Organic Syntheses, Vol. 76, 57
Checked by Evan G. Antoulinakis and Robert K. Boeckman, Jr..
1. Procedure
B. Pseudoephedrine L-allylglycinamide. A
1-L, single-necked, round-bottomed flask is equipped with a Teflon-coated magnetic stirring bar and a rubber septum through which is placed a needle connected to a source of vacuum and
argon. The system is evacuated, the flask is flame-dried and then allowed to cool to 23°C under reduced pressure. When the reaction flask has cooled to 23°C, it is flushed with
argon and charged with
200 mL of dry THF (Note
3) and
63.0 mL (0.450 mol, 1.025 equiv) of diisopropylamine (Note
10). The resulting solution is cooled to 0°C in an ice bath. With efficient stirring, the solution is deoxygenated at 0°C by alternately evacuating the reaction vessel and flushing with
argon three times. After the solution is deoxygenated,
167 mL (0.439 mol, 1 equiv) of a 2.63 M solution of butyllithium in hexanes (Note
11) and (Note
12) is added via syringe over a 20-min period. After the addition is complete, the solution is stirred at 0°C for 15 min.
Separately, a
2-L, three-necked, round-bottomed flask is equipped with an inlet adapter connected to a source of vacuum and
argon, two
rubber septa, and a Teflon-coated magnetic stirring bar. The flask is charged with
57.2 g (1.35 mol, 6 equiv) of anhydrous lithium chloride (Note
1) and, with efficient stirring of the solid, the reaction vessel is evacuated and flame-dried. The flask and its contents are allowed to cool to 23°C under reduced pressure. When the flask has cooled to 23°C, it is flushed with
argon,
50.0 g (0.225 mol, 1 equiv) of solid (R,R)-(−)-pseudoephedrine glycinamide is added, and one of the septa is replaced with a Teflon thermometer adapter fitted with a
thermometer for internal measurement of the reaction temperature. The solids are suspended in
500 mL of dry THF (Note
3) and the resulting milky-white slurry is cooled to an internal temperature of 0°C in an ice bath. With efficient stirring, the slurry is deoxygenated by alternately evacuating the reaction vessel and flushing with
argon three times.
The two reaction flasks are connected via a
wide-bore (14 gauge) cannula so that one end of the cannula is immersed in the
lithium diisopropylamide solution and the other is suspended above the
(R,R)-(−)-pseudoephedrine glycinamide-lithium chloride slurry. The flask containing the
lithium diisopropylamide solution and its ice bath are raised to a height just above that of the flask containing the
glycinamide slurry. The reaction flask containing the
glycinamide slurry is very briefly evacuated to initiate siphon transfer of the
lithium diisopropylamide solution. Once the siphon flow is established, the flask containing the
glycinamide slurry is flushed with
argon. By raising or lowering the height of the flask containing the
lithium diisopropylamide solution, the rate of addition is modulated so that the temperature of the reaction mixture does not rise above 5°C (approximately 45 min addition time) (Note
13). After the addition is complete, the reaction mixture is stirred at 0°C for 30 min (Note
14). To the resulting pale yellow suspension is added
19.5 mL (0.225 mol) of allyl bromide (Note
15) via syringe over a 20-min period. The rate of addition of
allyl bromide is also modulated to prevent the internal reaction temperature from rising above 5°C (Note
16). After the addition of
allyl bromide is complete, the reaction mixture is stirred for 45 min at 0°C. The reaction is terminated by the addition of 500 mL of water. The resulting biphasic mixture is slowly acidified by the addition of
300 mL of 3 M aqueous hydrochloric acid solution. The biphasic mixture is transferred to a 2-L separatory funnel and is extracted with
1 L of ethyl acetate. The organic layer is separated and extracted sequentially with
300 mL of 3 M aqueous hydrochloric acid solution and
