CN103819357B - The preparation method of (-)-effective mould alcohol nitrine tetraacetate - Google Patents

Abstract

The invention discloses the preparation method of one (-)-effective mould alcohol nitrine tetraacetate, first with (+)-valiolamine for raw material, adopt imidazoles alkylsulfonyl azide salt hydrochlorate (ImSO ₂n ₃hCl) change amino one step in (+)-valiolamine molecule into azido-through turning diazo reaction, then use acetylize guard method, prepare (-)-effective mould alcohol nitrine tetraacetate.Usedly turn diazo reagent---imidazoles alkylsulfonyl azide salt hydrochlorate is easy to prepare, low price, be convenient to preserve, dangerous little, the amino of metal catalytic turns doazo reaction mild condition, and yield is high, and product is easily separated.

Description

(-)-The preparation method of effective mycodol azide tetraacetate

technical field

The invention relates to a method for synthesizing organic compounds, in particular to a method for synthesizing (-)-effective mycodol azide tetraacetate.

Background technique

(-)-effective mycodol azide tetraacetate, its molecular formula is C ₁₅ H ₂₁ N ₃ O ₉ , and the English system name is (1S, 2R, 3S, 4S, 6S)-4-(acetoxymethyl)-6- Azido-4-hydroxycyclohexane-1,2,3-triyltriacetate, its structural formula is shown in S-1, the pure product is a colorless crystal with a melting point of 122-124°C, soluble in dichloromethane, chloroform and toluene. Specific rotation [α] ^D ₂₅ =-13.4 (c=1.00, CHCl ₃ ), the spectral data of this compound are as follows: FT-IR(neat)υ _max =2927,2105,1739,1375,1229,1162,1038, 914,810,744cm- ¹ ; ¹ HNMR(400MHz,CDCl ₃ )δ5.64(t,J=10.2Hz,1H),5.04(dd,J=10.4,3.9Hz,1H),5.01(d,J=10.2Hz, 1H), 4.21(q, J=3.5Hz, 1H), 3.95(d, J=11.4Hz, 1H), 3.66(d, J=11.4Hz, 1H), 3.39(s, 1H), 2.08(d, J=3.0Hz,1H),2.05(s,3H),2.01(s,3H),2.00(s,3H),1.95(s,3H),1.91(d,J= ^3.6Hz ,1H); (101MHz, CDCl ₃ ) δ169.23, 168.96, 168.84, 168.70, 72.32, 72.11, 70.90, 67.54, 64.64, 57.31, 32.27, 19.73, 19.54, 19.50, 19.40. According to literature (S. Ogawa, K. Sato, Y. Miyamoto. Journal of the Chemical Society, Perkin Transactions 11993, 691-696.), this compound can be used as a key intermediate in the synthesis of trehalase inhibitor iminodieffective mycosamine , whose structural formula is shown in S-2.

According to literature reports, (-)-effective mycodol azide tetraacetate can be prepared by (-)-7-endo-oxobicyclo[2.2.l]hept-5-ene-2-carboxylic acid respectively (references: S.Ogawa, K.Sato, Y.Miyamoto.JournaloftheChemicalSociety, PerkinTransactions11993,691-696.) (see S-3) or shikimic acid (references: N.Quan, L.-D.Nie, R.-H. Zhu, X.-X.Shi, W.Ding, X.Lu.Eur.J.Org.Chem.2013, 2013, 6389-6396.) (see S-4) as raw materials and chemical methods for total synthesis. The disadvantages of these methods are that the reaction route is long, the yield is low (9.0% and 38.3%, respectively), and the reagents used are expensive or have high hazards.

Contents of the invention

The technical problem to be solved by the present invention is to provide a high yield, low cost, green and safe preparation method of (-)-effective mycodol azide tetraacetate.

In order to solve the above-mentioned technical problems, the present invention provides a preparation method of (-)-effective mycodol azide tetraacetate. (ImSO ₂ N ₃ ·HCl) converts the amino group in the (+)-effective mycodolamine molecule into an azido group through a diazo group reaction, and then uses the acetylation protection method (the acetylation protection method is a conventional method) ), to prepare (-)-effective mycodol azide tetraacetate.

