KR101540435B1 - Stereoselective synthesis of valiolamine - Google Patents

Abstract

The present invention relates to valiol amines and intermediates compounds and processes for their preparation, said intermediate compounds having the chemical structure as shown in formula (21). The compound of formula (14) containing an isomer by C-acylation can be obtained by forming a bicyclic compound carbamate derivative of formula (21) and then removing the R group of the compound of formula (21) and / To obtain a valiolamine (1) having a purity of about 99%. The high purity valiolamine obtained according to the present invention can be further used for the preparation of high purity voglibose which is a medicine for the treatment of diabetes. The obtained voglibose has a purity of about 99.5% or more as measured by HPLC.

Description

(STEREOSELECTIVE SYNTHESIS OF VALIOLAMINE)

The present invention relates to pharmaceutical intermediate compounds and processes for their preparation, in particular intermediate compounds of valiolamine and processes for their preparation.

The valiolamine (1) is a (1S) - (1 (OH), 2,4,5 / 1,3) -5-amino- It is known as the chemical name of tetrol and has potential inhibitory activity on alpha-D-glucosidase.

Derivatives thereof also have an inhibitory activity on alpha-D-glucosidase, and some compounds have also been developed as drugs such as voglibose and have been used clinically for the treatment of diabetes (J. Med. Chem., 1986, 29, 1038-1046). The valiolamine is the main intermediate in the preparation of voglibose (Reaction Procedure 1) (EP56194, 1982).

Reaction procedure 1

Currently, the preparation of valiolamine can be divided into two types, one based on biosynthesis and the other by chemical synthesis.

The biosynthetic based method initially involves the fermentation of microorganisms to produce valiolamine directly by Streptomyces hygroscopicus sublime Rimnose IFO 12703 (J. Antibiot., 1984, 37, 1301-1307) . It has later been shown that validamycin A can be degraded by microorganisms and decomposed to valienamine and valideamine (Patent Nos. JP57054593, JP58152496, JP62181793, and WO2005098014). WO2006107134, WO2004000782 and WO2005151967 also disclose methods for preparing valienamine from acabos and derivatives thereof, and valienamine and valideamine can be further converted to valiolamine (Patent No. JP57179174, CN1683320, JP58046044) .

Reaction Process 2 is a process for producing valiolamine (1) from valienamine (3) disclosed in Japanese Patent JP57179714.

Reaction procedure 2

Chinese patent CN1683320 discloses a method for producing valiolamine (1) from valienamine (3), as shown in reaction scheme 3. [

Reaction procedure 3

This method involves the first acylation of valienamine (3) to produce compound (7), followed by selective epoxidation to produce compound (8), and finally the opening and deacetylation of the ring structure To produce valiolamine (1). Both Reaction 2 and Reaction 3 use valienamine (3) prepared by fermentation as a raw material, which is not widely used because of limitations due to certain bacteria in the production of valienamine fermentation. Incidentally, it is far from industrial advantages due to the need for post-treatment of unnecessary fermentation broth, low yields, and environmental treatment requirements for significant waste liquids.

Reaction process 4 is the preparation of valiolamine from valued amines (9) through a multistage reaction.

Reaction process 4

As shown through the reaction process, valiolamine is produced through 9 chemical reaction steps. Such a long process results in low yield, high cost, low product competitiveness in mass production, and low industrial value.

In contrast, chemical synthesis methods can achieve mass production, adjustable conditions, high yield, low cost, and visible industrial advantages in a short period of time. J. Org. Chem. An early synthesis disclosed in 1992, 57, 3651-3658 condensed compound 12 with hydroxylamine to produce oxime 13 followed by hydrogenation to the 5'anomer 14 ' ) And the benzyl group is removed to produce the valiolamine (1) and the 5 ' amino anomer (15). The content of the anomer (15) is about 6%. Careful column chromatography is required to obtain the pure valiolamine (1), which is an obstacle to a large amount of industrial production.

Reaction process 5

JP2003146957 discloses a method for synthesizing valiolamine (1), which is subjected to at least 10 steps starting from glucose (16) and producing valiolamine (1) as shown in reaction scheme 6.

Reaction process 6

This process involves low yield and high cost, and lowers the competitiveness of the product.

WO2005 / 049547 and WO2005 / 092834 disclose methods for synthesizing valiolamine (1). This process involves the reductive amination of compound (12) and ammonium acetate to form crude tetrabenzyl-valiol amine (14 ') as shown in reaction scheme 7, and removal of the benzyl group to produce valiolamine (1) do.

Reaction process 7

The benzyl group was further removed from the obtained tetrabenzyl-valiol amine (14 ') to obtain a more pure valiolamine (1) having a purity of only 88% and a purity of 98.7%, followed by column chromatography It must go through.

