Deprotection method for protected hydroxyl group

Abstract

To deprotect an alcoholic hydroxyl group protected by a t-butyldimethylsilyl group without influencing a functional group unstable to an acid. In the presence of a solvent, an alcohol having a hydroxyl group protected by a t-butyldimethylsilyl group is deprotected in the presence of an acid or an acid salt having a pKa of from 1.0 to 3.0 in water.

Claims

1. A method to remove the t-butyldimethylsilyl group from a t-butyldimethylsilyl ether compound of a secondary or tertiary alcohol, comprising: preparing a reaction mixture by adding the t-butyldimethylsilyl ether compound and an acid substance to a mixture of water and a solvent selected from the group consisting of a nitrile, an amide and an ester; hydrolyzing the t-butyldimethylsilyl ether compound to obtain the secondary or tertiary alcohol; and isolating the secondary or tertiary alcohol from the hydrolyzed reaction mixture; wherein the acid substance is selected from the group consisting of an organic acid, a salt of an organic acid, an inorganic acid and a salt of an inorganic acid; and a pKa of the acid substance in water is from 1.0 to 3.0.

2. The method according to claim 1, wherein the isolation comprises: adding water or an aqueous sodium chloride solution to the hydrolyzed reaction mixture; and extracting the secondary or tertiary alcohol from the aqueous phase with an organic solvent.

3. The method according to claim 1, wherein the acid substance is a carboxylic acid.

4. The method according to claim 3, wherein the carboxylic acid comprises at least two carboxyl groups per molecule.

5. The method according to claim 3, wherein the carboxylic acid is oxalic acid or maleic acid.

6. The method according to claim 1, wherein a proportion of water in the mixed solvent is 0.01water/(organic solvent+water)0.8 by volume ratio.

7. The method according to claim 1, wherein the hydrolysis reaction temperature is from 0 to 100 C.

8. The method according to claim 1, wherein the secondary or tertiary alcohol comprises at least one moiety unstable to an acid, selected from the group consisting of a vinyl ether moiety, an allyl ether moiety, an allyl alcohol moiety, an acetal moiety, a beta-hydroxycarbonyl moiety, a tetrahydropyranyloxy group, an epoxy group, an amide bond, an ester bond and a polyene moiety.

9. The method of claim 1, wherein the organic solvent is selected from the group consisting of N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, N,N-dimethylimidazoline, ethyl acetate, acetonitrile and propionitrile.

10. The method of claim 1, wherein the mixture of water and solvent is free of tetrahydrofuran.

11. A method to remove the t-butyldimethylsilyl group from a t-butyldimethylsilyl ether compound of an alcohol, comprising: preparing a reaction mixture by adding the t-butyldimethylsilyl ether compound and an acid substance to a mixture of water and a solvent selected from the group consisting of a nitrile, an amide and an ester: hydrolyzing the t-butyldimethylsilyl ether compound to obtain the alcohol; and isolating the alcohol from the hydrolyzed reaction mixture; wherein the acid substance is selected from the group consisting of an organic acid, a salt of an organic acid, an inorganic acid and a salt of an inorganic acid: a pKa of the acid substance in water is from 1.0 to 3.0, the mixture of water and the solvent is free of tetrahydrofuran.

Description

EXAMPLES

(1) Measuring methods adopted in the present invention are as follows. Gas chromatography; Agilent 6850 Series manufactured by Agilent Technologies. HPLC; Agilent 1200 Series manufactured by Agilent Technologies. NMR; JNM-AL300, manufactured by JEOL Ltd.

Example 1

(2) To a suspension prepared by mixing 0.2 g (0.82 mmol) of t-butyldimethyl(octyloxy)silane as a compound having 1-octanol protected by TBS, 12 ml of acetonitrile and 4 ml of water, 0.66 g (5.7 mmol) of maleic acid was added, followed by stirring in air at room temperature. Two hours later, the liquid was found to be uniform, and after confirming disappearance of the raw materials by thin-layer chromatography, 10 ml of water was added, followed by extraction twice with 10 ml of chloroform. The organic phase was concentrated under reduced pressure to obtain 0.13 g of a liquid, which was analyzed by gas chromatography and HPLC, whereby the yield of 1-octanol was 98%, and no maleic acid was detected.

(3) The structural characteristics of the 1-octanol were as follows:

(4) .sup.1H-NMR (CDCl.sub.3): 0.88 (m, 3H), 1.29-1.55 (m, 12H), 2.40 (s, 1H), 3.60 (t, 2H)

Example 2

(5) To a suspension prepared by mixing 0.2 g (0.82 mmol) of t-butyldimethyl(2-octan-2-yloxy)silane as a compound having 2-octanol protected by TBS, 12 ml of acetonitrile and 4 ml of water, 0.66 g (5.7 mmol) of maleic acid was added, followed by stirring in air at room temperature. Two hours later, the liquid was found to be uniform, and after confirming disappearance of the raw materials by thin-layer chromatography, 10 ml of water was added, followed by extraction twice with 10 ml of chloroform. The organic phase was concentrated under reduced pressure to obtain 0.12 g of a liquid, which was analyzed by gas chromatography and HPLC, whereby the yield of 2-octanol was 96%, and no maleic acid was detected.