As the improvement of the preparation method of (-)-effective mycodol azide tetraacetate of the present invention, comprise the following steps:

1) Dissolve (+)-effective mycodolamine, alkali and metal salt catalyst in methanol, add (one-time addition) imidazolesulfonyl azide hydrochloride, and stir the obtained reaction solution at 0℃～60℃ Carry out the diazonium conversion reaction under certain conditions, and the reaction time is 3h to 18h; after the reaction, remove methanol (the method of adding toluene to azeotrope can be used, and the rotary evaporation under reduced pressure can remove methanol and toluene at the same time);

Remarks: The purpose of adding toluene is to use the azeotropy of toluene and methanol to remove the original solvent methanol as much as possible at a lower temperature;

The molar ratio of imidazole sulfonyl azide hydrochloride to (+)-effective mycodolamine is 1.2-2.0:1, and the molar ratio of alkali to (+)-effective mycodolamine is 1.5-3.0:1 , the molar ratio of metal salt catalyst to (+)-effective mycodolamine is 0.005～0.1:1;

2) Triethylamine, acetic anhydride and 4-dimethylaminopyridine (DMAP) were added to the syrupy substance obtained in step 1), and the reaction mixture was stirred and reacted at room temperature for 12 to 24 hours. The triethylamine, ethyl The molar ratios of acid anhydride and 4-dimethylaminopyridine (DMAP) to (+)-effective mycodolamine in step 1) are 5-10:1 (for example 8:1), 5-10:1 (for example 8:1), 0.01～0.05:1 (for example, 0.01:1);

After the reaction is completed, triethylamine, acetic acid and unreacted acetic anhydride are removed by rotary evaporation under reduced pressure, diluted with water, extracted, washed, dried and filtered in sequence;

3) The filtrate obtained in step 2) was rotary evaporated under reduced pressure to remove the solvent used in the above extraction step to obtain a light yellow syrupy substance, which was separated and purified by column chromatography to obtain (-)-effective mycodol azidetetraacetic acid Esters (as white crystalline solids); purity can be checked by HPLC.

As a further improvement of the preparation method of (-)-effective mycodol azide tetraacetate of the present invention:

The base in step 1) is potassium carbonate, potassium bicarbonate, sodium carbonate, triethylamine (TEA) or N,N-diisopropylethylamine (DIPEA);

The metal salt catalyst is copper sulfate, nickel nitrate, zinc acetate, zinc chloride or hydrates thereof.

As a further improvement of the preparation method of (-)-effective mycodol azide tetraacetate of the present invention: step 2) is: extract with dichloromethane, and extract the organic phase obtained with 5% hydrochloric acid and 5% _NaHCO3 solution in turn Wash with saturated brine, then dry with anhydrous Na ₂ SO ₄ , and filter; the above-mentioned % are mass %.

In the present invention, imidazolesulfonyl azide hydrochloride is the diazonium-transfer reagent.

The present invention prepares the reaction equation of (-)-effective mycodol azide tetraacetate as follows:

In the present invention, used raw material is prior art; For example:

The CAS number of (+)-effective mycodolamine is 83465-22-9, which has been published in L.Ji, D.F.Zhang, Q.Zhao, S.M.Hu, C.Qian, X.Z.Chen.Tetrahedron2013,69,7031- 7037. Informed about its preparation.

The CAS number of imidazolesulfonyl azide hydrochloride (ImSO ₂ N ₃ ·HCl) is 952234-36-5, which has been published in EDGoddard-Borger, RVStick.Org.Lett.2007, 9, 3797-3800. its preparation method.

In step 1) of the present invention, 20-40 mL of methanol is used for every 10.0 mmol of (+)-effective mycodolamine;

The room temperature means 10 to 25°C.