Since valiolamine can be used to produce voglibose via a single reaction step, the quality of the valiolamine directly affects the quality of the final product, voglibose. Highly purified valiolamine is required for the production of high purity voglibose. In the present analysis of the production method of valiolamine, the method based on the biological synthesis has a disadvantage that there is a limitation in using and promoting such a method because it is difficult to easily obtain the raw material. In addition, the production of the above raw materials requires a fermentation process, which results in a large amount of fermentation, low yield, unstable microorganism species, difficult and complex separation processes, excessive labor, large amounts of waste, environmental pollution and other disadvantages . In comparison, chemical synthesis has short cycle processes, ease of mass production, low cost, relative cleanliness and stability, ease of control, and other advantages. However, chemical synthesis methods also have some problems, such as long reaction times, low product purity and other difficulties, especially low purity and difficulty in 5 'anomer removal, and separation and purification difficulties. Therefore, it is urgently required to provide a convenient method of producing a high-purity valiolamine at a large capacity.

The present invention provides intermediate compounds for the preparation of high purity valiol amines (1). Also provided are methods of making the compounds.

The present invention provides intermediate compounds and processes for the preparation of high purity valiol amines (1). The compound has the following structure,

Wherein R is a benzyl, benzyl, t-butyldimethylsilyl group, preferably a hydroxyl protecting group such as a benzyl group.

The high purity valiolamine obtained according to the present invention can be further used for the preparation of high purity voglibose which is a medicine for the treatment of diabetes. The obtained voglibose has a purity of about 99.5% or more as measured by HPLC.

Figures 1 to 3 are X-ray powder diffraction patterns of compound crystals of formula (21 ').
Figure 4 shows the IR spectrum of the compound crystals of formula (21 ').
5 shows the ¹ H-NMR spectrum of the compound crystals of the formula (21 ').
6 shows a differential scanning calorimetric curve of a compound crystal of formula (21 ').

The present invention provides intermediate compounds for the preparation of high purity valiol amines (1). The compound has the following structure,

Wherein R is a benzyl, benzyl, t-butyldimethylsilyl group, preferably a hydroxyl protecting group such as a benzyl group.

In particular, when R is a benzyl group, the compound is a tetrabenzyl-valiolamine-1,5-carbamate of formula (21 ') and the chemical name is (1S, 5S, 6S, 7R, 8S) -Benzyl-1-benzyloxymethyl-3-oxo-2-oxa-4-azabicyclo [3.3.1] nonane.

The present invention also provides a process for preparing a compound of formula (21). That is, the compound of formula (14) containing the isomer is subjected to C-acylation to form a bicyclic compound valiolamine-1,5-carbamate derivative of formula (21).

The process further comprises recrystallizing the compound of formula (21) to obtain a crystallized product thereof.

For example, the isomer-containing compound tetrabenzyl-valiolamine of the above formula (14 ') can be converted to the bicyclic compound tetrabenzyl-valiolamine-1,5-carbamate of formula (21' .

The compound of formula (21 ') is further purified through recrystallization to obtain crystals of the compound of formula (21').

Therefore, another object of the present invention is to provide a crystalline form of the compound of formula (21 ') having the following peak in X-ray powder diffraction (Cu):

2θ = 4.70 ± 0.2 °, 6.52 ± 0.2 °, 8.38 ± 0.2 °, 9.40 ± 0.2 °, 13.06 ± 0.2 °, 15.64 ± 0.2 °, 16.14 ± 0.2 °, 16.82 ± 0.2 °, 18.40 ± 0.2 °, °, 22.64 ± 0.2 °, 23.24 ± 0.2 °, 24.02 ± 0.2 °, 25.36 ± 0.2 ° and 27.12 ± 0.2 °.

The crystals have characteristic absorption peaks at about 173.8 DEG C on Differential Scanning Calorimetry (DSC).

The crystals have an infrared spectrum as shown in the infrared (IR) spectroscopic analysis of FIG.

At this time, the melting point of the compound is 168-172 占 폚.

It is still another object of the present invention to provide a process for preparing a compound of formula (22) by hydrolyzing a compound of formula (21) and / or a crystal thereof and a process for preparing a compound of formula (22) Step; Or a compound of the formula (21), which comprises the step of removing the R group in the compound of the formula (21) and / or the crystal thereof to prepare a compound of the formula (6), and hydrolyzing the compound to prepare a valiolamine (1) by using a compound of the formula (1).

The process of this reaction is as follows:

Reaction procedure 8

Here, the R group is a benzoyl, benzyl, t-butyldimethylsilyl group, and preferably a hydroxyl protecting group such as a benzyl group.

