WO2016145997A1 - Pharmaceutically active sugar molecule and synthesis method thereof - Google Patents

Abstract

Disclosed are a pharmaceutically active sugar molecule and a synthesis method thereof. The sugar molecule has a structure as shown by formula (I) or (II) and can be used for synthesizing a sulfonated sugar molecule, so that it can be further applied to research on E. coli pathogenesis. The synthesis method provided by the present invention is simple, convenient and easy to operate, and can be used for synthesis of a variety of sugar molecules.

Description

Drug active sugar molecule and synthesis method thereof Technical field

The invention relates to the technical field of medicinal chemistry, in particular to a medicinal active sugar molecule and a synthetic method thereof.

Background technique

Escherichia coli is a common bacterium that usually occurs in humans and animals. Most strains are harmless, but some of them are harmful to humans. For example, H4 has caused 50 deaths in Germany and France.

FebF is the end of E. coli F18 fimbriae. When FebF captures sugar molecules in the intestinal mucosa, it causes diseases such as diarrhea or edema. FebF was found to usually bind to sulfonated acetylgalactosamine and sulfonated lactose, but specific ligands have not been confirmed. To further investigate the structure of the binding site carbohydrates, different sulfonated sugar molecular structures need to be synthesis. The active sugar molecule synthesized by the present invention can be used as an important synthetic intermediate of a sulfonated sugar molecule.

Summary of the invention

(1) Technical problems to be solved

The present invention provides a pharmaceutically active sugar molecule having a structure represented by Formula I or II, which can be used to synthesize various sulfonated sugar molecules, thereby being applied to the study of the pathogenic mechanism of Escherichia coli.

Wherein R 1 and R 2 are each independently selected from a C _1-20 alkylene group substituted by one or more Ra;

Each Ra is independently selected from H, alkyl, alkoxy, heterocyclyl, aryl, heteroaryl, halogen or amino, wherein the heterocyclyl and heteroaryl comprise 1-5 independently selected from N , O and S heteroatoms.

As an example, R1, R2 are, independently of each other, selected from _C1-10 alkyl groups substituted by one or more Ra;

Each Ra is independently selected from the group consisting of H, C _1-10 alkyl, 3-10 membered heterocyclyl, C _6-10 aryl, 5-10 membered heteroaryl, F, Cl, Br, I or amino, wherein The heterocyclic group and heteroaryl group contain 1 to 5 hetero atoms independently selected from N, O and S.

In a more preferred embodiment, R1, R2 are independently selected from each other by one or more Ra substituted _C1-10 alkylene groups;

Each Ra is independently selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, benzene ring, substituted benzene ring, 5-6 membered heterocyclic ring, 5-6 membered heteroaryl, F, Cl, Br, I or NH ₂ wherein the heterocyclic group and heteroaryl group contain 1-3 heteroatoms independently selected from N, O and S.

In some embodiments of the invention, R1, R2 are, independently of each other, selected from methylene substituted with one or more Ra;

Each Ra is independently selected from the group consisting of H, methyl, ethyl, benzene rings, substituted benzene rings or NH ₂ .

As an example, the compound of formula (I) or (II) according to the invention may be selected from the following compounds:

The invention also provides a method for synthesizing the compound represented by the formula (I) or (II), which specifically comprises the following reaction course:

Wherein R1 and R2 have the above definitions independently of each other;

X is a halogen.

As an example, the preparation method of the present invention comprises the following reaction steps:

1) reacting a compound of formula (1) with an acid anhydride in the presence of a base to give a compound of formula (2);

2). The compound of the formula (2) is reacted with a halohydrin to obtain a lactosyl compound of the formula (3);

3). The compound of the formula (3) is reacted with an azide to obtain a compound of the formula (4);

4) The compound of the formula (4) is hydrolyzed to obtain a compound of the formula (5);

5). The compound of the formula (5) is reacted with an acetal or a ketal to obtain a compound of the formula (I) or (II);

Wherein the halogen of the halohydrin in the step 2) is F, Cl, Br or I; wherein the alcohol formed is a C _1-10 alkyl alcohol; wherein an acid anhydride is used as a catalyst;

The azide in step 3), preferably sodium azide or potassium azide;

R1 and R2 have the above definition independently of each other; and X is a halogen.

Definition and interpretation of terms

Unless otherwise stated, when "a compound of the invention" or "a compound of the invention" is used herein, it is intended to encompass all compounds of formula (I) and (II).

