METHOD FOR PREPARING (2S,3S)-3-AMINO-BICYCLO[2.2.2]OCTANE-2-CARBOXYLATE

Abstract

A method for preparing (2S,3S)-3-amino-bicyclo[2.2.2]octane-2-carboxylate is in the field of pharmaceutical intermediate synthesis. The method uses 3-carbonyl-bicyclo[2.2.2]octane-2-carboxylate as the starting material and performs reductive amination, alkalinity configuration flip, and hydrogenation to remove the protecting group in sequence to obtain the target product. This synthesis method of (2S,3S)-3-amino-bicyclo[2.2.2]octane-2-carboxylate is characterized by a novel route, mild reaction conditions and low cost, with a yield of more than 65%.

Claims

1. Method for preparing (2S,3S)-3-amino-bicyclo[2.2.2]octane-2-carboxylate, wherein, the method comprises: using 3-carbonyl-bicyclo[2.2.2]octane-2-carboxylate as raw material, carrying out reductive amination, flip of ester group conformation and removal of protecting group to obtain the (2S,3S)-3-amino-bicyclo[2.2.2]octane-2-carboxylate, and reaction process is shown below, ##STR00010## wherein, X, Y and R are all organic substituents.

2. The method according to claim 1, wherein, the method comprises: S1, reacting 3-carbonyl-bicyclo[2.2.2]octane-2-carboxylate with chiral amines in presence of acid to give 3-amino-bicyclo[2.2.2]octene-2-carboxylate; S2, carrying out reduction with a reducing agent or metal-catalyzed hydrogenation of the 3-amino-bicyclo[2.2.2]octene-2-carboxylate to give (2R,3S)-3-amino-bicyclo[2.2.2]octane-2-carboxylate; S3, under strong base conditions, carrying out ester configuration flip of the (2R,3S)-3-amino-bicyclo[2.2.2]octane-2-carboxylate to give (2S,3S)-3-amino-bicyclo[2.2.2]octane-2-carboxylate; S4, carrying out hydrogenation of the (2S,3S)-3-amino-bicyclo[2.2.2]octane-2-carboxylate to remove the protecting group to give the (2S,3S)-3-amino-bicyclo[2.2.2]octane-2-carboxylate.

3. The method according to claim 1, wherein, the R is methyl, ethyl, propyl, butyl, phenyl or benzyl, preferably ethyl; the X is methyl, ethyl, phenyl or 1-naphthyl, the Y is methyl, ethyl, phenyl or 1-naphthyl, and the X and the Y are not identical, the X group is larger than the Y group; preferably, the X is phenyl, the Y is methyl.

4. The method according to claim 2, wherein, in the S2, the metal-catalyzed hydrogenation is carried out using a metal catalyst, the metal catalyst comprising at least one selected from the group consisting of platinum carbon, platinum dioxide and ruthenium metal catalyst; the reducing agent comprising at least one selected from the group consisting of sodium borohydride, sodium triacetoxy borohydride, sodium cyanoborohydride and sodium trifluoroacetoxy borohydride; preferably, the metal catalyst is platinum dioxide; the reducing agent is sodium triacetoxy borohydride.

5. The method according to claim 2, wherein, in the S3, the strong base comprises at least one selected from the group consisting of sodium tert-butoxide, sodium tert-amylate, lithium diisopropylamide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide and potassium bis(trimethylsilyl)amide; preferably, the strong base is sodium tert-butoxide.

6. The method according to claim 2, wherein, in the S1, the acid is organic acid or inorganic acid; preferably, the acid is strong organic acid; further preferably, the acid comprises p-toluenesulfonic acid or trifluoroacetic acid.

7. A compound of formula V, wherein, the R is methyl, ethyl, propyl, butyl, phenyl or benzyl, preferably ethyl; the X is methyl, ethyl, phenyl or 1-naphthyl, and the Y is methyl, ethyl, phenyl or 1-naphthyl, and the X and the Y are not identical and the X is larger than the Y, preferably, the X is phenyl, the Y is methyl, ##STR00011##

8. Use of the compound V according to claim 7 for preparation of (2S,3S)-3-amino-bicyclo[2.2.2]octane-2-carboxylate.

9. A compound of formula VI, wherein, the R is methyl, ethyl, propyl, butyl, phenyl or benzyl, preferably ethyl; the X is methyl, ethyl, phenyl or 1-naphthyl, and the Y is methyl, ethyl, phenyl or 1-naphthyl, and the X and the Y are not identical and the X is larger than the Y, preferably, the X is phenyl, the Y is methyl, ##STR00012##

10. Use of the compound VI according to claim 9 for preparation of (2S,3S)-3-amino-bicyclo[2.2.2]octane-2-carboxylate.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0036] The following is a detailed description of preferred embodiments of the present invention to make the advantages and features of the present invention more easily understood by those skilled in the art, so that the scope of protection of the present invention can be more clearly defined.