In the present invention, a precursor compound (21) of valiolamine is synthesized stereoselectively, and then the R group is removed, followed by hydrolysis or hydrolysis, followed by removing the R group to obtain a highly pure valiolamine (1). The high purity valiolamine of the present invention can be used in the production of high purity boglibose (2). Therefore, the present invention also provides a method for producing voglibose. The reaction process is as follows:

Reaction process 9

For example, the tetrabenzyl-valiol amine (14 ') containing an isomer can be reacted via C-acylation with a dicyclic compound (21'), i.e. tetrabenzyl-valiolamine-1,5-carbamate Benzyl-1-benzyloxymethyl-3-oxo-2-oxa-4-azabicyclo [3.3.1] nonane) was synthesized in the same manner as in (1S, 5S, 6S, 7R, . The cyclic compound (21 ') may first hydrolyze through opening of the ring structure to form tetrabenzyl-valiol amine (22'), and then remove the benzyl group to remove the high purity valiolamine (1) Or; Alternatively, the tetrabenzyl-valiolamine-1,5-carbamate compound (21 ') may first be debenzylated to form the compound (6), followed by hydrolysis to produce the valiolamine (1) have. The reaction procedure is as follows.

Reaction procedure 10

A key feature of the present invention is that the valiolamine (1) is produced via the main intermediate (21). By forming the dicyclic compound of the formula (21), the hydroxy group of the S 'configuration of the 1' (1-C) is linked to the 5 '(5-C) S-type amino group through a carbonyl group, The resulting dicyclic compound (21) becomes a very stable crystal, thereby facilitating separation and purification. However, since the 5 'R-type amino group can not be linked to the 1' S-type hydroxyl group to form a cyclic compound, the compound of formula (21) The anomer derivative having an R-type amino group is also completely removed, thereby achieving the object of purification and obtaining a high-purity cyclic compound (21).

In the present invention, highly purified dicyclic compound (21) crystals are obtained by reacting a compound of formula (14) with a corresponding C-acylating reagent, and achieve the object of stereoselective synthesis of the precursor of valiolamine ; Then, by removing the R group and the carbonyl protecting group, high purity valiolamine (1) is obtained. The valiolamine produced through this reaction has few impurities, especially the 5 'amino anomer (15).

More specifically, the compound of formula (14), which may include an isomer, is reacted with a C-acylating reagent such as phosgene, trichloromethyl chloroformate, bis (trichloromethyl) , The compound of formula (14) undergoes an intramolecular condensation reaction in which the 1 '(1-C) S-type hydroxy group is converted to the 5' (5-C) S- An amino group and a carbonyl group to form a bicyclic compound (21), while an anomer having an R-type amino group of 5 'can not participate in such an intramolecular condensation reaction. This reaction is stereoselective and the bicyclic compound 21 can be easily crystallized and purified and the anomer and its derivatives and other impurities can be removed together, Lt; RTI ID = 0.0 > stereoselectivity < / RTI >

Compounds of formula (14) which may contain impurities or isomers may be obtained, for example, by reduction of the corresponding hydrazoates (20) (JP2003146957); Or reductive amination of compound (12) (WO2005 / 049547, WO2005 / 092834); Or reduction after oximation of the compound (12) (J. Org. Chem. 1992, 57, 3651-3658); However, the compounds of the formula (14) obtained by the above method can be directly used in the present invention without needing to be purified by other methods such as column chromatography.

The resulting impure compound 14, such as compound 14 ', is dissolved in a polar aprotic solvent or a nonpolar solvent, wherein the polar aprotic solvent is dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran But are not limited to, furan, 1,4-dioxane, ethyl ether, diisopropyl ether, diethylene glycol dimethyl ether, ethyl acetate, acetone, 2-butanone, cyclohexanone, dimethylsulfoxide, Lt; / RTI > may be one or several selected from the group; The nonpolar solvent may be selected from the group consisting of carbon tetrachloride, cyclohexane, and hexane. Then, a base is added, which may be an organic base or an inorganic base; The organic base may be selected from the group consisting of triethylamine, N-methylmorpholine, pyridine and 4-dimethylaminopyridine; The inorganic base may be selected from the group consisting of potassium carbonate, sodium carbonate, sodium bicarbonate, potassium hydroxide, sodium hydroxide, lithium hydroxide and lithium carbonate. In the temperature range of -20 to 50 캜, a C-acylating reagent in a polar aprotic or nonpolar solvent is added dropwise. The corresponding C-acylating reagent may be selected from the group consisting of phosgene, trichloromethyl chloroformate and bis (trichloromethyl) carbonate, preferably bis (trichloromethyl) carbonate Because it is solid, easy to weigh and low in risk; The polar aprotic solvents include but are not limited to dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, ethyl ether, diisopropyl ether, diethylene glycol dimethyl ether, ethyl acetate, acetone, Cyclohexanone, dimethylsulfoxide, or a mixture thereof; The nonpolar solvent may be carbon tetrachloride, cyclohexane or hexane. Polar aprotic solvents are preferred, in which case dichloromethane, diisopropyl ether and tetrahydrofuran are more preferred. After addition of the C-acylation reagent, the reaction is carried out for 1-24 hours; Preferably 8-10 hours, and after completion of the reaction, the reaction solution is treated in a conventional manner. For example, the reaction solution is poured into water or extracted with an organic solvent. The corresponding organic solvent may be a polar aprotic solvent such as chloroform, dichloromethane, ethyl acetate, ethyl ether, isopropyl ether, butanone or cyclohexanone. The extracted liquid phase is then washed sequentially with water, 2N hydrochloric acid solution, 5% aqueous sodium carbonate solution, saturated brine, and dried with anhydrous sodium sulfate. The extraction solution is recovered and the remaining solids are a crystallized crude cyclized product 21 '.