The term "halogen" refers to fluoro, chloro, bromo and iodo.

The term "C _1-20 alkyl" is understood to preferably denote a straight or branched saturated monovalent hydrocarbon radical having from 1 to 20 carbon atoms, preferably a C _1-10 alkyl group. "C1-6 alkyl" is understood to preferably denote a straight or branched saturated monovalent hydrocarbon radical having 1, 2, 3, 4, 5 or 6 carbon atoms, such as methyl, ethyl, propyl, butyl. , pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2 - dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2 -ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethyl Butyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl or their isomers. In particular, the group has 1, 2, 3 or 4 carbon atoms ("C1-4 alkyl"), such as methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec. Butyl, tert-butyl, more particularly, the group has 1, 2 or 3 carbon atoms ("C1-3 alkyl"), such as methyl, ethyl, n-propyl or isopropyl.

The term "alkylene" refers to any divalent straight or branched hydrocarbon group, and "C _1-20 alkylene" is understood to preferably denote a straight or branched saturated divalent having from 1 to 20 carbon atoms. a hydrocarbyl group, preferably a C _1-10 alkyl group, is understood to preferably denote a straight or branched saturated divalent hydrocarbon radical having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, The alkylene group including -(CH ₂ ) _1-10 -, particularly -CH ₂ -, -(CH ₂ ) ₂ -, -(CH ₂ ) ₃ -, -(CH ₂ ) ₄ -, -( CH ₂ ) ₅ -, -(CH ₂ ) ₆ - or -CH(CH ₃ )-, -C(CH ₃ ) ₂ -, -CH(C ₆ H ₅ )-, -CH(CH ₂ CH ₃ )- Wait.

The term "heterocyclyl" means a saturated monovalent monocyclic or bicyclic hydrocarbon ring containing from 1 to 5 heteroatoms independently selected from N, O and S, preferably "3-10 membered heterocyclyl". The term "3-10 membered heterocyclyl" means a saturated monovalent monocyclic or bicyclic hydrocarbon ring containing from 1 to 5, preferably from 1 to 3, heteroatoms selected from N, O and S.

The term "C6-10 aryl" is understood to preferably denote a monovalent aromatic or partially aromatic ring having 6 to 10 carbon atoms. It is understood to preferably denote a monovalent aromatic or partially aromatic ring having 6, 7, 8, 9, 10 carbon atoms.

The term "5-10 membered heteroaryl" is understood to include a monovalent monocyclic, bicyclic or tricyclic aromatic ring system having from 5 to 10 ring atoms and containing from 1 to 5 independently selected from N, O. And the hetero atom of S.

The beneficial effects of the invention:

1. The sugar molecule of the present invention can be used as an important intermediate for synthesizing sulfonated sugar molecules for studying the pathogenic mechanism of Escherichia coli;

2. The compound provided in the present invention has an azide group as a linking group, and can be better linked to other molecular structures, and can be used for studying the molecular structure of Escherichia coli, and has important significance in drug research and development;

3. The synthetic method provided by the present invention can be used to prepare different pharmaceutically active sugar molecules, and the operation is simple and convenient.

detailed description

The compounds of the general formula of the present invention, as well as the preparation methods and applications thereof, will be further described in detail below in conjunction with specific examples. The following examples are merely illustrative of the invention and are not to be construed as limiting the scope of the invention. The technology that is implemented based on the above-described contents of the present invention is encompassed within the scope of the present invention.

The starting materials and reagents used in the examples are commercially available unless otherwise stated.

Example 1: Preparation of Active Sugar Molecules (001)

1.1 Preparation of Compound (2)

Anhydrous sodium acetate (2 eq, 25.0 g, 0.31 mol) and acetic anhydride (10.7 eq, 175 ml, 1.85 mol) were mixed and heated to reflux temperature, then compound 1 (D-lactose, 1 eq, 50.0 g, 0.15 mol) was added portionwise. The reaction was further heated to reflux for 30 minutes, and the reaction solution was poured into 500 ml of ice water and stirred overnight. The precipitated solid was separated by filtration, washed with water, dried under reduced pressure, and then recrystallized from 600 ml of ethanol to give the objective product 2 (80.6 g, 81%).