The preparation method of (-)-effective mycodol azidetetraacetate of the present invention has the following advantages:

1. (+)-effective mycylamine is produced by reliable reaction of (+)-effective mycylamine. It is the key intermediate of α-glucosidase inhibitor voglibose, and the source of raw materials is relatively abundant;

2. The diazonium-transfer reagent used --- imidazolesulfonyl azide hydrochloride is easy to prepare, cheap, easy to store, and less dangerous. The metal-catalyzed amino-transfer diazo reaction has mild conditions, high yield, and easy separation of products .

Description of drawings

The specific implementation manners of the present invention will be described in further detail below in conjunction with the accompanying drawings.

Fig. 1 is (-)-effective mycodol azide tetraacetate of the present invention ¹ HNMR spectrogram;

Fig. 2 is (-)-effective mycodol azidetetraacetate ¹³ CNMR spectrogram of the present invention;

Fig. 3 is (-)-effective mycodol azide tetraacetate MS spectrogram of the present invention;

Fig. 4 is the FT-IR spectrogram of (-)-effective mycodol azidetetraacetate of the present invention.

detailed description

Embodiment 1, a kind of preparation method of (-)-effective mycodol azide tetraacetate, take (+)-effective mycodolamine as starting material, carry out the following steps successively:

1) Dissolve 1.93g (10.0mmol) of (+)-effective mycodolamine, 2.35g (17.0mmol) of K ₂ CO ₃ and 25mg (0.1mmol) of CuSO ₄ 5H ₂ O in methanol (25mL). 2.52 g (12.0 mmol) of acyl azide hydrochloride was added at one time, and the resulting reaction solution was stirred at 25°C for 12 hours (diazo reaction). After the reaction was completed, methanol and toluene were removed by rotary evaporation under reduced pressure (vacuum degree 0.1 MPa) by adding toluene (20 mL×2) to azeotrope.

2) Add 8.10 g (80.0 mmol) of triethylamine, 8.17 g (80.0 mmol) of acetic anhydride and 12 mg (0.1 mmol) of DMAP to the syrupy substance obtained in step 1), and stir the reaction mixture at room temperature for 24 h.

After the reaction was completed, triethylamine, acetic acid and unreacted acetic anhydride were removed by rotary evaporation under reduced pressure (vacuum degree 0.1MPa), diluted with 100 mL of water, extracted with dichloromethane (3×50 mL), and the obtained organic phase was successively washed with 5% (mass%) hydrochloric acid (2×50mL), 5% (mass%) NaHCO ₃ solution (2×50mL) and saturated brine (2×50mL) washed, then dried with anhydrous Na ₂ SO ₄ and filtered.

3) The filtrate obtained in step 2) was decompressed (vacuum degree 0.1MPa) and rotated to remove dichloromethane, the solvent used for extraction, to obtain a light yellow syrupy substance, which was separated and purified by column chromatography to obtain a white crystalline solid -- -(-)-effective mycodol azide tetraacetate 3.1g (yield 80%), purity 99.2% (HPLC).

The specific content of described column chromatography separation and purification is:

Dilute the above light yellow syrupy substance with 2.0mL of dichloromethane, pass through a chromatography column (with 50g of 300-400 mesh silica gel inside), and use a mixed solvent of ethyl acetate and n-hexane (volume ratio 1:2) as elution (amount of 800mL), collect the eluent containing only Rf=0.3 (ethyl acetate:n-hexane=1:2, v:v), and carry out rotary evaporation under reduced pressure (vacuum degree 0.1MPa) to obtain (-)-active mycodol azide tetraacetate.

Embodiment 2～10,

Change the process parameters in the diazonium reaction in step 1), that is, change the type of base (including the amount), the type of the metal salt catalyst (including the amount), the amount of imidazolesulfonyl azide hydrochloride, Reaction temperature and reaction time; the amount of the substrate—(+)-effective mycodolamine remains unchanged, and the rest of the content is the same as in Example 1; thus corresponding Examples 2-10 are obtained. Specifically as described in Table 1.

Table 1

Comparative Example 1. The imidazolesulfonyl azide hydrochloride (ImSO ₂ N ₃ ·HCl) in Example 1 was changed to trifluoromethanesulfonyl azide, and the molar weight remained unchanged; the rest of the content was the same as in Example 1.