The crude cyclic product can be effectively purified through recrystallization, and a white crystal having a purity of about 99% or more can be obtained. The solution of recrystallization is a C1-C5 lower aliphatic alcohol such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol; Or ethers such as ether, isopropyl ether, tetrahydrofuran, 1,4-dioxane; Or esters such as ethyl acetate, methyl acetate; Or ketones such as acetone, butanone, and cyclohexanone. Which may be one of the above solvents or mixtures thereof.

The resulting product (21 ') has a white acicular crystalline appearance and a melting point at 168-172 DEG C, and its structure can be determined by ¹ H-NMR spectrum, ¹³ C-NMR spectrum IR spectrum, elementary analysis, rotation, and differential scanning calorimetry.

In addition, the aspect of the crystal has a feature by the X-ray diffraction pattern of the powder. In particular, there are x-ray diffraction peaks at 2? = 4.70 ± 0.2 °, 6.52 ± 0.2 °, 9.40 ± 0.2 °, 18.40 ± 0.2 °, 24.02 ± 0.2 ° and 25.35 ± 0.2 °; This is due to the fact that the x-rays at 2θ = 8.38 ± 0.2 °, 13.06 ± 0.2 °, 15.64 ± 0.2 °, 16.14 ± 0.2 °, 16.82 ± 0.2 °, 20.60 ± 0.2 °, 22.64 ± 0.2 °, 23.24 ± 0.2 ° and 27.12 ± 0.2 ° It has additional features due to diffraction peaks.

The compound of the above formula (22) can be obtained by basic hydrolysis of the purified crystalline product such as hydrolyzing the crystal of the compound (21 ') in an alkaline medium. The base in the alkaline medium may be an inorganic base such as sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, barium hydroxide, sodium carbonate, potassium carbonate; The solvent may be an aqueous solution containing a short chain aliphatic alcohol of C1-C5, such as methanol, ethanol, isopropanol, in a concentration of 10% -90% (v / v); The medium is an aqueous solution of 10% -90% of acetone, tetrahydrofuran, 1,4-dioxane, DMF (N, N-dimethylformamide) and DME (N, N-dimethylacetamide) Lt; / RTI > Preferably a short chain aliphatic alcohol of C1-C5, more preferably ethanol, isopropanol, and the preferred concentration is 75-80% (water: ethanol) (v / v). The reaction temperature may range from room temperature to reflux temperature; The reaction time is 2-48 hours, preferably 24 hours. The end point of the reaction can be deduced through the disappearance of the raw materials at the end of the reaction by thin layer chromatography (TLC). After completion of the reaction, the reaction solution is treated in a conventional manner. For example, the reaction solution may be poured into ice water or extracted with an organic solvent, and the corresponding solvent may be a polar aprotic solvent such as chloroform, dichloromethane, ethyl acetate, ethyl ether, isopropyl ether, butanone, Can be used daily; The extract was then washed sequentially with water, 2N hydrochloric acid solution, 5% aqueous sodium carbonate solution and saturated brine; It can be dried with anhydrous sodium sulfate and then recovered with an extraction solvent. The remaining colorless oil is tetrabenzyl-valiolamine (22 '). In addition, the reaction solution is first concentrated and then subjected to layered extraction with an organic solvent and water, and the corresponding organic solvent may be chloroform, methylene chloride, toluene, ethyl ether, isopropyl ether, and the like , Preferably toluene, methylene chloride; The extract was then washed sequentially with water, 2N hydrochloric acid solution, 5% aqueous sodium carbonate solution and saturated brine; It can be dried with anhydrous sodium sulfate and then recovered with an extraction solvent. The remaining colorless muconic oil is a compound of formula (22 ') which can be used directly in the next reaction.