The NMR spectral data are as follows: ¹ H-NMR 2. (500 MHz, CDCl ₃ = 7.31 ppm): δ = 5.66 (d, 1H, H-1, J 1, ₂ = 8.4 Hz), 5.33 (dd, 1H, J = 1.2Hz, J=3.6Hz H-4'), 4.46(d,1H, J=7.6Hz, H-1'), 4.42(d,1H,H-6'a),4.13-4.04(m,3H , H-5', H-6A, H-6'B), 3.88-3.85 (m, 2H, H-4', H-6b) 2.14, 2.10, 2.08, 2.05, 2.04, 2.02, 2.01, 1.95 ( 8s, 24H, 8CH ₃ ) ppm;

¹³ C-NMR (125 MHz, CDCl ₃ = 77.16): δ = 170.48, 170.44, 170.26, 170.18, 169.74, 169.68, 169.14, 168.98 (8C, 8C=0), 101.68 (C-1'), 91.67 (C- 1), 75.81, 73.63, 72.76, 71.09, 70.87, 70.65, 69.14, 66.74, (8C), 61.87 (C-6), 60.98 (C-6'), 20.95, 20.93, 20.87, 20.75, 20.73, 20.71, 20.62, 18.53 (CH ₃ ) ppm.

1.2 Preparation of Compound (3)

Compound 2 (1 eq., 10.0 g, 14.7 mmol) was taken and purified by rotary distillation with toluene and dissolved in DCM; 3-chloropropanol (2 eq., 2.5 mL, 29.4 mmol) and BF3.Et2O (2.5 eq, 4.7 mL, and 36.8 mmol) was added to the reaction solution, and the reaction was carried out under a nitrogen atmosphere. The mixture was stirred at room temperature for 3 hours, and the reaction was monitored by TLC (toluene/EtOAc, 1:1). After the reaction was completed, the solution was poured into ice water and stirred for 30 minutes. After the mixed solution was allowed to stand for stratification, the organic layer was washed with saturated NaHCO ₃ and brine, and distilled under reduced pressure. The crude product was separated by silica gel column to afford lactose 3 (8.2 g, 82%) with long chain.

The NMR spectral data are as follows: ¹ H-NMR (500 MHz, CDCl3 = 7.31 ppm): δ = 5.33 (dd, 1H, J = 1.2 Hz, J = 4.4 Hz, H-4'), 5.14 (dd = t, 1H) , H-3), 5.10 (dd, 1H, H-2'), 4.94 (dd, 1H, J = 3.6 Hz, J = 10.4 Hz, H-3'), 4.87 (dd, 1H,, J = 8.0 Hz, J=9.6Hz, H-2), 4.50-4.45 (m, 3H, H-1', H-6a, H-1), 4.14-4.04 (m, 3H, H-5', H-6a , H-6'b), 3.96-3.91 (m, 1H, -OCH2a-), 3.88-3.84 (m, 1H, H-6b), 3.80-3.75 (dd=t, 1H, H-4), 3.69 -3.55 (m, 4H, H-5, -OCH ₂ b, -CH ₂ N ₃ ), 2.14, 2.11, 2.05, 2.04, 2.03, 2.29, 1.95 (7s, 21H, -COCH ₃ ) ppm;

¹³ C-NMR (125 MHz, CDCl ₃ = 77.16 ppm): δ = 170.50, 170.47, 170.27, 170.18, 169.86, 169.83, 169.19 (c=0), 101.21 (C1), 100.93 (C1'), 76.4, 72.84, 72.80, 71.79, 71.13, 70.83, 69.25 (7C), 66.74 (-OCH ₂ CH ₂ CH ₂ Cl), 66.50, 62.11, 60.95 (3C), 41.43 (2C, -OCH ₂ CH ₂ CH ₂ Cl), 32.29 ( -OCH ₂ CH ₂ CH ₂ Cl), 20.99, 20.93, 20.94, 20.82, 20.77, 20.76, 20.74 (CH ₃ ) ppm. MALDI-TOF MS: 737.06 [M+Na] ⁺ ±27 ppm.

1.3 Preparation of Compound (4)

The compound 3 (1 eq, 4.0 g, 5.6 mmol) and NaI (2 eq, 1.7 g, 11.3 mmol) were dissolved in dry DMF and heated to 50 ° C for 1 hour; then NaN ₃ was added and the reaction solution was warmed to 140. After refluxing for 1 hour, the reaction solution was poured into ice water; EtOAc was added, and the mixture was allowed to stand for separation. The organic phase was separated and extracted twice with EtOAc. The extracts were combined and washed with saturated brine and evaporated to dryness. Compound 4 (3.2 g, 80%).

