroformate, which avoids the use of SOCl2 to form the acid chloride or the need for expensive coupling agents that, moreover, are difficult to remove at the end of the reaction.
This preparation can be also applied to obtain the enantiomer of the desired product, (Ra,R)-N-[2´-(4-methylphenylsulfonamido)-1,1´-binaphthyl-2-yl]pyrrolidine-2-carboxamide, as well as the (Ra,S)- and (Sa,R)-diastereomers.
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