The valiolamine (1) may be prepared from the compound of formula (22 ') by debenzylation. More specifically, it is possible to use ammonia / lithium metal (see Synthesis 1999, (4), 571-573) or boron tribromide (see J. Am. Chem. Soc., 1999, 121, 6973-6983) , Or palladium-carbon / hydrogen (see WO 2005/049547; J. Am. Chem. Soc., 1999, 121, 6973-6983); Or palladium black / formic acid (J. Org. Chem. 1992, 57, 3651-3658), through which benzyl can be easily removed and valiolamine can be obtained.

The valiolamine (1) obtained according to the present invention is crystallized as white crystals in methanol. The structure is verified by ¹ H-NMR spectrum, ¹³ C-NMR spectrum, IR spectrum, elementary analysis, specific rotation, and differential scanning calorimetry. The purity is 99% or more as measured by high pressure liquid chromatography (HPLC), and more specifically, the purity can reach 99.5% or more.

The valiolamine (1) can also be prepared by a reaction process comprising removal of the R group such as benzyl of the compound (21) provided in the present invention followed by hydrolysis (as shown in reaction step 8). For example, the method of debenzylation can be carried out in a liquid ammonia / lithium metal (see Synthesis, 1999, (4), 571-573), or boron tribromide (J. Am. Chem. Soc. -6983) or palladium-carbon / hydrogen (see WO 2005/049547; J. Am. Chem. Soc., 1999, 121, 6973-6983); Or palladium black / formic acid (J. Org. Chem. 1992, 57, 3651-3658). The present invention provides a process using palladium-carbon / hydrogen, ie, a process wherein the cyclic compound (21 ') is dissolved in ethanol / tetrahydrofuran (1: And the mixture is reacted under 10 atm of hydrogen for 10 hours to prepare the debenzylated product (6). Compound (6) can be further hydrolyzed to produce valiolamine (1), and the specific conditions for hydrolysis are described in J. Med. Chem., 1986, 29, 1038-1046 or U.S. Pat. No. 4,803,303. In the present invention, the hydrolysis is carried out in an aqueous solution of barium hydroxide, and the reflux is carried out for 8 hours. After completion of the reaction, carbon dioxide gas is added so that the pH becomes almost neutral. The excess caustic baryta is removed and the barium carbonate precipitate is filtered, the aqueous solution is concentrated and the residue is added to methanol to separate the white crystalloid valiolamine.

The above-mentioned valiol amines prepared by the method involving hydrolysis after debenzylation are identified as valiol amines prepared via hydrolysis and debenzylation. The purity when measured by HPLC is 99%, in particular 99.5% or more.

The high purity valiolamine produced in accordance with the present invention can be further used to produce high purity voglibose, a drug for treating diabetes. The prepared voglibose has a purity of 99.5% or more, especially 99.8% or more when measured by HPLC.

Detector:

Nuclear Magnetic Resonator

The nuclear magnetic resonance apparatus is Bruker's AVANCE AV500 superconducting nuclear magnetic resonance apparatus.

An elemental analyzer

The elemental analyzer is a Bario EL elemental analyzer manufactured by ELEMENTAL.

Polarimeter

Polarimeter POLARTRONIC HHW5

X-ray powder diffraction

The X-ray powder diffractometer is D / max-rC type from Rigaku (Japan).

The x-ray is emitted from the copper target (x-ray tube with a copper target cathode)

Divergence slit 1 °, receiving slit 0.15 mm, scatter slit 1 °, tube voltage 40 KV, tube flow 50 mA

Differential Scanning Calorimetry (DSC)

The differential scanning calorimeter is NETZSCH DSC204 type.

Sample weight: 3.11 mg

Temperature range: 30-200 ℃

Heating rate: 10 ° C / min

IR spectrum

The IR spectrum was of the Bruker EQUINOX55 type and measured by the potassium bromide-disc method.

Example  One. Crude Tetrabenzyl - Valiolamine  (14 ') < / RTI >

Org. Chem. 1992, 57, 3651-3658, Compound (12) (50 g), 100 g of hydroxylamine hydrochloride and 50 g of anhydrous sodium acetate were mixed in 1000 ml of methanol and reacted by stirring overnight. The reaction solution was concentrated, and the residue was layer-separated into 2000 ml of ethyl acetate and 500 ml of water. The ethyl acetate layer was washed successively with 2N hydrochloric acid solution, saturated sodium bicarbonate solution and saturated brine and dried over anhydrous sodium sulfate. The ethyl acetate was recovered and the colorless oil remaining was dissolved in 500 ml of methanol, 15 g of Raney Ni was added and the hydrogenation was carried out under 10 atm of hydrogen for 5 hours. The reaction solution was filtered and the filtrate was concentrated to give 50 g of a reddish brown oil, i.e., product (14 '), which can be used directly for the next reaction.