The NMR spectral data are as follows: ¹ H-NMR (500 MHz, CDCl ₃ = 7.31 ppm): δ = 5.39 (dd, 1H, J = 1.2 Hz, J = 3.6 Hz H-4'), 5.23 (dd = t, 1H) , H-3), 5.15 (dd, 1H, H-2'), 5.00 (dd, 1H, J = 3.6 Hz, J = 10.4 Hz, H-3'), 4.93 (dd, 1H, H-2) , 4.55-4.50 (dd, 1H, H-6'a), 4.52 (d, 1H, H-1'), 4.51 (d, 1H, H-1), 4.18-4.09 (m, 3H, H-5 ', H-6a, H-6'b), 3.97-3.89 (m, 2H, H-6b, -OCH ₂ ^a -), 3.83 (dd = t, 1H, J = 9.6 Hz, H-4), 3.66-3.59 (m, 2H, H-5, OCH ₂ ^b -), 3.41-3.36 (m, 2H, -CH ₂ N ₃ ), 2.19, 2.16, 2.10, 2.09, 2.08, 2.01, 2.00 (7s, 21H) , -CH ₃ ), 1.90 - 1.82 (m, 2H, -CH ₂ CH ₂ CH ₂ N ₃ ) ppm;

¹³ C-NMR (125 MHz, CDCl ₃ = 77.16 ppm): δ = 170.40, 170.39, 170.19, 170.10, 169.80, 169.68, 169.12 (c=0), 101.22 (C1), 100.71 (C1'), 76.38 (C- 4), 72.89 (C-3), 72.81 (C-5), 71.79 (C-2), 71.12 (C-5'), 70.83 (C-3'), 69.24 (C-2'), 66.74 ( C-4'), 66.59 (-OCH ₂ CH ₂ CH ₂ N ₃ ), 62.06 (C-6'), 60.93 (C-6), 48.08 (-OCH ₂ CH ₂ CH ₂ N ₃ ), 29.11 (- OCH ₂ CH ₂ CH ₂ N ₃ ), 20.98-20.64 (7CH ₃ ) ppm. MALDI-TOF MS: 742.21 [M+Na] ⁺ ±40 ppm.

1.4 Preparation of Compound (5)

The mixture was taken up in dry methanol (10 mL). , 3:1) monitoring; after the reaction is completed, Dowex H ⁺ ion exchange resin is added to the reaction solution, and stirred for 30 minutes; the neutralization reaction is carried out under the monitoring of pH. After the reaction is completed, the exchange resin is filtered off and washed with methanol. The filtrate was subjected to distillation under reduced pressure to give pale yellow crystalline compound 5 (510 mg, 88%).

The NMR spectroscopy data are as follows: ¹ H-NMR (500 MHz, D ₂ O = 4.80 ppm): δ = 4.49 (2xd, 2H, H-1 ', H-1), 4.04-3.98 (m, 2H), 3.95 ( m, 1H), 3.84 (m, 1H), 3.81-3.77 (m, 3H), 3.75 (m, 1H), 3.70-3, 65 (m, 3H), 3.64 - 3.60 (m, 1H), 3.58- 3.54 (m, 1H), 3.48 (m, 2H), 3.35-3.31 (m, 1H), 1.93 (m, 2H, -OCH ₂ CH ₂ CH ₂ N ₃ ) ppm;

¹³ C-NMR (125 MHz, D ₂ O, TMS = ppm): δ = 102.91 (C-1 '), 102.11 (C-1), 78.37, 75.33, 74.75, 74.36, 72.79, 72.50, 70.93, 68.52, 67.35 (-OCH ₂ CH ₂ CH ₂ N ₃ ), 61.00, 60.06, 47.85 (-OCH ₂ CH ₂ CH ₂ N ₃ ), 28.21 (-OCH ₂ CH ₂ CH ₂ N ₃ ) ppm.; MALDI-TOF MS: 448.18 [M+Na] ⁺ ±45ppm.

1.5 Preparation of active sugar molecule (001)

VO(OTf) ₂ (0.05 eq, 40 mg) was added to a round bottom flask, and dry acetonitrile (1.77 mL) and dimethoxypropane (10 eq., 2.9 mL) were added and stirred for 10 minutes to dissolve thoroughly. The color turned brown; then the mixture 5 (50 mg, 118 mmol) was added and the reaction was carried out at room temperature for two days; the progress of the reaction was monitored by TLC (EtOAc/MeOH, 4:1). The title product 001 (36 mg, 69%) was obtained.