Example 1

[0037] ##STR00008##

1. Synthesis of ethyl (S)-3-(1-phenylethylamino)-bicyclo[2.2.2]octene-2-carboxylate

[0038] To the reactor was added 1000 L toluene, 100.0 kg ethyl 3-carbonyl-bicyclo[2.2.2]octane-2-carboxylate, 12 kg p-toluenesulfonic acid, 80.0 kg S-1-phenylethylamine, and the reaction was refluxed under nitrogen protection for 12 h to obtain the enamine intermediate ethyl (S)-3-(1-phenylethylamino)-bicyclo[2.2.2]octene-2-carboxylate, which was used in the next reaction step.

2. Synthesis of ethyl (2R,3S)-3-((S)-1-phenylethylamino)-bicyclo[2.2.2]octane-2-carboxylate

[0039] The above enamine intermediate (S)ethyl-3-(1-phenylethylamino)-bicyclo[2.2.2]octene-2-carboxylate solution was desolvated, then 1500 L of tetrahydrofuran and 500 L of acetic acid was added, then 106.2 kg of sodium triacetoxyborohydride was added after cooling. Bring to room temperature and reacted for 3 h. 3N sodium hydroxide solution was added dropwise to adjust to alkaline, extracting with ethyl acetate (800 Lx 2), the combined organic phases were washed with saturated salt water and concentrated to give 115 g of ethyl (2R,3S)-3-((S)-1-phenylethylamino)-bicyclo[2.2.2]octane-2-carboxylate (corresponding to compound IV in the synthetic route of the present invention) as a pale yellow oil, in yield 85%. .sup.1HNMR (400 MHz, CDCl.sub.3) δ7.22-7.32 (m, 5H), δ4.18 (q, 2H), δ3.65 (q, 1H), δ2.81-2.89 (m, 2H), δ1.83 (m, 2H), δ1.27-1.56 (m, 11H), δ1.25 (t, 3H); ESI-MS: m/z 302.34 [M+1]

3. Synthesis of ethyl (2S,3S)-3-((S)-1-phenylethylamino)-bicyclo[2.2.2]octane-2-carboxylate

[0040] To the reactor was added 500 L tetrahydrofuran, 500 L tert-butanol, 64 kg sodium tert-butoxide, and cooled to 0-10° C. under nitrogen protection. Add tetrahydrofuran solution of ethyl (2R,3S)-3-((S)-1-phenylethylamino)-bicyclo[2.2.2]octane-2-carboxylate (100 kg dissolved in 100 L tetrahydrofuran) dropwise. After dropwise addition, the reaction was held for 2 h. The reaction solution was transferred to 500 L saturated ammonium chloride solution for quenching. After extraction with ethyl acetate (800 L×2), the combined organic phases were washed with saturated brine and concentrated to give 90.0 kg of ethyl (2S,3S)-3-((S)-1-phenylethylamino)-bicyclo[2.2.2]octane-2-carboxylate (corresponding to compound V in the synthetic route of the present invention) as pale yellow oily form with 90.0% yield and diastereomeric purity 97.4%.

[0041] .sup.1HNMR (400 MHz, CDCl.sub.3) δ7.21-7.31 (m, 5H), δ4.13 (q, 2H), δ3.79 (q, 1H), δ3.12 (d, 1H), δ2.22 (d, 1H), δ1.93 (d, 1H), δ1.42-1.76 (m, 8H), δ1.23-1.34 (m, 8H); ESI-MS: m/z 302.34 [M+1]

4. Synthesis of ethyl (2S,3S)-3-amino-bicyclo[2.2.2]octane-2-carboxylate

[0042] 500 L of ethanol, 8.00 kg of ethyl (2S,3S)-3-((S)-1-phenylethylamino)-bicyclo[2.2.2]octane-2-carboxylate, and 8 kg of 10% palladium carbon were added to a 1000 L stainless steel autoclave. The reactor was evacuated and full filled with nitrogen, then exchanged to hydrogen and pressurized to 0.6 MPa. The reaction mixture was heated to 50° C. and kept for 12 hours. The palladium carbon was removed by filtration and the filtrate was concentrated to give 50 kg of ethyl (2S,3S)-3-amino-bicyclo[2.2.2]octane-2-carboxylate (corresponding to compound I in the synthetic route of the present invention) as a pale yellow oil in 97.0% yield and 97.5% chiral purity.

