PROCESSES FOR PREPARING

6,7,8-TRIHYDROXY-l-(HYDROXYMETHYL)-3-OXO-2-OXA-4-

AZABICYCLO[3.3.1]NONANE

Technical Field

[1] The present invention relates to processes for preparing

6,7,8-trihydroxy-l-(hydroxymethyl)-3-oxo-2-oxa-4-azabicyc lo[3.3. l]nonane. And, the present invention also relates to processes for preparing valiolamine or its derivatives using the same. Background Art

[2] Valiolamine, whose chemical name is

(lS)-(l(OH),2,4,5/l,3)-5-amino-l-C-(hydroxymethyl)-l,2,3, 4-cyclohexanetetrol, possesses a suppressive activity against α-glucosidase (U.S. Patent No. 4,446,319). Further, N-substituted derivatives of valiolamine, e.g., N-

(l,3-dihydroxy-2-propyl)valiolamine, also have α-glucosidase inhibitory activity (U.S. Patent No. 4,701,559). Valiolamine and N-(l,3-dihydroxy-2-propyl)valiolamine are useful for preventing or treating hyperglycemic symptoms and various disorders caused by hyperglycemia, such as diabetes, obesity, and hyperlipemia. Valiolamine and N-(l,3-dihydroxy-2-propyl) valiolamine are represented by the following formulas (Ia) and (Ib).

[3]

[4] Chem, Lett, 1581-1582, 1985 discloses synthetic methods for DL- penta-N,O-acetylvaliolamine from DL- l,2,3-tri-O-acetyl-(l,3/2,4)-4-bromo-6-methylen-l,2,3-cycloh exanetriol. However, these methods have to perform long and complicated resolution and synthetic processes, which cannot apply for industrial-scale mass production.

[5] U.S. Patent No. 4,446,319 discloses methods for preparing valiolamine which comprise performing dehalogenation of

9-bromo-trihydroxy-l-(hydroxymethyl)-3-oxo-2-oxa-4-azabicycl o[3.3.1]nonane (the compound of formula (III) in the following Scheme 1) obtained from valienamine to give 6 ,7 , 8 - trihy droxy- 1 - (hy droxymethy 1) - 3 -oxo-2-oxa-4-azabicy clo [3.3.1] nonane (the compound of formula (II) in the following Scheme 1) and hydrolyzing the compound of formula (II). Further, U.S. Patent No. 4,701,559 discloses methods for preparing N- (l,3-dihydroxy-2-propyl)valiolamine which comprise reacting valiolamine or its nontoxic salt with dihydroxyacetone. The overall processes disclosed in U.S. Patent Nos. 4,446,319 and 4,701,559 are represented by the following Scheme 1:

[6] Scheme 1

[7]

Dehalogenation

Valienamine /III ^

Hydrolysis

(II) (Ia)

(Ib)

[8] In order to perform dehalogenation of the compound of formula (III), U.S. Patent

Nos. 4,446,319 and 4,701,559 disclose several methods; (1) dehalogenation using metal hydride complex reducing agents, such as alkali metal boron hydride, e.g., sodium borohydride; (2) dehalogenation by catalytic reduction procedure using transition metal catalysts, e.g., palladium carbon; (3) dehalogenation using an organic tin hydride, e.g., (n-C H ) SnH; (4) dehalogenation using alkali metal complexes of aluminum hydride, e.g., lithium aluminum hydride; (5) dehalogenation using zinc and hydrochloric acid; and (6) dehalogenation by electrolytic reduction.

[9] However, the methods (1) and (4) generate hydrogen gas, which is very explosive.

Further, in order to isolate the product (i.e., the compound of formula (H)), special manufacturing equipment is required for column chromatography using activated carbon, which is not suitable for industrial-scale mass production.

[10] The method (2) is also explosive and requirs special manufacturing equipment such as hydrogenating reactor.

[11] An organic tin hydride used in the method (3) is one of environmental hormones and may be remained in the product. Therefore, the method (3) is not suitable for preparing medicinal products or synthetic intermediates thereof.

[12] The methods (5) and (6) also require special manufacturing equipment, which is not suitable for industrial- scale mass production. Disclosure of Invention Technical Problem

[13] The present invention provides a process for the dehalogenation of a compound of formula (III), i.e.,

9-bromo-6,7,8-trihydroxy-l-(hydroxymethyl)-3-oxo-2-oxa-4- azabicyclo[3.3.1]nonane, which is safe and can be applied for industrial- scale mass production.

Technical Solution

[14] The present invention provides a process for dehalogenation of a compound of formula (III), wherein phosphite derivatives are employed as a radical-reducing agent, thereby making it possible to apply for industrial-scale mass production.