Example 2: Preparation of active sugar molecule (002)

5 (1 eq., 1 g, 1.95 mmol) was dissolved in dry acetonitrile (10 mL), benzaldehyde dimethyl acetal (2 eq., 800 μL) and catalyst amount of camphorsulfonic acid; reaction at 30 ° C After stirring overnight, the progress of the reaction was monitored by TLC (EtOAc/MeOH/water, 7:2:1). After the reaction was completed, triethylamine (330 μL) was added, and the reaction solution was concentrated and separated on silica gel column to give compound 002 (1 g, 83%); MICRO-TOF MS: 513.325 [M+] ± 41 ppm.

The invention adopts azide group as a linking group, can be better connected with other molecular structures, and is used for synthesizing sulfonated sugar molecules, thereby being applied to research on the pathogenic mechanism of Escherichia coli and applied to the field of medical technology research. And the method can be used for synthesizing a plurality of compounds, and the operation is simple.

The embodiments described above are merely illustrative of the preferred embodiments of the invention and are not intended to limit the scope of the invention. Various modifications and improvements made by those skilled in the art to the technical solutions of the present invention are intended to fall within the scope of the present invention.

Claims (10)

1. A pharmaceutically active sugar molecule having the structure of formula (I) or (II):

   

   Wherein R 1 and R 2 are each independently selected from a C _1-20 alkylene group substituted by one or more Ra;

   Each Ra is independently selected from H, alkyl, alkoxy, heterocyclyl, aryl, heteroaryl, halogen or amino, wherein the heterocyclyl and heteroaryl comprise 1-5 independently selected from N , O and S heteroatoms.
2. The pharmaceutically active sugar molecule of claim 1 wherein:

   R1, R2 are, independently of each other, selected from _C1-10 alkylene groups substituted by one or more Ra;

   Each Ra is independently selected from the group consisting of H, C _1-10 alkyl, 3-10 membered heterocyclyl, C _6-10 aryl, 5-10 membered heteroaryl, F, Cl, Br, I or amino, wherein The heterocyclic group and heteroaryl group contain 1 to 5 hetero atoms independently selected from N, O and S.
3. The pharmaceutically active sugar molecule of claim 2 wherein:

   R1, R2 are, independently of each other, selected from _C1-10 alkylene groups substituted by one or more Ra;

   Each Ra is independently selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, benzene ring, substituted benzene ring, 5-6 membered heterocyclic ring, 5-6 membered heteroaryl, F, Cl, Br, I or NH ₂ wherein the heterocyclic group and heteroaryl group contain 1-3 heteroatoms independently selected from N, O and S.
4. The pharmaceutically active sugar molecule of claim 3 wherein:

   R1, R2 are independently of each other selected from methylene substituted by one or more Ra;

   Each Ra is independently selected from the group consisting of H, methyl, ethyl, benzene rings, substituted benzene rings or NH ₂ .
5. The pharmaceutically active sugar molecule of claim 1 selected from the group consisting of:

   
6. A method for preparing a pharmaceutically active sugar molecule according to any one of claims 1 to 5, comprising the following reaction scheme:

   

   Wherein R1, R2 independently of each other have the definitions of any one of claims 1-4;

   X is selected from halogen.
7. A method of preparing a pharmaceutically active sugar molecule according to claim 5, comprising the following reaction steps:

   1) reacting a compound of formula (1) with an acid anhydride in the presence of a base to give a compound of formula (2);

   2) a compound of the formula (2) is reacted with a halohydrin to give a compound of the formula (3);

   3). The compound of the formula (3) is reacted with an azide to obtain a compound of the formula (4);

   4) The compound of the formula (4) is hydrolyzed to obtain a compound of the formula (5);

   5). The compound of the formula (5) is reacted with an acetal or a ketal to obtain a compound of the formula (I) or (II);

   Wherein R1 and R2 have the definitions of claim 5 independently of each other;

   X is selected from halogen.
8. The method for preparing a pharmaceutically active sugar molecule according to claim 7, wherein the halogen of the halohydrin in the step 2) is F, Cl, Br or I; wherein the alcohol formed is a C _1-10 alkyl alcohol; As a catalyst.
9. The method for preparing a pharmaceutically active sugar molecule according to claim 7, wherein the azide used in the step 3) is sodium azide or potassium azide.
10. The method for producing a pharmaceutically active sugar molecule according to claim 7, wherein the compound of the formula (5) is separated by a cation exchange resin in the post-treatment.