Organic Syntheses, Vol. 76, 46
Checked by Stephanie A. Lodise and Amos B. Smith, III.
1. Procedure
C.
(1S,2R)-1-Aminoindan-2-ol (100% ee). A
500-mL, three-necked, round-bottomed flask equipped with a large magnetic stir bar, a 125-mL addition funnel, a pH probe, and a thermocouple is charged with the hydrolysis solution from Part B and
1-butanol (100 mL).
Sodium hydroxide (80 mL of an aqueous 50% solution, (Note 12)) is added slowly with
external ice bath cooling to maintain the temperature below 30°C until the reaction mixture reaches a pH of 12-13. The upper
1-butanol layer is separated, and the aqueous layer is extracted with another
100 mL of 1-butanol. The combined
butanol extracts are diluted with
methanol (200 mL), and vacuum-filtered through a Büchner funnel into a
2000-mL, three-necked, round-bottomed flask equipped with a mechanical overhead stirrer, 250-mL addition funnel, and reflux condenser. The reaction mixture is stirred vigorously and heated to reflux, and a solution of
L-tartaric acid (35.5 g, 0.24 mol, 1.2 equiv) in methanol (200 mL) is added over 15-30 min while reflux is maintained. Heating is discontinued until a thick but stirrable slurry is formed (Note
13). The suspension is reheated to reflux for 2 hr (Note
14). At this point, the mixture is cooled to room temperature and allowed to stand for 1 hr. The resulting solids are collected on a Büchner funnel and washed with
methanol (2 × 100 mL). The white solid thus obtained is then dried under reduced pressure to yield
47.4 g of the 1:1 tartrate salt (Note
15).
A
300-mL, three-necked, round-bottomed flask equipped with a large magnetic stir bar, a 125-mL addition funnel, a pH probe, and a thermocouple is charged with the
aminoindanol-tartrate salt. Water (95 mL, 2:1 v/w) is added, and the mixture is stirred under a N
2 atmosphere. Aqueous
sodium hydroxide (50 wt-%, 23 mL, 2 equiv, (Note 12) and (Note 16)) is added with external ice bath cooling until the reaction mixture reaches pH 12-13, resulting in precipitation of the
aminoindanol free base. The mixture is cooled to 0°C and allowed to stand at that temperature for an additional 30 min. The white to tan solid is collected by vacuum filtration, washed with ice-cold water (20 mL), and air-dried on the filter. The solid is dissolved in
hot toluene (1:10 w/v, (Note 17)), and the resulting solution is allowed to cool to room temperature, then further cooled to 4°C for 1 hr. The resulting white solid is collected by vacuum filtration, washed with
cold toluene (20 mL), and dried under reduced pressure. The total yield of
aminoindanol (100% ee, (Note
18)) is
17.2 g, mp
122-124°C (Note
19).
2. Notes
1.
Technical grade indene (92%) was obtained from Aldrich Chemical Company, Inc., and was passed through a
10 × 10-cm column of basic alumina to remove highly colored impurities. The compound was then distilled under a N
2 atmosphere from a small amount of CaH
2. The distillate was stored under N
2 at 4°C.
2. The epoxidation catalyst was prepared according to the published procedures.
5 6 Alternatively, research quantities can be purchased from Aldrich Chemical Company, Inc., or bulk quantities can be purchased from ChiRex Ltd, Dudley, UK.
3.
4-Phenylpyridine N-oxide was purchased from Aldrich Chemical Company, Inc., and used as received. Other
pyridine N-oxide derivatives have been used with success in the epoxidation reaction. The choice of the
pyridine N-oxide derivative has been demonstrated to have a small yet measurable impact on both the rate of reaction and the enantiomeric excess of the product epoxide.
7 8 9
4. Commercial
10-13% NaOCl was purchased from Aldrich Chemical Company, Inc., and stored at 4°C. The concentration of bleach was determined according to the method of Kolthoff and Belcher.
10
To a
250-mL Erlenmeyer flask containing a magnetic stir bar was added
2 mL of the commercial NaOCl solution, 100 mL of water,
1.5 mL of concd HCl, and
7 g of potassium iodide. The resulting dark brown solution was titrated with a
1 M solution of sodium thiosulfate (Na2S2O3). The endpoint is reached when the solution becomes colorless. Using the following equations, the concentration of the NaOCl solution can be calculated.
OCl
− + 2I
− + 2H
+
H2O + Cl
− + I
2
2S
2O
3 + I
2 
S
4O
6 + 2I
−
The solution (191 mL) used by the submitters was found to be 1.7 M in NaOCl and was then made 0.2 M in
sodium hydroxide (NaOH) by the addition of
1.52 g of solid NaOH.
5. The epoxidation reaction is exothermic. The bleach is added over a period of 2-2.5 hr in order to maintain the desired temperature range. If the rate of addition appears to be faster, then the rate of stirring should be increased to ensure proper mixing of the biphasic mixture.
6. The physical properties are as follows:
1H NMR (400 MHz, CDCl
3) δ: 2.95 (dd, 1 H, J = 2.9, 18.2), 3.19 (d, 1 H, J = 18.2), 4.10 (t, 1 H, J = 2.9), 4.25 (m, 1 H), 7.15-7.25 (m, 3 H), 7.48 (d, 1 H, J = 7.4);
13C NMR (100 MHz, CDCl
3) δ: 34.5, 57.5, 59.0, 125.0, 126.0, 126.1, 128.4, 140.8, 143.4; IR (NaCl): ν (cm
−1) 3045, 3029, 2913, 1474, 1466, 1419, 1372, 1230, 1175, 1000, 983;
[α]23D +23.3° (hexanes,
c 1.31); HRMS (CI, cool probe): calcd for C
9H
12NO [M+NH
4] 150.0919, observed 150.0913.