300 mL of 1 M aqueous hydrochloric acid solution. The aqueous layers are combined and cooled to an internal temperature of 5°C by stirring in an ice bath. The cold aqueous solution is then cautiously made basic (pH 14) by the slow addition of
120 mL of aqueous 50% sodium hydroxide solution. The temperature of the solution should not be allowed to rise above 25°C during the addition of base. The basic solution is extracted sequentially with one
500-mL portion and four 250-mL portions of dichloromethane (Note
17). The combined organic layers are dried over anhydrous
potassium carbonate and filtered, and the filtrate is concentrated under reduced pressure. The oily residue is dissolved in
200 mL of toluene, and the resulting solution is concentrated under reduced pressure to remove residual
dichloromethane and
diisopropylamine. The solid residue is recrystallized by suspending it in
100 mL of toluene and heating the resulting suspension until the solids dissolve (ca. 70°C). The recrystallization mixture is allowed to cool to 23°C. After 3 hr, when crystallization of the product is nearly complete, the recrystallization flask is cooled to 0°C in an ice bath to complete the recrystallization process. After standing at 0°C for 1 hr, the crystals are collected by filtration and rinsed sequentially with two
50-mL portions of cold (0°C) toluene and one
100-mL portion of ether at 23°C. The crystals are dried under reduced pressure (0.5 mm) at 23°C for 2 hr to provide
31.3 g (
53%) of diastereomerically pure
pseudoephedrine L-allylglycinamide (Note
18). The mother liquors are concentrated and the oily residue is dissolved in
50 mL of toluene at 23°C. The resulting solution is cooled to −20°C and seeded with authentic
pseudoephedrine L-allylglycinamide. After standing at −20°C for 6 hr, the crystals that have formed are collected by filtration and rinsed with
25 mL of cold (0°C) toluene and
50 mL of ether at 23°C. The product is dried under reduced pressure (0.5 mm) at 23°C for 2 hr to afford a second crop of the alkylation product. The second crop of crystals (
4.8 g) is recrystallized a second time by suspending it in
20 mL of toluene and warming to ca. 70°C to dissolve the solids (Note
19). The resulting solution is allowed to cool slowly to 23°C, whereupon the product crystallizes within 1 hr. The recrystallization flask is cooled to −20°C to complete the crystallization process. After standing at −20°C for 90 min, the crystals are collected by filtration and washed sequentially with two
10-mL portions of cold (0°C) toluene and one
25-mL portion of ether. The crystals are dried under reduced pressure (0.5 mm) at 23°C for 2 hr to afford
3.6 g (
6%) of diastereomerically pure
pseudoephedrine L-allylglycinamide. To obtain additional product, the mother liquors are concentrated under reduced pressure and the oily residue is purified by chromatography on
silica gel (100 g, 5-cm i.d. column) eluting with
4% methanol,
4% triethylamine and
92% dichloromethane. The oily residue obtained after concentration of the appropriate fractions is dissolved in
25 mL of warm (50°C) toluene. The resulting solution is cooled to −20°C and held at that temperature for 12 hr. The crystals that form are collected by filtration and rinsed with
20 mL of cold (0°C) toluene and
30 mL of ether at 23°C. The crystals are dried under reduced pressure (0.5 mm) at 23°C for 2 hr to provide an additional
5.0 g (
8%, total yield:
39.1-42.0 g,
66-71%) of diastereomerically pure
pseudoephedrine L-allylglycinamide.
2. Notes
1.
Reagent-grade anhydrous lithium chloride (Mallinckrodt Inc.) is further dried by transferring the solid to a flask equipped with a vacuum adapter. The flask is evacuated (0.5 mm) and immersed in an oil bath at 150°C. After 12 hr at 150°C, the flask is allowed to cool to 23°C and is flushed with
argon for storage.
3.
Tetrahydrofuran was obtained from EM Science and was distilled under
nitrogen (atmospheric pressure) from
sodium benzophenone ketyl.
