Asymmetrical hydrogenation reaction of ketonic acid compound

Abstract

The present invention relates to the technical field of organic chemistry, specifically an asymmetrical hydrogenation of an ∂-ketonic acid compound, the technical proposal being as shown by the following formula:

##STR00001##

Wherein R.sup.1 is a phenyl, a substituted phenyl, a naphthyl a substituted naphthyl, a C.sub.1-C.sub.6 alkyl or aralkyl, the substitute is a C.sub.1-C.sub.6 alkyl, a C.sub.1-C.sub.6 alkoxy, a halogen, the number of the substituents is 1-3.

M is a chiral spiro-pyridyl amido phosphine ligand iridium complex having the following structure,

##STR00002##

Wherein, R is hydrogen, 3-methyl, 4-.sup.tBu or 6-methyl

Claims

1. A preparation method of the structure of formula B, ##STR00043## Wherein R.sup.1 is a phenyl, a substituted phenyl, a naphthyl, a substituted naphthyl, a C.sub.1-C.sub.6 alkyl or aralkyl, the substitute is a C.sub.1-C.sub.6alkyl, a C.sub.1-C.sub.6 alkoxy, a halogen, the number of the substituents is 1-3 Wherein M is the following structure chiral spiro-pyridylamidophosphine ligand iridium complex: ##STR00044## Wherein R is hydrogen, 3-methyl, 4-.sup.tBu or 6-methyl, The said base is selected from sodium hydroxide, potassium hydroxide, sodium tert-butyl oxide or potassium test-butyl oxide, The molar dosage ratio of the said base to the substrate A compound is (1.0˜3):1.

2. The preparation method according to claim 1, wherein, the molar dosage ratio of the said base to the substrate A compound is (1.001∥1.5):1.

3. The preparation method according to claim 1, wherein, R.sup.1 is a phenyl, a substituted phenyl, a naphthyl or a substituted naphthyl.

4. The preparation method according to claim 1, wherein, R is 4-.sup.tBu.

5. The preparation method according to claim 1, wherein, the said base is sodium hydroxide or potassium hydroxide.

6. The preparation method according to any claims of 1, 3-5, wherein, under the protection of nitrogen atmosphere, at a hydrogen pressure of 0.5-10 MPa, with a base dosage 1.0˜3.0 molar equivalent, in the presence of organic solvent, ∂-ketonic acid compound is formed into B compound in the catalytic of chiral spiro-pyridylamidophosphine ligand iridium complex (M) with the molar dosage 0.00001˜0.01 molar equivalent.

7. The preparation method according to any claims of 1, 3-5, wherein, under the protection of nitrogen atmosphere, were added into the inner hydrogenation tube substrate A, 1.0˜3.0 molar equivalent base, chiral spiro-pyridylamidophosphine ligand iridium complex (M) with the molar dosage 0.00001˜0.01 molar equivalent and the solvent; The inner reaction tube was placed into the hydrogenation reactor at a hydrogen pressure of 0.5-10 MPa was filled; The reaction was stirred for 1-30 hours at a temperature of 10˜90° C. to obtain B compound; the base selected from sodium hydroxide, potassium hydroxide, sodium tert-butyl oxide or potassium tert-butyl oxide.

8. The preparation method according to claim 1, wherein, the said solvent is selected from methanol, ethanol, propanol isopropanol, tetrahydrofuran, toluene, methyl tert-butyl ether, dioxane or DMF.

Description

DESCRIPTION OF THE DRAWINGS

[0017] FIG. 1 illustrates the spectrum of High Performance Liquid Chromatography (HPLC) of the 3a compound prepared in accordance with Example 12 of the present invention.

[0018] FIG. 2 illustrates the spectrum of High Performance Liquid Chromatography (HPLC) of the 3c compound prepared in accordance with Example 17 of the present invention.

[0019] FIG. 3 illustrates the spectrum of High Performance Liquid Chromatography (HPLC) of the 31compound prepared in accordance with Example 26 of the present invention.