Example  2. Tetrabenzyl valiolamine -1,5-carbamate (21 ')  Produce

50 g of the obtained compound (14 ') was dissolved in 500 ml of methylene dichloride, 100 ml of triethylamine was added, and then 12 g of bis (trichloromethyl) carbonate was added dropwise slowly dropwise The reaction mixture was stirred for 2 hours after the dropwise addition. The reaction solution was poured into ice water and the methylene dichloride layer was separated and washed successively with 2N hydrochloric acid solution, 5% sodium carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The methylene dichloride was recovered and the remaining crystals were the crude product of compound (21 '). The crude product was recrystallized from 1000 ml of pure ethanol to obtain 40 g of white precipitate. HPLC purity: 99.8%. Mp: 170-172 ° C, ¹ H-NMR (CDCl ₃ , 500 MHz) δ 1.92 (2H, m, 9 -CH 2), δ 3.46 (1H, dd, J = 2.7, 8.7 Hz, 6- CH), δ3.38 (1H, d , J = 8.9, 1-CH 2 OBn), δ3.64 (1H, m, 5-CH), δ3.68 (1H, d, J = 11.7, 1-OCH _{2 Ph), δ4.42 (1H,} d, J = 11.7, 1-OCH 2 Ph), δ4.58 (1H, d, J = 11.5, 8-OCH2), δ4.61 (1H, d, J = J = 11.4, 6-OCH2),? 4.80 (1H, d, J (d, J = = 10.8,7-OCH2),? 4.86 (1H, d, J = 11.4,8-OCH2),? 6.81 (1H, d, J = 4.5, -NH),? 7.15-7.35 , Ar-H).

¹³ C-NMR (CDCl 3, 125 MHz)? 27.5, 47.5, 71.2, 72.1, 73.3, 75.2, 75.9, 81.8, 81.9, 82.4, 83.2, 137.5, 137.9, 138.4, 138.5, _{^{[α] 20 D + 34.0 °}} ( value CHCl _3); Elemental analysis: C ₃₆ H ₃₇ NO ₆ , calculated (%) C, 74.59; H, 6.43; N, 2.42; Experimental value (%) C, 74.20; H, 6.39; N, 2.33; IR (KBr) v 3302, 3086, 3063, 031, 2916, 2865, 1714, 1673, 1453, 1331, 1087, 1067, 735, 697; MS (EI) m / e: 580 (M ⁺ +1), 579 (M ⁺ ), 488, 91 (100); The x-ray powder diffraction pattern is as shown in Fig. 1, and the related data are shown in Table 1. The IR spectrum of the compound is shown in FIG. 4, the 1 H-NMR spectrum is shown in FIG. 5, and the differential scanning calorimetry pattern is shown in FIG.

Table 1 shows X-ray powder diffraction data.

2? d-value I / I ₀ 4.700 18.7856 26 6.520 13.5453 100 8.380 10.5425 10 9.400 9.4007 33 13.060 6.7733 18 15.640 5.6613 15 16.140 5.4870 14 16.820 5.2667 18 18.400 4.8178 34 20.600 4.3080 16 22.640 3.9242 11 23.240 3.8423 13 24.020 3.7018 19 25.360 3.5092 23 27.120 3.2853 9

Example  3. Tetrabenzyl - Valiolamine -1,5-carbamate (21 ')

25 g of the compound (14 ') obtained in Example 1 was dissolved in 250 ml of chloroform, 60 g of potassium carbonate was added, and then 5 g of trichloromethyl chloroformate was added dropwise dropwise at 0 캜 with stirring. After completion, the reaction was allowed to proceed by stirring for 2 hours. The reaction mixture was poured into ice water and the chloroform layer was separated and washed sequentially with 2N hydrochloric acid solution, 5% sodium carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. Chloroform was recovered and the remaining crystals were the crude product of compound (21 '). The crude product was recrystallized using 800 ml of methanol to obtain about 18 g of white precipitate. Melting point (mp): 169-171 DEG C Purity: 99.7%. Verification of the structure data is the same as in the second embodiment. The X-ray powder diffraction pattern is shown in Fig.