[15] According to an aspect of the present invention, there is provided a process for preparing a compound of formula (II), which comprises reacting a compound of formula (III) with a compound of formula (IV):

[16]

[17]

[18] o

H-P-O-X (IV)

R

[19] wherein, X is hydrogen, C - C alky 1, or an alkali metal and R is hydrogen or C - C

1 4 1

alkoxy.

[20] According to another aspect of the present invention, there is provided a process for preparing valiolamine or its non-toxic salt, which comprises hydrolyzing the compound of formula (II) obtained from the above process.

[21] According to still another aspect of the present invention, there is provided a process for preparing N-(l,3-dihydroxy-2-propyl)valiolamine or its non-toxic salt, which comprises hydrolyzing the compound of formula (II) obtained from the above process to give valiolamine or its non-toxic salt; and reacting the valiolamine or its non-toxic salt with dihydroxyacetone. Mode for the Invention

[22] A process for preparing a compound of formula (II) according to an embodiment of the present invention includes reacting a compound of formula (III) with a compound of formula (IV), in accordance with the following Reaction Scheme 2 described below:

[23] Scheme 2

[24]

(IV)

(ill) (M)

[25] In the above Reaction Scheme 2, X is hydrogen, C - C alkyl, or an alkali metal and

R is hydrogen or C - C alkoxy.

[26] The compound of formula (III) may be prepared using a known method (e.g., U.S.

Patent No. 4,446,319) and the compound of formula (IV) is commercially available.

[27] In the process of the present invention, the compound of formula (IV) is used as a radical-reducing agent. The compound of formula (IV) is very safe and easy to treat. And, the compound of formula (IV) can be easily removed with a solvent used, at a step for isolating the product, i.e., the compound of formula (II). Further, the de- halogenation using the compound of formula (IV) can be carried out in conventional manufacturing equipments, which can be easily applied for industrial-scale mass production.

[28] The compound of formula (IV) includes hypophosphorous acid, sodium hy- pophosphite, dimethyl phosphite, and diethyl phosphite. Among them, sodium hy- pophosphite may be preferably used. The amount of the compound of formula (IV) may be in the range of about 1 ~ 10 eq., preferably 1 ~ 2 eq., to 1 eq. of the compound of formula (III).

[29] The reaction of a compound of formula (III) with a compound of formula (IV) may be carried out in the presence of an initiator for radical reaction, e.g., azo compounds such as α,α'-azobisisobutyronitrile, peroxides such as benzoyl peroxide, or triph- enylborate, etc. The initiator may be used in a catalytic amount to the compound of formula (III).

[30] Further, the reaction of a compound of formula (III) with a compound of formula

(IV) may be carried out in a solvent selected from the group consisting of water, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, C - C alcohol such as methanol or ethanol, ethers such as tetrahydrofuran, ketons such as acetone or methyl ethyl ketone, esters such as methyl acetate or ethyl acetate, benzenes such as toluene, and a mixture thereof. Among them, a mixed solvent of water and C - C alcohol may be preferably used.

[31] The reaction of a compound of formula (III) with a compound of formula (IV) may be carried out under inert gas, such as nitrogen and argon. Further, the reaction may be carried out at 40 ~ 100 ⁰ C or at a refluxing temperature of a solvent used, for about 3 ~ 5 hours.

[32] The compound of formula (II) obtained according to the processes mentioned in the above may be converted into valiolamine or its non-toxic salt and/or N- (l,3-dihydroxy-2-propyl)valiolamine or its non-toxic salt, in accordance with known methods, e.g., U.S. Patent Nos. 4,446,319 and/or 4,701,559.

[33] For example, the compound of formula (II) may be hydrolyzed to convert into valiolamine or its non-toxic salt. Further, N-substituted derivatives of valiolamine or its non-toxic salt may be obtained, by performing reductive alkylation of the valiolamine or its non-toxic salt with a ketone compound, e.g., dihydroxyacetone.

[34] Therefore, according to another aspect of the present invention, there is provided a process for preparing valiolamine or its non-toxic salt, which comprises hydrolyzing the compound of formula (II) obtained from the above-mentioned process.

[35] Further, according to still another aspect of the present invention, there is provided a process for preparing N-(l,3-dihydroxy-2-propyl) valiolamine or its non-toxic salt, which comprises hydrolyzing the compound of formula (II) obtained from the above- mentioned process to give valiolamine or its non-toxic salt; and reacting the valiolamine or its non-toxic salt with dihydroxyacetone.

[36] Hereinafter, the present invention will be described more specifically by examples.

However, the following examples are provided only for illustrations and thus the present invention is not limited to or by them.

[37] Preparation Example 1.