The product yield is: 55%.

Comparative Example 2. The imidazolesulfonyl azide hydrochloride (ImSO ₂ N ₃ ·HCl) in Example 1 was changed to perfluorobutylsulfonyl azide, and the molar weight remained unchanged; the rest of the content was the same as in Example 1

The yield of the product is: 51%.

Finally, it should be noted that the above examples are only some specific embodiments of the present invention. Obviously, the present invention is not limited to the above embodiments, and many variations are possible. All deformations that can be directly derived or associated by those skilled in the art from the content disclosed in the present invention should be considered as the protection scope of the present invention.

Claims (3)

1. The preparation method of (-)-effective mycodol azide tetraacetate is characterized in that: at first with (+)-effective mycodolamine is raw material, adopts imidazole sulfonyl azide hydrochloride (ImSO ₂ N ₃ ·HCl) through diazo group reaction to convert the amino group in (+)-effective mycoholamine molecule into azido group in one step, and then use acetylation protection method to prepare (-)-effective mycodol azidetetraacetic acid ester; Include the following steps: 1) Dissolve (+)-effective mycodolamine, alkali and metal salt catalyst in methanol, add imidazolesulfonyl azide hydrochloride, and convert the obtained reaction solution to weight under stirring at 0°C to 60°C Nitrogen-based reaction, the reaction time is 3h ~ 18h; after the reaction, remove methanol; The molar ratio of imidazole sulfonyl azide hydrochloride to (+)-effective mycodolamine is 1.2-2.0:1, and the molar ratio of alkali to (+)-effective mycodolamine is 1.5-3.0:1 , the molar ratio of metal salt catalyst to (+)-effective mycodolamine is 0.005～0.1:1; The base is potassium carbonate, potassium bicarbonate, sodium carbonate, triethylamine or N,N-diisopropylethylamine; The metal salt catalyst is copper sulfate, nickel nitrate, zinc acetate, zinc chloride or copper sulfate hydrate, nickel nitrate hydrate, zinc acetate hydrate, zinc chloride hydrate; 2), adding triethylamine, acetic anhydride and 4-dimethylaminopyridine to the syrupy substance obtained in step 1), the reaction mixture was stirred and reacted at room temperature for 12 to 24 hours, and the triethylamine, acetic anhydride and 4 -The molar ratios of dimethylaminopyridine to (+)-effective mycodolamine in step 1) are 5-10:1, 5-10:1, 0.01-0.05:1 respectively; After the reaction is completed, triethylamine, acetic acid and unreacted acetic anhydride are removed by rotary evaporation under reduced pressure, diluted with water, extracted, washed, dried and filtered in sequence; 3), the filtrate obtained in step 2) was rotary evaporated under reduced pressure to remove the solvent used in the above extraction step to obtain a light yellow syrupy substance, which was separated and purified by column chromatography to obtain (-)-effective mycodol azidetetraacetic acid ester. 2. the preparation method of (-)-effective mycodol azide tetraacetate according to claim 1, is characterized in that: described step 2) is: extract with methylene chloride, extract gained organic phase with 5 successively % hydrochloric acid, 5% NaHCO ₃ solution and saturated brine, then dried with anhydrous Na ₂ SO ₄ and filtered; The above-mentioned % are all mass %. 3. the preparation method of (-)-effective mycodol azide tetraacetate according to claim 2, is characterized in that: Described step 1) is: Dissolve (+)-effective mycodolamine, triethylamine and Ni(NO ₃ ) ₂ ·6H ₂ O in methanol, add imidazolesulfonyl azide hydrochloride, and carry out the reaction solution under stirring at 10°C Transfer diazo reaction, the reaction time is 12h; The molar ratio of imidazole sulfonyl azide hydrochloride to (+)-effective mycodolamine is 2.0:1, the molar ratio of triethylamine to (+)-effective mycodolamine is 1.5:1, Ni The molar ratio of (NO ₃ ) ₂ ·6H ₂ O to (+)-effective mycodolamine is 0.01:1.