(6) The structural characteristics of the 2-octanol were as follows:

(7) .sup.1H-NMR (CDCl.sub.3): 0.89 (m, 3H), 1.18-1.51 (m, 12H), 1.68 (s, 1H), 3.80 (m, 2H)

Example 3

(8) Deprotection of the following compound 2 as a compound having the following compound 1 protected by TBS, was carried out.

(9) To a suspension prepared by mixing 1.5 g (2.2 mmol) of 4-[(Z)-(1S,5R,6R,7R)-6-[(1E,3R,4R)-3-t-butyldimethylsiloxy-4-(m-tolyl)-1-pentenyl]-7-t-butyldimethylsiloxy-2-oxa-4,4-difluoro-bicyclo[3.3.0]octan-3-ylidene]-1-(tetrazol-5-yl)butane (compound 2), 22.5 ml of acetonitrile and 7.5 ml of water, 0.37 g (3.2 mmol) of maleic acid was added, followed by stirring in air at room temperature. 24 hours later, the liquid was found to be uniform, and after confirming disappearance of the raw materials by thin-layer chromatography, 30 ml of water was added, followed by extraction twice with 30 ml of chloroform. The organic phase was concentrated under reduced pressure to obtain 1.1 g of a solid, which was analyzed by NMR, gas chromatography and HPLC, whereby the yield of 4-[(Z)-(1S,5R,6R,7R)-6-[(1E,3R,4R)-3-hydroxy-4-(m-tolyl)-1-pentenyl]-7-hydroxy-2-oxa-4,4-difluoro-bicyclo[3.3.0]octan-3-ylidene]-1-(tetrazol-5-yl)butane (compound 1) was 98%, and no maleic acid was detected.

(10) The structural characteristics of the compound 1 were as follows:

(11) .sup.1H-NMR (CD.sub.3OD): 1.30 (d, J=7.0 Hz, 3H), 1.69 (dddd, J=14.6, 7.6, 3.0, 2.6 Hz, 1H), 1.82-1.95 (m, 2H), 2.10-2.16 (m, 2H), 2.29 (s, 3H), 2.31-2.41 (m, 2H), 2.48-2.56 (m, 1H), 2.72 (q, J=7.0 Hz, 1H), 2.93 (t, J=7.6 Hz, 2H), 3.78 (q, J=7.6 Hz, 1H), 4.04-4.10 (m, 1H), 4.69 (dt, J=6.48, 2.96 Hz, 1H), 4.79 (dt, J=7.6, 5.0 Hz, 1H), 5.36-5.46 (m, 2H), 6.95-7.13 (m, 4H).

(12) .sup.19F-NMR (CD.sub.3OD): 116.6 (d, J=250.5 Hz), 84.8 (ddd, J=251.9, 17.3, 14.4 Hz).

(13) ##STR00002##

Example 4

(14) To a suspension prepared by mixing 1.5 g (2.2 mmol) of 4-[(Z)-(1S,5R,6R,7R)-6-[(1E,3R,4R)-3-t-butyldimethylsiloxy-4-(m-tolyl)-1-pentenyl]-7-t-butyldimethylsiloxy-2-oxa-4,4-difluoro-bicyclo[3.3.0]octan-3-ylidene]-1-(tetrazol-5-yl)butane (the above compound 2), 27 ml of acetonitrile and 3 ml of water, 0.60 g (4.4 mmol) of sodium hydrogen sulfate monohydrate was added, followed by stirring in air at room temperature. 24 hours later, the liquid was found to be uniform, and after confirming disappearance of the raw materials by thin-layer chromatography, 60 ml of 1.2% sodium bicarbonate water was added, followed by washing three times with 27 ml of heptane. To the acetonitrile-water mixed liquid phase, 1.2 g of sodium hydrogen sulfate was added, followed by extraction with 27 ml of ethyl acetate, and the organic phase was washed with 30 ml of a 5% sodium chloride aqueous solution. The organic phase was concentrated under reduced pressure to obtain 1.1 g of a solid, which was analyzed by NMR, gas chromatography and HPLC, whereby the yield of 4-[(Z)-(1S,5R,6R,7R)-6-[(1E,3R,4R)-3-hydroxy-4-(m-tolyl)-1-pentenyl]-7-hydroxy-2-oxa-4,4-difluoro-bicyclo[3.3.0]octan-3-ylidene]-1-(tetrazol-5-yl)butane (the above compound 1) was 98%.