2? d-value I / I ₀ 4.660 18.9468 36 6.480 13.6288 100 8.340 10.5930 14 9.360 9.4408 52 13.020 6.7940 18 15.620 5.6685 33 16.080 5.5073 24 16.780 5.2791 23 18.340 4.8335 44 20.500 4.3288 24 22.580 3.9345 15 23,200 3.8308 20 23.980 3.7079 27 25.300 3.5173 33 27.080 3.2900 15

Example  4. Tetrabenzyl valiolamine -1,5- Carbamate  Produce

25 g of compound (14 ') obtained in Example 1 was dissolved in 250 ml of chloroform, 50 ml of pyridine was added, and then phosgene gas was slowly added with stirring at -10 캜. After the starting material 14 'has disappeared in thin layer chromatography (TLC), the reaction solution is poured into ice water and the chloroform layer is separated and washed successively with 2N hydrochloric acid solution, 5% sodium carbonate solution and saturated brine, ≪ / RTI > and dried over sodium sulfate. Chloroform was recovered and the remaining crystals were the crude product of compound (21 '). The crude product was recrystallized using 300 ml of n-propanol to obtain about 19 g of white precipitate. Melting point: 168-170 占 폚. HPLC purity: 99.6%. The structure data are the same as those in the second embodiment. The x-ray powder diffraction pattern is shown in Fig.

2? d-value I / I ₀ 4.680 18.8658 51 6.520 13.5453 100 8.360 10.5677 18 9.380 9.4207 70 13.040 6.7836 18 15.640 5.6613 22 16.100 5.5005 34 16.800 5.2729 34 18.380 4.8230 64 20.540 4.3204 29 22.620 3.9276 19 23.220 3.8272 23 23.980 3.7079 44 25.340 3.5119 46 27.100 3.2877 17

Example  5. Valiolamine  Produce

Tetrabenzyl - Valiolamine  (22 ') < / RTI >

126 g of compound (21 '), 80 g of sodium hydroxide, 800 ml of water and 3400 ml of ethanol were mixed and refluxed for 24 hours. After completion of the reaction, the ethanol was recovered and the residue was extracted with 1000 ml of toluene. The toluene layer was washed successively with water, 2N hydrochloric acid solution, 5% sodium carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The colorless mucilage oil remaining on recovery of the toluene was the product (22 '), which was about 120 g, which can be used directly in the next reaction.

Valiolamine  Produce

About 50 g of the resulting product oil 22 'was dissolved in 1000 ml of methanol, 50 ml of 94% formic acid and 5 g of palladium black were added and reacted for 18 hours at room temperature with stirring. The reaction solution was filtered. The filtrate was concentrated and the residue was loaded on a strong acid ion exchange resin column, extracted with water and extracted with 0.5N ammonia water. The extracted solution was concentrated to dryness and methanol was added thereto to separate white crystals, that is, valiolamine. The valiolamine was further recrystallized with methanol to obtain a white crystal having a purity of 99.6% as measured by HPLC Can be obtained.

Example  6. Valiolamine  Produce

Valiolamine -1,5- Carbamate  (6) (chemical name: (1S, 5S, 6S, 7R, 8S) 6,7,8- Trihydroxy -One- Hydroxymethyl -3-oxo-2-oxa-4- Azabicyclo [3.3.1] nonane  Produce

20 g of tetrabenzyl valiolamine-1,5-carbamate (21 ') was dissolved in 500 ml of tetrahydrofuran / ethanol (1: 1) (v / v) and 5 g of 10% Pd / Hydrogenation debenzylation reaction was allowed to take place for 10 hours under a pressure of 10 atm H _{2 at} room temperature. After completion of the reaction, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to recover the reaction solvent. The residue was recrystallized from methanol to give about 8 g of white crystals, valiolamine-1,5-carbamate (6).

Valiolamine  Produce

5 g of valiolamine-1,5-carbamate was dissolved in 150 ml of water, and 20 g of caustic baryta was added thereto, followed by stirring for 3 hours while maintaining the temperature at 70-80 占 폚. The reaction solution was cooled to 20 < 0 > C and carbon dioxide gas was added for 30 minutes. The resulting precipitate was removed and washed with water. The filtrate and the washing solution were combined and evaporated under reduced pressure to remove water. The residue was recrystallized from methanol to give about 4 g of valiolamine white powder crystals. HPLC purity: 99.8%.