4.
Lithium methoxide was purchased from Aldrich Chemical Company, Inc., and used as received.
Butyllithium (BuLi) (10 M in hexanes) may be substituted for
lithium methoxide in this reaction and produces a more rapid reaction. For example, the use of 0.25 equiv of 10 M BuLi requires only 1-2 hr for complete reaction and affords
65-69% yield of anhydrous
pseudoephedrine glycinamide on a
40-60-g scale.
2 The submitters describe the use of
lithium methoxide as a less hazardous alternative to the highly pyrophoric 10 M BuLi.
5.
Glycine methyl ester is prepared by the method of Almeida et al.
3 In a
mortar and pestle,
80 g of glycine methyl ester hydrochloride (used as received from Aldrich Chemical Company, Inc.) is ground to a fine powder. The powder is suspended in
600 mL of dry ether in a
1-L Erlenmeyer flask equipped with a Teflon-coated magnetic stirring bar. Gaseous
ammonia is bubbled rapidly through the vigorously stirred suspension. After 2 hr, the addition of
ammonia is discontinued, the product slurry is filtered through a
coarse-fritted glass filter, and the filtrate is concentrated under reduced pressure at 23°C. The liquid residue is distilled under reduced pressure (54-55°C at 18 mm) to provide
51.3 g (
90%) of
glycine methyl ester as a colorless liquid.
Glycine methyl ester will polymerize upon storage at room temperature, but may be stored at −20°C for short periods (up to two weeks) without significant decomposition.
6. The monohydrate and anhydrous product show identical spectroscopic properties (Note
9). The monohydrate exhibits the following physical properties: mp
83-85°C; Anal. Calcd for C
12H
18N
2O
2·H
2O, C, 59.93; H, 8.32; N, 11.66; Found C, 59.81; H, 8.42; N, 11.51.
7. Alternatively, azeotropic drying with
acetonitrile may be employed in lieu of
dichloromethane/
potassium carbonate.
2 A solution of
50.3 g of (R,R)-(−)-pseudoephedrine glycinamide monohydrate in ca.
200 mL of acetonitrile is concentrated under reduced pressure. The oily residue is dissolved in
250 mL of toluene and the resulting solution is concentrated under reduced pressure. The oily residue obtained may be carried on directly in the alkylation procedure with only a slight decrease in yield from the procedure described above. Alternatively, anhydrous
(R,R)-(−)-pseudoephedrine glycinamide may be precipitated and the resulting solid dried and carried forward as outlined above.
8. Proper drying of
(R,R)-(−)-pseudoephedrine glycinamide is essential to achieve high yields in the subsequent alkylation step. Complete drying may not be achieved at temperatures below 50°C. To prevent melting of the solid product, it should not be heated above 65°C. A preliminary indication of the hydration state of the product is its melting point. Material that is partially hydrated routinely has a melting point that is depressed relative to that of pure anhydrous product (mp
78-80°C). A more accurate determination of the water content may be obtained either from C,H,N analysis or by Karl Fischer titration. The product is somewhat hygroscopic. It may be weighed on the open benchtop without significant hydration; however, it should be stored under
argon. The glycinamide should be redried at 60°C under reduced pressure (0.5 mm) if it has been stored for an extended period, or if the yield of the subsequent alkylation reaction is lower than expected.