Examples 5 to 12 and Comparative Examples 1 to 5

(15) The reaction was carried out under the same conditions as in Example 3 except that the type of the acid, the amount of the acid, the solvent, the reaction temperature and the reaction time were respectively changed (Examples 5 to 12). Further, by using an acid other than the acid in the present invention, the reaction was likewise carried out under the same conditions as in Example 3 (Comparative Examples 1 to 5).

(16) The results are shown in Table 1.

(17) In Table 1, abbreviations, etc. are as follows. NaHSO.sub.4: sodium hydrogen sulfate mono-hydrate TfOH: trifluoromethane sulfonic acid AN: acetonitrile THF: tetrahydrofuran *1: Compound 2 underwent decomposition. *2: The reaction did not proceed.

(18) TABLE-US-00001 TABLE 1 Molar ratio Reaction Reaction time Yield of Type of acid (acid/compound 2) Solvent temperature ( C.) (hr) compound 1 (%) Ex. 5 Maleic acid 1.5 AN:Water = 3:1 Room temp. 28 >99 Ex. 6 Maleic acid 14 AN:Water = 3:1 60 2 89 Ex. 7 Oxalic acid 1.5 AN:Water = 3:1 Room temp. 95 >99 Ex. 8 Oxalic acid 14 AN:Water = 3:1 Room temp. 44 95 Ex. 9 NaHSO.sub.4 2 AN:Water = 3:1 Room temp. 126 >99 Ex. 10 NaHSO.sub.4 2 AN:Water = 9:1 Room temp. 24 >99 Ex. 11 NaHSO.sub.4 2 AN:Water = 19:1 Room temp. 7 98 Ex. 12 NaHSO.sub.4 2 AN:Water = 19:1 40 8 95 Comp. Ex. 1 Sulfuric acid 14 Methanol Room temp. 3 22*.sup.1 Comp. Ex. 2 TfOH 14 THF 0 3 0*.sup.1 Comp. Ex. 3 TfOH 14 Methylene Room temp. 3 0*.sup.1 chloride Comp. Ex. 4 Citric acid 14 Methanol Room temp. 24 0*.sup.2 Comp. Ex. 5 Formic acid 14 AN:Water = 1:1 Room temp. 100 0*.sup.2

Example 13

(19) To a suspension prepared by mixing 1.0 g (2.5 mmol) of bisTBS ether of 3-phenoxypropane-1,2-diol, 18 ml of acetonitrile and 2 ml of water, 0.72 g (5.0 mmol) of sodium hydrogen sulfate monohydrate was added, followed by stirring in air at room temperature for 18 hours. After confirming disappearance of the raw materials by thin-layer chromatography, 18 ml of saturated sodium bicarbonate water and 5 ml of a saturated sodium chloride aqueous solution were added, followed by extraction twice with 18 ml of ethyl acetate. The organic phase was concentrated under reduced pressure to obtain 0.38 g of a liquid, which was analyzed by gas chromatography and NMR, whereby the yield of 3-phenoxypropane-1,2-diol was 88%.

(20) The structural characteristics of the 3-phenoxypropane-1,2-diol were as follows:

(21) .sup.1H-NMR (CDCl.sub.3): 3.49 (bs, 1H), 3.69-3.83 (3H), 3.96 (d, 2H), 4.07 (m, 1H), 6.87 (m, 2H), 6.94 (m, 1H), 7.24 (m, 2H)

Comparative Example 6

(22) To a solution prepared by adding 0.51 g (1.29 mmol) of bisTBS ether of 3-phenoxypropane-1,2-diol to 10 ml of tetrahydrofuran (THF), 3.8 ml (3.8 mmol) of a 1 mol/L solution of tetrabutylammonium fluoride was added, followed by stirring in a nitrogen atmosphere at room temperature for 3 hours. After confirming disappearance of the raw materials by thin-layer chromatography, 10 ml of saturated sodium bicarbonate water was added, followed by extraction twice with 10 ml of ethyl acetate and then by washing with a saturated sodium chloride aqueous solution. The organic phase was concentrated under reduced pressure to obtain 0.45 g of a liquid, which was analyzed by gas chromatography and NMR, whereby the yield of 3-phenoxypropane-1,2-diol was 89%. In the formed crude product, a tetrabutylammonium salt was contained in an amount of 1.2 times by mol of the 3-phenoxypropane-1,2-diol.

INDUSTRIAL APPLICABILITY

(23) By using the deprotection method of the present invention, it is possible to protect various alcohols by TBS and carry out various reactions, and it is thereby possible to diversify the reaction designs. Particularly, the method of the present invention effectively contributes to designing reactions of alcohols having moieties unstable to acids (e.g. an alcohol having a vinyl ether in its molecule).

(24) This application is a continuation of PCT Application No. PCT/JP2012/060623, filed on Apr. 19, 2012, which is based upon and claims the benefit of priority from Japanese Patent Application No. 2011-095211 filed on Apr. 21, 2011. The contents of those applications are incorporated herein by reference in its entirety.