DETAILED EMBODIMENTS

[0020] In order to further understand the present invention, preferable embodiments of the present invention will be described by reference to the examples, but it should be appreciated that these descriptions are merely intended to further illustrate the features and advantages of the present invention, rather than limiting the claims of the invention.

[0021] HPLC analytical instrument and method

[0022] instrument model: Agilent 1200

[0023] chromatographic column: Chiracel OD-H, 4.6 mm×250 mm×5 μm

[0024] mobile phase A n-hexane

[0025] mobile phase B: isopropanol

[0026] flow velocity: 1.0 mL/min

[0027] column temperature: 35° C.

[0028] wave length: 210 nm

[0029] sample size: 5 μL

EXAMPLE 1

Preparation of 2-hydroxyl-2-phenyl acetic acid

[0030] ##STR00006##

[0031] Under the protection of nitrogen atmosphere, to the inner hydrogenation tube (200 mL), were added substrate ∂-ketonic acid 2a (3 g, 20 mmol), potassium tert-butyl oxide (112 mg, 1 mmol), catalyst M (20 mg, 0.02 mmol, R=3-methyl) and solvent (50 mL). The inner reaction tube was placed into the hydrogenation reactor. After substitution by hydrogen, with hydrogen filled to a pressure of 15atm, the reaction was stirred under the hydrogen pressure at room temperature for 24 hours. After the hydrogenation was finished, release hydrogen, and open the hydrogenation reactor. The reaction solution was filtered through a short silica gel column to remove the catalyst, and the conversion rate and yield of the reaction were analyzed by nuclear magnetic resonance (NMR). And the optical purity of the product was analyzed after derived to methyl ester compound. The results are listed as table 1.

The experimental results of Example 2-15 in the following table 1 were carried out according to or referred to the same method of the Example 1.

##STR00007##

TABLE-US-00001 TABLE 1 Exam- P.sub.H2 Time Conv. Ee ple M B/S (atm) Solvent (h) (%) (%) 1 1b 0.05 15 EtOH 24 trace not determing 2 1b 0.5 15 EtOH 24 trace not determing 3 1b 1.0 15 EtOH 10 100 87 (S) 4 1b 1.06 15 EtOH 2 100 87 (S) 5 1b 1.5 15 EtOH 2 100 87 (S) 6 1b 3 15 EtOH 2 100 85 (S) 7 1b 1.06 15 MeOH 21 92 78 (S) 8 1b 1.06 15 .sup.iPrOH 20 100 87 (S) 9 1b 1.06 15 .sup.nPrOH 2 100 88 (S) 10 1b 1.06 15 .sup.nBuOH 2 100 89 (S) 11 1a 1.06 15 .sup.nBuOH 3 100 85 (S) 12 1c 1.06 15 .sup.nBuOH 1.5 100 96 (S) 13 1d 1.06 15 .sup.nBuOH 2 100 83 (S) 14 1c 1.06 5 .sup.nBuOH 8 100 91 (S) 15 1c 1.06 60 .sup.nBuOH 1.5 100 92 (S)

[0032] Wherein B/S represents the molar ratio of basic dosage and substrate ∂-ketonic acid dosage, conv. represents the conversion rate analyzed by nuclear magnetic resonance (NMR). The experimental results of Example 16-30 in the following table 2 were carried out in the catalytic of 1c according to or referred to the same method of the Example 1.

##STR00008##

TABLE-US-00002 TABLE 2 Reaction time yield Ee example substrate product (h) (%) (%) 16 [00009] [00010]  1 93 91 (S) 2b 3b 17 [00011] [00012]  1 98 98 (S) 2c 3c 18 [00013] [00014]  3 97 92 (S) 2d 3d 19 [00015] [00016]  5 94 91 (S) 2e 3e 20 [00017] [00018]  3 95 92 (S) 2f 3f 21 [00019] [00020]  4 97 94 (S) 2g 3g 22 [00021] [00022]  5 94 90 (S) 2h 3h 23 [00023] [00024]  4 97 88 (S) 2i 3i 24 [00025] [00026]  4 97 90 (S) 2j 3j 25 [00027] [00028]  8 96 90 (S) 2k 3k 26 [00029] [00030]  1 98 99.2 (S) 2l 3l 27 [00031] [00032] 12 98 91 (S) 2m 3m 28 [00033] [00034]  2 95 82 (S) 2n 3n 29 [00035] [00036] 21 92 77 (R) 2o 3o 30 [00037] [00038]  1 96 56 (S) 2p 3p