9-Bromo-6,7,8-trihydroxy-l-(hydroxymethyl)-3-oxo-2-oxa-4- azabicyclo[3.3.1]nonane

[38] 200 ml of an aqueous solution of 9.3 g of N-(benzyloxycarbonyl)valienamine and

250 ml of an aqueous solution of 5.3 g of bromine were simultaneously added dropwise to 100 ml of water cooled to 5 10 ⁰ C over a period of about 1 hour. The reaction mixture was further stirred at the same temperature for 1.5 hours, adjusted to pH 6 with a solution of sodium hydrogen carbonate, and then washed with ethyl acetate. The aqueous solution was concentrated under reduced pressure, and then the residue was chromatographed on a column of MCI Gel CHP 2OP (produced by Mitsubishi Chemical Ind., Ltd., Japan, 600 ml). The eluate was concentrated. The resulting residue was crystallized and then filtered to give 6.5 g of the titled compound.

[39] ¹ H NMR (D ₂ O, 400MHz) δ 4.70 (IH, s), 4.30 (IH, d, / 9.6 Hz), 4.14 (IH, d, / 9.6

Hz), 4.07 (IH, d, / 13.2 Hz), 3.93-3.87 (2H, m), 3.69-3.59 (IH, m)

[40] Example 1. 6,7,8-Trihydroxy-l-(hydroxymethyl)-3-oxo-2-oxa-4-azabicyclo[ 3.3.1] nonane

[41] To a suspension of 100 g of

9-bromo-6,7,8-trihydroxy-l-(hydroxymethyl)-3-oxo-2-oxa-4- azabicyclo[3.3.1]nonane in a mixed solvent of 400 ml of water and 300 ml of methanol, were added 1.1 g of α,α'-azobisisobutyronitrile and 46.2 g of sodium hypophosphite. The reaction mixture was stirred at 80 ~ 85 ⁰ C for 3 hours and then cooled to 50 ~ 60 ⁰ C. The reaction mixture was filtered to discard insoluble materials, and the filtrate was concentrated under reduced pressure. 500 ml of methanol was added to the resulting residue, which was then refluxed for 30 minutes. The reaction mixture was stirred at room temperature for 1 hour and then filtered. The resulting crystal was dried under reduced pressure to give 67 g of the titled compound as a white crystal.

[42] ¹ H NMR (D O, 400MHz) δ 3.82 (IH, d, / 12.4 Hz), 3.69-3.63 (3H, m), 3.60 (IH, d, J 9.2 Hz), 3.49 (IH, t, / 9.2 Hz), 2.15 (IH, dd, / 14.4, 4.4 Hz), 1.94 (IH, dd, / 14.4, 2.0 Hz)

[43] Example 2. 6,7,8-Trihydroxy-l-(hydroxymethyl)-3-oxo-2-oxa-4-azabicyclo[ 3.3.1] nonane

[44] To a suspension of 100 g of

9-bromo-6,7,8-trihydroxy-l-(hydroxymethyl)-3-oxo-2-oxa-4- azabicyclo[3.3.1]nonane in 400 ml of water, were added 1.1 g of α,α'-azobisisobutyronitrile and 46.2 g of sodium hypophosphite. The reaction mixture was stirred at 80 ~ 85 ⁰ C for 3 hours and then cooled to 50 ~ 60 ⁰ C. The reaction mixture was filtered to discard insoluble materials, and the filtrate was concentrated under reduced pressure. 500 ml of methanol was added to the resulting residue, which was then refluxed for 30 minutes. The reaction mixture was stirred at room temperature for 1 hour and then filtered. The resulting crystal was dried under reduced pressure to give 68.3 g of the titled compound as a white crystal.

[45] Example 3. 6,7,8-Trihydroxy-l-(hydroxymethyl)-3-oxo-2-oxa-4-azabicyclo[ 3.3.1]

nonane

[46] To a suspension of 100 g of

9-bromo-6,7,8-trihydroxy-l-(hydroxymethyl)-3-oxo-2-oxa-4- azabicyclo[3.3.1]nonane in 400 ml of ethanol, were added 1.1 g of α,α'-azobisisobutyronitrile and 46.2 g of sodium hypophosphite. The reaction mixture was stirred at 80 ~ 85 ⁰ C for 3 hours. A portion of solvent was distilled off under reduced pressure. The reaction mixture was stirred at room temperature for 1 hour and then filtered. The resulting crystal was dried under reduced pressure to give 58.1 g of the titled compound as a white crystal.