7. The enantiomeric excess of the epoxide is determined by HPLC analysis using a Chiracel OB column (25 cm × 4.6 mm, Daicel) eluted with EtOH/hexanes (5:95) at 1 mL/min, while monitoring at 254 nm. The retention times of the epoxide enantiomers are 11.1 (1S,2R) and 15.3 (1R,2S) min.
8. The submitters distilled the
epoxyindane at lower pressure, bp
47-48°C (0.005 mm).
9. Solvents were freshly distilled from CaH
2 prior to reaction.
10.
Fuming sulfuric acid was purchased from Aldrich Chemical Company, Inc., and used as received. Approximately 10% of the acid is added before addition of the epoxide solution is begun.
11. The weight of the hydrolysis mixture is
225-250 g.
12. Slightly more or less NaOH solution may be required to reach the desired pH range.
13. The precipitation of the diastereomeric salt is rapid, and the solid may need to be broken up with a spatula in order to maintain proper mixing. Additional
methanol may be added if needed.
14. The salt that precipitates initially is not diastereomerically pure, and the additional reflux period is necessary to allow equilibration to the diastereomerically pure material.
15. The salt is isolated as a
methanol solvated complex, FW = 331.
16. The pH of the initial mixture is approximately 3.5. The free base begins to precipitate around pH 8.5.
17. The product is recrystallized from
toluene in order to remove any of the trans isomer, as well as to dry the product. The hot mixture should be heated long enough to azeotropically remove water from the product.
18. The stereochemical purity of the product is determined by reacting a sample of the product (15 mg) with
2,4-dinitrofluorobenzene (13 μL) in CH2Cl2 (5 mL). The yellow solution is diluted with
ethanol (1:10), then analyzed by HPLC on an
N-naphthylleucine column (4.6 × 25 mm, Regis) eluted with IPA/hexanes (8:92) at 1 mL/min while monitoring at 350 nm. The retention times of the trans enantiomers are 17.4 and 19.1 min, while those of the cis enantiomers are 24.4 (1R,2S) and 27.1 (1S,2R) min. The product is enantio- and diastereomerically pure after recrystallization from
toluene.
19. The physical properties are as follows:
1H NMR (400 MHz, CD
3OD) δ: 2.88 (dd, 1 H, J = 2.9, 16.1), 3.05 (dd, 1 H, J = 5.4, 16.1), 4.13 (d, 1 H, J = 5.0), 4.39 (m, 1 H), 7.17-7.22 (m, 3 H), 7.38 (m, 1 H);
13C NMR (100 MHz, CD
3OD) δ: 40.0, 60.4, 75.2, 125.3, 126.1, 127.8, 128.6, 141.8, 145.1; IR (NaCl): ν (cm
−1) 3343, 3290, 3170-3022, 2918, 1618, 1605, 1474, 1344, 1180, 1058;
[α]23D −41.2° (MeOH,
c 1.00, MeOH); HRMS (CI, cool probe): calcd for C
9H
12NO [M+H] 150.0919, observed 150.0913.
All toxic materials were disposed of in accordance with "Prudent Practices in the Laboratory"; National Academy Press; Washington, DC, 1995.
3. Discussion
The development of practical routes to the title compound has been the focus of intensive research effort since
cis-aminoindanol was identified as a critical component of the highly effective HIV protease inhibitor indinavir (Crixivan®).
11,12 Reported routes include racemate synthesis followed by resolution via diastereomeric salts,
12 enzymatic resolution,
13 14 and asymmetric hydroxylation.
15 However, the use of a modified Ritter reaction to convert
indene oxide to the corresponding cis-amino alcohol as described in this procedure constitutes the most direct and economical route devised thus far.
16 17 The application of the (salen)Mn-catalyzed epoxidation reaction
18 19 20 21 22 in the first step allows access to the requisite epoxide in good yield and good enantiomeric excess, thus rendering the overall process highly efficient. A final purification of the amino alcohol product involving formation of the
L-tartrate salt serves to enhance both the chemical and stereochemical purity of the final product.
Appendix
Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)
(1S,2R)-1-Aminoindan-2-ol: 1H-Inden-2-ol, 1-amino-2,3-dihydro-, (1S-cis)- (12); (126456-43-7)
(1S,2R)-Indene oxide: Indan, 1,2-epoxy- (8); 6H-Indeno[1,2-b]oxirene, 1a,6a-dihydro- (9); (768-22-9)
Indene (8); 1H-Indene (9); (95-13-6)
(R,R)-N,N'-Bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediaminomanganese(III) chloride: Manganese, chloro[[2,2'-[1,2-cyclohexanediylbis(nitrilomethylidyne)]bis[4,6-bis(1,1-dimethylethyl)phenolato]](2-)-N,N',O,O']-, [SP-5-13-(1S-trans)]- (12); (135620-04-1)
4-Phenylpyridine N-oxide: Pyridine, 4-phenyl-, 1-oxide (8,9); (1131-61-9)
Sodium hypochlorite solution: Hypochlorous acid, sodium salt (8,9); (7681-52-9)
Acetonitrile TOXIC (8,9); (75-05-8)
Sulfuric acid, fuming: Sulfuric acid, mixt. with sulfur trioxide (9); (8014-95-7)
L-Tartaric acid: Tartaric acid, L- (8); Butanedioic acid, 2,3-dihydroxy-, [R-(R,R)]- (9); (87-69-4)
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