EXAMPLE 31

Preparation of (R)-2-hydroxyl-2-(2-chlorin phenyl) acetic acid

[0033] S/C=50000 Carry out the highly conversion experiment in accordance with the same method disclosed in Example 1.

##STR00039##

EXAMPLE 32

Preparation of (S)-2-hydroxyl-2-phenyl acetic acid

[0034] ##STR00040##

[0035] Under the protection of nitrogen atmosphere, to the inner hydrogenation tube (200 mL), were added substrate ∂-ketonic acid 2a (3 g, 20 mmol), potassium tert-butyl oxide (1.68 g, 30 mmol), catalyst 1c (20 mg, 0.02 mmol) and n-butanol(50 mL). The inner reaction tube was placed into the hydrogenation reactor. After substitution by hydrogen, with hydrogen filled to a pressure of 30 atm, the reaction was stirred under the hydrogen pressure at room temperature for 10 hours. After the hydrogenation was finished, release hydrogen and open the hydrogenation reactor. The reaction solution was filtered through a short silica gel column to remove the catalyst, and the conversion rate and yield of the reaction were analyzed by nuclear magnetic resonance (NMR). The conversion rate is 100%. And the optical purity of the product was analyzed after derived to methyl ester compound. The optical purity is 84% ee.

EXAMPLE 33

Preparation of (S)-2-hydroxyl-2-(2-naphthyl) acetic acid

[0036] ##STR00041##

[0037] Under the protection of nitrogen atmosphere, to the inner hydrogenation tube (200 mL), were added substrate ∂-ketonic acid 2m (4 g, 20 mmol), potassium tert-butyl oxide (3.36 g, 30 mmol),catalyst 1b (20 mg, 0.02 mmol) and n-butanol(50 mL). The inner reaction tube was placed into the hydrogenation reactor. After substitution by hydrogen, with hydrogen filled to a pressure of 15 atm, the reaction was stirred under the hydrogen pressure at room temperature for 12 hours. After the hydrogenation was finished, release hydrogen, and open the hydrogenation reactor. The reaction solution was filtered through a short silica gel column to remove the catalyst, and the conversion rate and yield of the reaction were analyzed by nuclear magnetic resonance (NMR). The conversion rate is 100%. And the optical purity of the product was analyzed after derived to methyl ester compound. The optical purity is 95% ee.

EXAMPLE 34

Preparation of (R)-2-hydroxyl-3,3-dimethyl butanoic acid

[0038] ##STR00042##

[0039] Under the protection of nitrogen atmosphere, to the inner hydrogenation tube (200 mL), were added substrate ∂-ketonic acid 2o (2.6 g, 20 mmol) potassium tert-butyl oxide (3.36 g, 30 mmol), catalyst 1b (40 mg, 0.04 mmol) and n-butanol(50 mL). The inner reaction tube was placed into the hydrogenation reactor. After substitution by hydrogen, with hydrogen filled to a pressure of 15 atm, the reaction was stirred under the hydrogen pressure at room temperature for 24 hours. After the hydrogenation was finished, release hydrogen, and open the hydrogenation reactor. The reaction solution was filtered through a short silica gel column to remove the catalyst, and the conversion rate and yield of the reaction were analyzed by nuclear magnetic resonance (NMR). The conversion rate is 100%. And the optical purity of the product was analyzed after derived to benzyl ester compound. The optical purity is 85% ee.

[0040] Although fully description has been made for the present application in combing the specific Examples, it is apparent that modification, or appropriate change and combination can be made to achieve the present invention. In particular, it should be pointed out that all similar replacements and modifications become apparent to those skilled in the art, and they are deemed to be within the spirit, scope and contents of the present invention.