[47] Example 4. 6,7,8-Trihydroxy-l-(hydroxymethyl)-3-oxo-2-oxa-4-azabicyclo[ 3.3.1] nonane

[48] To a suspension of 100 g of

9-bromo-6,7,8-trihydroxy-l-(hydroxymethyl)-3-oxo-2-oxa-4- azabicyclo[3.3.1]nonane in a mixed solvent of 400 ml of water and 300 ml of ethanol, were added 1.1 g of α,α'-azobisisobutyronitrile and 46.2 g of sodium hypophosphite. The reaction mixture was stirred at 80 ~ 85 ⁰ C for 3 hours and then cooled to 50 ~ 60 ⁰ C. The reaction mixture was filtered to discard insoluble materials, and the filtrate was concentrated under reduced pressure. 500 ml of methanol was added to the resulting residue, which was then refluxed for 30 minutes. The reaction mixture was stirred at room temperature for 1 hour and then filtered. The resulting crystal was dried under reduced pressure to give 71 g of the titled compound as a white crystal.

[49] Example 5. 6,7,8-Trihydroxy-l-(hydroxymethyl)-3-oxo-2-oxa-4-azabicyclo[ 3.3.1] nonane

[50] To a suspension of 100 g of

9-bromo-6,7,8-trihydroxy-l-(hydroxymethyl)-3-oxo-2-oxa-4- azabicyclo[3.3.1]nonane in 400 ml of acetonitrile, were added 1.1 g of α,α'-azobisisobutyronitrile and 46.2 g of sodium hypophosphite. The reaction mixture was stirred at 80 ~ 85 ⁰ C for 3 hours. A portion of solvent was distilled off under reduced pressure. The reaction mixture was stirred at room temperature for 1 hour and then filtered. The resulting crystal was dried under reduced pressure to give 60 g of the titled compound as a white crystal.

[51] Example 6. 6,7,8-Trihydroxy-l-(hydroxymethyl)-3-oxo-2-oxa-4-azabicyclo[ 3.3.1] nonane

[52] To a suspension of 100 g of

9-bromo-6,7,8-trihydroxy-l-(hydroxymethyl)-3-oxo-2-oxa-4- azabicyclo[3.3.1]nonane in 400 ml of water, were added 1.1 g of α,α'-azobisisobutyronitrile and 40.6 g of dimethyl phosphite. The reaction mixture was stirred at 80 ~ 85 ⁰ C for 4 hours and then cooled to 50 ~ 60 ⁰ C. The reaction mixture was filtered to discard insoluble materials, and the filtrate was concentrated under reduced pressure. 500 ml of methanol was added to the resulting residue, which was then filtered. The resulting

crystal was dried under reduced pressure to give 57.6 g of the titled compound as a white crystal.

[53] Example 7. 6,7,8-Trihydroxy-l-(hydroxymethyl)-3-oxo-2-oxa-4-azabicyclo[ 3.3.1] nonane

[54] To a suspension of 100 g of

9-bromo-6,7,8-trihydroxy-l-(hydroxymethyl)-3-oxo-2-oxa-4- azabicyclo[3.3.1]nonane in 400 ml of water, were added 1.1 g of α,α'-azobisisobutyronitrile and 39.1 g of sodium hypophosphite. The reaction mixture was stirred at 80 ~ 85 ⁰ C for 4 hours and then cooled to 50 ~ 60 ⁰ C. The reaction mixture was filtered to discard insoluble materials, and the filtrate was concentrated under reduced pressure. 500 ml of methanol was added to the resulting residue, which was then filtered. The resulting crystal was dried under reduced pressure to give 61 g of the titled compound as a white crystal.

[55] Example 8. 6,7,8-Trihydroxy-l-(hydroxymethyl)-3-oxo-2-oxa-4-azabicyclo[ 3.3.1] nonane

[56] To a suspension of 100 g of

9-bromo-6,7,8-trihydroxy-l-(hydroxymethyl)-3-oxo-2-oxa-4- azabicyclo[3.3.1]nonane in 400 ml of water, were added 1.1 g of α,α'-azobisisobutyronitrile and 46.2 g of sodium hypophosphite. The reaction mixture was stirred at 40 ~ 50 ⁰ C for 5 hours. The reaction mixture was filtered to discard insoluble materials, and the filtrate was concentrated under reduced pressure. 500 ml of methanol was added to the resulting residue, which was then filtered. The resulting crystal was dried under reduced pressure to give 54 g of the titled compound as a white crystal. Industrial Applicability

[57] The present invention provides a process for the dehalogenation of

9-Bromo-6,7,8-trihydroxy-l-(hydroxymethyl)-3-oxo-2-oxa-4- azabicyclo[3.3.1]nonane, which is safe and can be applied for industrial- scale mass production. Further, the present invention provides a process for preparing valiolamine or N-(1, 3-di hydroxy- 2-propyl)valiolamine.