[0043] .sup.1HNMR (400 MHz, CDCl.sub.3) δ4.18 (q, 2H), δ3.37-3.38 (m, 1H), δ2.13-2.17 (m, 3H), δ1.98-2.00 (m, 1H), δ1.78-1.83 (m, 1H), δ1.36-1.67 (m, 9H), δ1.27 (t, 3H); ESI-MS: m/z 198.26 [M+1]

Example 2

[0044] ##STR00009##

1. Synthesis of ethyl (S)-3-(1-naphthylethylamino)-bicyclo[2.2.2]octene-2-carboxylate

[0045] 1000 L of toluene, 100.0 kg of ethyl 3-carbonyl-bicyclo[2.2.2]octane-2-carboxylate, 10.0 kg of trifluoroacetic acid, 113 kg of S-1-naphthyl ethylamine were added to the reactor and reacted under nitrogen protection at reflux for 12 hours. Cooled to room temperature, washed with 300 L saturated sodium bicarbonate solution, the organic layer was concentrated to 200 L, 500 L n-heptane was added and stirred for 3 h at room temperature, filtered, washed with a small amount of n-heptane and dried under vacuum to give 133.6 kg ethyl (S)-3-(1-naphthylethylamino)-bicyclo[2.2.2]octene-2-carboxylate as a white solid in 75.3% yield.

2. Synthesis of ethyl (2R,3S)-3-((S)-1-naphthylethylamino)-bicyclo[2.2.2]octane-2-carboxylate

[0046] 300 L of ethanol, 200 L of ethyl acetate, 100.0 kg of ethyl (S)-3-(1-naphthylethylamino)-bicyclo[2.2.2]octene-2-carboxylate, 10.0 kg of 5% platinum carbon to 1000 L were added to stainless steel autoclave, degassing with nitrogen and then ventilating with hydrogen to 1 MPa, then the mixture was raised to 35° C. and kept for 10 hours. Filtered to remove the platinum carbon and the filtrate was concentrated to obtain 100.0 kg ethyl (2R,3S)-3-((S)-1-naphthylethylamino)-bicyclo[2.2.2]octane-2-carboxylate as an off-white solid in 99.4% yield.

3. Synthesis of ethyl (2S,3S)-3-((S)-1-naphthylethylamino)-bicyclo[2.2.2]octane-2-carboxylate

[0047] 500 L tetrahydrofuran, 500 L tert-butanol, 50.0 kg sodium tert-butoxide were added to the reactor, cooled down to 0-10° C. under nitrogen protection, and added dropwise a tetrahydrofuran solution of ethyl (2R,3S)-3-((S)-1-naphthylethylamino)-bicyclo[2.2.2]octane-2-carboxylate (100.0 kg dissolved in 100 L tetrahydrofuran). After dropwise addition, the reaction was held for 2 h. The reaction solution was quenched by pouring into 500 L saturated ammonium chloride solution, then extracted with ethyl acetate (800 L×2). The combined organic phases were washed with saturated brine and concentrated to give 92.0 kg of ethyl (2S,3S)-3-((S)-1-naphthylethylamino)-bicyclo[2.2.2]octane-2-carboxylate as a pale yellow solid in 92.0% yield and 98.0% diastereomeric purity.

4. Synthesis of ethyl (2S,3S)-3-amino-bicyclo[2.2.2]octane-2-carboxylate

[0048] To a 1000 L stainless steel hydrogenator was added 500 L of ethanol, 90.0 kg of ethyl (2S,3S)-3-((S)-1-naphthylethylamino)-bicyclo[2.2.2]octane-2-carboxylate, 9 kg of 10% palladium carbon. After degassing with nitrogen, then ventilating with hydrogen to 1 MPa and the reaction was carried out at 50° C. for 12 h. The palladium carbon was removed by filtration and the filtrate was concentrated to give 50.0 kg of ethyl (2S,3S)-3-amino-bicyclo[2.2.2]octane-2-carboxylate as a pale yellow oil in 99.0% yield and 98.1% chiral purity.