9. The product shows the following physical and spectroscopic properties: mp
78-80°C; [α]23D −101.2° (CH
3OH,
c 1.2); TLC R
f = 0.18 (5% CH
3OH, 5% NEt
3, 90% CH
2Cl
2); IR (neat) cm
−1: 3361, 2981, 1633, 1486, 1454, 1312, 1126, 1049, 926, 760, 703;
1H NMR (1:1 ratio of rotamers, CDCl
3) δ: 0.99 (d, 1.5 H, J = 6.7), 1.09 (d, 1.5 H, J = 6.7), 2.11 [s(br), 3 H], 2.79 (s, 1.5 H), 2.97 (s, 1.5 H), 3.37 (d, 0.5 H, J = 17.1), 3.46 [d(obs)], 1 (H, J = 16.6), 3.72 (d, 0.5 H, J = 15.5), 3.88 (m, 0.5 H), 4.53-4.63 (m, 1.5 H), 7.29-7.40 (m, 5 H);
13C NMR (CDCl
3) δ: 14.4, 15.3, 27.1, 30.1, 43.4, 43.7, 57.2, 57.5, 74.9, 75.8, 126.7, 126.9, 127.9, 128.2, 128.5, 128.7, 142.1, 142.3, 173.5, 174.1. Anal. Calcd for C
12H
18N
2O
2: C, 64.84; H, 8.16; N, 12.60. Found: C, 64.65; H, 8.25; N, 12.53.
11. It is absolutely imperative that the solution of
butyllithium be accurately titrated. If an excess of
butyllithium (or LDA) is used, reduced yields will result as a consequence of a decomposition reaction that releases
pseudoephedrine. This is easily monitored by TLC analysis (
5% methanol,
5% triethylamine, and
90% dichloromethane eluent; UV and ninhydrin visualization). It should be noted that even optimal reaction conditions produce small amounts of this cleavage product (2-4%); however, the amount of cleavage is greatly enhanced in the presence of excess base. To titrate the alkyllithium solution we recommend the method of Watson and Eastham.
4 5 A standard solution of 1.00 M
2-butanol (freshly distilled from
calcium hydride) in
toluene (freshly distilled from
calcium hydride) is prepared in a
volumetric flask. A
50-mL, round-bottomed flask equipped with a Teflon-coated magnetic stirring bar and a rubber septum is charged with
5 mg of 2,2'-dipyridyl and
20 mL of ether. The flask is flushed with
argon, and a small amount (ca.
0.5 mL) of the standard 1.00 M solution of 2-butanol in
toluene is added to the solution. The
butyllithium solution to be titrated is added slowly, dropwise, to a single-drop end point that turns the solution dark red. This initial titration eliminates complications due to moisture or
oxygen and should not be used in the calculation of the titer of the
butyllithium solution. Several repetitions of the titration cycle are conducted using the same indicator solution by using accurate, air-tight syringes and alternately adding aliquots of 1.00-M
2-butanol solution (1-2.5 mL) followed by titration of the
butyllithium to a dark-red end point.
12. The checkers employed
163 mL of a 2.70-M solution of butyllithium in hexanes whose titer was determined by the procedure given in (Note
11).
13. The addition required 80 min in the hands of the checkers.
14. The reaction mixture was stirred for 40 min at 0°C by the checkers.
15.
Allyl bromide was purchased from Aldrich Chemical Company, Inc., and was distilled under
argon (atmospheric pressure) from
calcium hydride immediately prior to use.
16. The
allyl bromide addition required 30 min in the hands of the checkers.
17. The pH of the aqueous layer is checked after each extraction to ensure that it is >12. If necessary, the pH of the aqueous layer is readjusted to 14 by the addition of aqueous
50% sodium hydroxide solution.