Example  7. Boglibose  Produce

2.0 g of valiolamine obtained in Example 5 was dissolved in 50 ml of N, N-dimethylformamide, and 3.4 g of 1,3-dihydroxyacetone, 1.5 ml of 2 mol / L hydrochloric acid and 2.6 g of sodium cyanide Norbornane hydride was added thereto, followed by stirring at room temperature for 16 hours. The reaction solution was concentrated, the concentrate was dissolved in 100 ml water, acidified with 2 mol / L hydrochloric acid, cooled with stirring for 30-40 minutes and loaded on a 250 ml Dowex 50 Wx8 (H ⁺ ) chromatography column. After washing with water, the product was completely eluted with 0.5 mol / L ammonia water. The extraction flow was concentrated under reduced pressure conditions, the residue was refluxed in 400 ml of pure ethanol for 30 minutes, 0.2 g of activated carbon was added upon cooling and refluxed for 15 minutes and filtered. The filtrate was cooled at room temperature. The resultant white powder was filtered and dried in a vacuum of 40 캜 for 12 hours to obtain 1.9 g of voglibose crystal powder. Melting point: 164.1-165.7 占 폚; HPLC purity: 99.8%.

Example  8. Boglibose  Produce

3.0 g of valiolamine obtained in Example 6 was dissolved in 75 ml of N, N-dimethylformamide, and 5.1 g of 1,3-dihydroxyacetone, 2.3 ml of 2 mol / L hydrochloric acid and 4 g of sodium cyanoborate Followed by stirring at room temperature for 16 hours. The reaction solution was concentrated. The concentrate was dissolved in 150 ml water, acidified with 2 mol / L hydrochloric acid, cooled with stirring for 30-40 minutes and loaded on a 375 ml Dowex 50 Wx8 (H ⁺ ) chromatography column. After washing with water, the product was completely eluted with 0.5 mol / L ammonia water. The elution flow was concentrated under reduced pressure conditions and the residue was refluxed in 600 ml of pure ethanol for 30 min, 0.3 g of activated carbon was added upon cooling and refluxed for 15 min and filtered. The filtrate was cooled at room temperature, and the resulting white powder was filtered and dried at 40 캜 under vacuum for 12 hours to obtain 2.8 g of voglibose crystal powder. Melting point: 164.3-165.8 占 폚; HPLC purity: 99.9%.

Claims (17)

delete delete delete delete delete delete (21), comprising the step of C-acylating a compound of formula (14) to prepare a bicyclic compound valiolamine-1,5-carbamate derivative of formula (21) , A method for producing an intermediate compound for producing valiolamine,

Wherein R is a hydroxyl protecting group.
The method of claim 7, wherein the compound of formula (14) is dissolved in a polar aprotic solvent or a nonpolar solvent, then a base is added and a C-acylating reagent in a polar aprotic solvent or a non- And further reacting for 1-24 hours.
9. The process of claim 8 wherein the polar aprotic solvent is selected from the group consisting of methylene dichloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, ethyl ether, diisopropyl ether, diethylene glycol dimethyl ether, Ethyl acetate, acetone, 2-butanone, cyclohexanone and dimethyl sulfoxide, or mixtures thereof; The nonpolar solvent is selected from the group consisting of carbon tetrachloride, cyclohexane, and n-hexane; Wherein the base is an organic base or an inorganic base, wherein the organic base is selected from the group consisting of triethyleneamine, N-methylmorpholine, pyridine and DMAP; The inorganic base is selected from the group consisting of potassium carbonate, sodium carbonate, sodium bicarbonate, potassium hydroxide, sodium hydroxide, lithium hydroxide and lithium carbonate; Wherein said C-acylating reagent is selected from the group consisting of phosgene, trichloromethyl chloroformate, and bis (trichloromethyl) -carbonate.
10. The method of claim 9, wherein the C-acylating reagent is bis (trichloromethyl) carbonate.
The method according to claim 7, wherein the compound of formula (21) is further purified by recrystallization to obtain a crystal of compound (21).
The compound according to claim 7, wherein the compound of formula (14 ') is tetrabenzyl-valiolamine which is C-acylated to produce a bicyclic compound (21') tetrabenzyl-valiolamine-1,5-carbamate How to.

13. The method according to claim 12, wherein the compound (21 ') is further purified by recrystallization to obtain a crystal of the compound (21').
Hydrolyzing a compound of the formula (21) or a crystal thereof to prepare a compound of the formula (22) as in the following reaction process, and then removing the R group to prepare valiolamine (1); or
Removing the R group of the compound of formula (21) or its crystal to prepare a compound of formula (6), and then hydrolyzing to prepare valiolamine (1);
(1), which comprises the steps of:

Wherein R is a hydroxy protecting group. 15. The method according to claim 14, wherein R is a benzyl group,

As in the following reaction process
1) preparing a bicyclic compound valiolamine-1,5-carbamate derivative of the formula (21) from the compound of the formula (14) via C-acylation;
2) preparing valiolamine (1) from the compound of formula (21); And
3) Preparation of voglibose (2) from valiolamine (1)
≪ / RTI >

Wherein R is a hydroxy protecting group.
17. The method according to claim 16, wherein R is a benzyl group.

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