18. The product shows the following physical and spectroscopic properties: mp
71-73°C; [α]23D −86.4° (CH
3OH,
c 1.1); TLC R
f = 0.59 (5% CH
3OH, 5% NEt
3, 90% CH
2Cl
2); IR (neat) cm
−1: 3354, 3072, 2978, 1632, 1491, 1453, 1109, 1051, 918, 762, 703;
1H NMR (3:1 rotamer ratio, CDCl
3) major rotamer δ: 1.03 (d, 3 H, J = 6.4), 2.13 (m, 1 H), 2.23 (m, 1 H), 2.87 (s, 3 H), 3.65 (dd, 1 H, J = 7.5, 5.3), 4.55-4.59 (m, 2 H), 5.07-5.14 (m, 2 H), 5.64-5.85 (m, 1 H), 7.23-7.38 (m, 5 H); minor rotamer δ: 0.96 (d, 3 H, J = 6.7), 2.61-2.66 (m, 2 H), 2.93 (s, 3 H), 3.69 (m, 1 H), 4.03 (m, 1 H);
13C NMR (CDCl
3) major rotamer δ: 14.4, 31.4, 39.6, 51.2, 57.6, 75.5, 118.1, 126.5, 127.6, 128.2, 133.7, 142.1, 176.1; minor rotamer δ: 15.5, 27.0, 39.8, 51.0, 74.9, 117.9, 126.8, 128.1, 128.5, 134.7, 141.8, 175.1. Anal. Calcd for C
15H
22N
2O
2: C, 68.67; H, 8.45; N, 10.68. Found: C, 68.57; H, 8.59; N, 10.70. Determination of the diastereomeric purity of the product by NMR is complicated by the presence of amide rotamers. The diastereomeric purity of the product may be determined accurately and conveniently by preparing the corresponding diacetate and analyzing by capillary gas chromatography. To prepare the diacetate, a
10-mL, round-bottomed flask equipped with a Teflon-coated magnetic stirring bar and a rubber septum is charged with a 16-mg sample of the alkylation product to be analyzed and
1 mL of pyridine. The product is acetylated by adding
1 mL of acetic anhydride and a catalytic amount (
5 mg) of 4-(N,N-dimethylamino)pyridine. The reaction mixture is stirred under
argon for 1 hr and excess
acetic anhydride is quenched by addition of 15 mL of water. The reaction mixture is extracted sequentially with one 30-mL portion and one
20-mL portion of ethyl acetate. The two organic extracts are individually and sequentially extracted with a single
15-mL portion of aqueous saturated sodium bicarbonate solution; the organic extracts are combined, dried over anhydrous
sodium sulfate and filtered. The filtrate is concentrated under reduced pressure, and the residue is dissolved in
ethyl acetate for capillary gas chromatographic analysis. Analysis was carried out using a
Chirasil-Val capillary column (25 m × 0.25 mm × 0.16 μm, available from Alltech Inc.) under the following conditions:
oven temp. 220°C, injector temp. 250°C, detector temp. 275°C. The following retention times were observed:
(R,R)-(−)-pseudoephedrine glycinamide diacetate, 6.69 min;
(R,R)-(−)-pseudoephedrine L-allylglycinamide diacetate, 6.94 min;
(R,R)-(−)-pseudoephedrine D-allylglycinamide diacetate, 6.32 min. Note that the retention times can vary greatly with the age and condition of the column. The checkers obtained the following values using an identical new column from Alltech with a flow rate of 4 mL/min, split ratio of 50:1, and an injection volume of 1 μL: retention times (min) 18.33 (
D-allyl isomer), 19.24 (glycinamide SM), 20.24 (
L-allyl isomer).
19. The second crop of product crystals (mp
69-71°C) was contaminated with 2% of the starting material,
(R,R)-(−)-pseudoephedrine glycinamide (as determined by GC analysis, (Note
18)), and was recrystallized to provide analytically pure product.
20. Although the
pseudoephedrine may be recovered by filtration at this stage, the recovery is not quantitative (ca. 50-60%). A more efficient recovery is achieved by the extraction procedure described.
22. The product shows the following spectroscopic and physical properties: mp
275-280°C (dec.); lit.
6 241-243°C (dec.); lit.
7 283°C (dec.);
[α]23D −37.2° (H
2O,
c 4); lit.
8 [α]23D −37.1 (H
2O,
c 4) (Note
26); IR (KBr) cm
−1: 3130, 2605, 1586, 1511, 1406, 1363, 1345, 1307, 919, 539;
1H NMR (D
2O) δ: 2.50 (m, 2 H), 3.67 (dd, 1 H, J = 7.0, 5.1), 5.13 (d, 1 H, J = 10.0), 5.14 (d, 1 H, J = 18.6), 5.64 (m, 1 H);
13C NMR (D
2O) δ: 35.6, 54.6, 120.9, 132.0, 175.1. Anal. Calcd for C
5H
9NO
2: C, 52.16; H, 7.88; N, 12.17. Found: C, 52.15; H, 7.74; N, 12.03.
The product is determined to be ≥99% ee by HPLC analysis on a
Crownpak CR(+) column (pH 1.5 HClO
4 mobile phase, 0.4 mL/min, 205 nm detection). The minor enantiomer was identified by comparison with an authentic sample prepared from
(S,S)-(+)-pseudoephedrine glycinamide. The following retention times are observed:
D-allylglycine, 4.68 min;
L-allylglycine, 5.45 min. Using an identical new column and the identical eluent at a flow rate of 0.8 mL/min, the checkers observed retention times of 13.86 min for
D-allylglycine and 15.19 min for
L-allylglycine.
23.
Reagent grade p-dioxane was used as received from Mallinckrodt Inc.
25. If necessary, residual
ether may be removed by placing the oily product under reduced pressure (0.5 mm) and warming briefly with a heat gun. The oily residue is typically found to be analytically pure product and requires no purification. The product shows the following physical and spectroscopic characteristics:
[α]23D +11.9° (CH
3OH,
c 1.4),
[α]23D −2.5° (CH
2Cl
2,
c 1.1); lit.
9 [α]23D −3.9° (CH
2Cl
2,
c 1) (Note
27); IR (neat) cm
−1: 3324, 3081, 2980, 2932, 1715, 1513, 1395, 1369, 1251, 1163, 1053, 1025, 922;
1H NMR (2:1 rotamer ratio, CDCl
3) major rotamer δ: 1.44 (s, 9 H), 2.57 (m, 2 H), 4.40 (m, 1 H), 5.14-5.19 (m, 3 H), 5.73 (m, 1 H), 8.86 [s(br), 1 H]; minor rotamer δ: 4.19 (m, 1 H), 6.37 (d, 1 H, J = 5.2);
13C NMR (CDCl
3) major rotamer δ: 28.1, 36.3, 52.7, 80.1, 119.1, 132.1, 155.4, 176.0; minor rotamer δ: 54.2, 81.7, 156.7. Anal. Calcd for C
10H
17NO
4: C, 55.80; H, 7.96; N, 6.51. Found: C, 55.71; H, 8.14; N, 6.56.
In order to determine the enantiomeric excess of the product, the Boc protective group must be removed prior to HPLC analysis. The sample is prepared by dissolving
23 mg of N-Boc allylglycine in
1 mL of tetrahydrofuran and adding
2 mL of a 3 M aqueous hydrochloric acid solution. The mixture is allowed to stir at 23°C for 1 hr and then is concentrated under reduced pressure to provide a solid residue. The solid is dissolved in water for HPLC analysis. The product is determined to be ≥99% ee by analysis on a Crownpak CR(+) column (Note
22) and (Note
27).
26. The checkers obtained material having mp
240-242°C and
[α]23D −37.2° (H
2O,
c 4), and ≥99% ee by HPLC analysis on a Crownpak CR(+) column (Note
22) in good agreement with the cited literature values.
6,7
27. The checkers obtained samples of material having rotations in
methanol in the range
[α]23D +8.6° to +11.4° (CH
3OH,
c 1.4), and
[α]23D −3.7° to −3.8° (CH
2Cl
2,
c 1.1), all of which were determined to be ≥99% ee by HPLC analysis on a Crownpak CR(+) column (Note
22).
All toxic materials were disposed of in accordance with "Prudent Practices in the Laboratory"; National Academy Press; Washington, DC, 1995.
3. Discussion
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