CN111748000B - 3-deoxy-5-hydroxy-1-amino carbo-carbohydrate compounds and uses thereof - Google Patents

3-deoxy-5-hydroxy-1-amino carbo-carbohydrate compounds and uses thereof Download PDF

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CN111748000B
CN111748000B CN201910248983.3A CN201910248983A CN111748000B CN 111748000 B CN111748000 B CN 111748000B CN 201910248983 A CN201910248983 A CN 201910248983A CN 111748000 B CN111748000 B CN 111748000B
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许佑君
姜春风
刘佳明
刘凯旋
段明飞
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Abstract

The invention belongs to the field of pharmacy, and particularly relates to a 3-deoxy-5-hydroxy-1-amino carbon saccharide compound with a general formula shown in the specification and application thereof, wherein R is shown in the claims and the specification. The invention synthesizes the protected 3-deoxy-5-hydroxycyclohexanone by a stereo and position selective reduction method, and the compound has a novel carbon-sugar framework. The compound is reacted with micromolecular amine by a reductive amination method to obtain a target object protected by a corresponding protecting group, and finally the amino carbosaccharide target object with the structural characteristic of 3-deoxy-5-hydroxyl is obtained by deprotection reaction. The target has good inhibitory activity to alpha-glycosidase, and has obvious inhibitory effect on blood sugar rise of normal ICR mice loaded with sucrose, suggesting that the target can be used as a hypoglycemic drugFurther development is carried out.

Description

3-deoxy-5-hydroxy-1-amino carbo-carbohydrate compounds and uses thereof
Technical Field
The invention belongs to the field of pharmacy, and relates to a 3-deoxy-1-hydroxy-5-amino carbon carbohydrate compound and application thereof.
Background
The carbon sugar series molecule has an oxygen atom (-O-) in the ring substituted by a methine (-CH)2-) substitution products which, after substitution, still retain the basic backbone or structural features of the original sugar, have similar biological activity but a more stable chemical structure and more stable biological characteristics (mccaland g.e., et al, j.org.chem.,1966,31, 1516). As carbon sugar mimetics (mimetics), compounds have been widely studied and reported, and have hypoglycemic activity and the like; it can also be used as a skeleton of sugar in nucleoside or nucleotide molecules to exhibit antibacterial, antitumor or antiviral activities (Lahiri r., et al., chem.soc.rev.,2013,42, 5102).
The commercial drugs acarbose (1) and voglibose (2) as sugar mimics are alpha-glycosidase inhibitors, which control postprandial blood glucose levels by inhibiting oligosaccharides and disaccharides in the small intestine to reduce the production of maltose and fructose as monosaccharides, and thus have great significance in reducing cardiovascular risks and complications in hyperglycemic patients (Lefebvre p.j., et al., Diabetic med.,1998,15, 63).
The 5 alpha-position is-CH2-characteristic C-glycosides 3-5 vs. Na+Glucose-dependent transport receptors (SGLT2) have a strong inhibitory effect, reducing the glucose concentration in blood by promoting the excretion of glucose from urine (Shing t.k.m., et al, angelw.chem.int.ed, 2013,125,8559). The carbon glycoside compounds 7-8 (SL0101, i.e. 6 analogues) with similar characteristics are P90 Ribosome S6Kinase (RSK), and have strong antitumor effects (Li m.z., et., org.lett.,2017,19, 2410). The natural product (+) -perceosine A (9) used as EGFR inhibitor also has good anti-tumor effect in vivo. The neuraminidase inhibitor osemivir (10) also has an amino carbon sugar backbone in the molecule and is useful for treating influenza a (Von Itzstein h., et al., Nat Rev Drug discov.,2007,6, 967).
Although carbo-sugars or carbo-sugar analogs have a wide range of biological activities, their synthesis remains a chemical challenge, particularly for new backbone type compounds, due to the multiple chiral centers, multifunctional structural features in their molecules.
Figure BDA0002011850060000011
Disclosure of Invention
The invention aims to report a novel method for constructing a 3-deoxy, namely 3-H type carbon sugar skeleton, designs and synthesizes novel amino carbon sugar compounds by using the skeleton compounds, discusses the inhibition effect of the skeleton compounds on alpha-glycosidase and the in vivo hypoglycemic activity of the skeleton compounds, and aims to search for novel hypoglycemic drugs.
1. The invention provides a 3-deoxy-5-hydroxy-1-amino carbo-carbohydrate compound, which has the following structural general formula:
Figure BDA0002011850060000021
wherein R represents hydrogen, C1～12Or a hydroxyalkyl group, or a hydrocarbyloxy group, or an aminoalkyl group, or an aminohydroxyalkyl group.
The following provides definitions of various groups of the compounds of the present invention, which are used throughout the specification and claims, unless otherwise defined.
“C1～12The hydrocarbyl group "means a straight or branched chain hydrocarbyl group having 1 to 12 carbon atoms, and preferably: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl or n-pentyl.
"cycloalkyl" refers to a monocyclic saturated carbocyclic group containing 3 to 7 carbon atoms, preferably: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
"cycloalkyl hydrocarbyl" refers to a monocyclic carbocyclic group of 3 to 7 carbon atoms in combination with a hydrocarbyl group of 1 to 6 carbon atoms, preferably: cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl.
"Hydroxyhydrocarbyl" means a straight or branched chain hydrocarbyl group containing 2 to 12 carbon atoms substituted with one or more hydroxyl groups, preferably: 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl or 2, 3-hydroxypropyl.
The term "hydrocarbyloxy" refers to a linear or branched hydrocarbyl group containing 2 to 12 carbon atoms substituted with a hydrocarbyloxy group, wherein hydrocarbyloxy refers to a hydrocarbyloxy group containing 1 to 6 carbon atoms. Preferably: 2-methoxyethyl, 3-methoxypropyl or 4-methoxybutyl, 2-ethoxyethyl, 3-ethoxypropyl or 4-ethoxybutyl, 2, 3-dihydroxypropyl.
"aminoalkyl" means a straight or branched chain hydrocarbyl group containing 2 to 12 carbon atoms substituted with an amino or substituted amino group, preferably: 2-aminoethyl or 3-aminopropyl.
"aminohydroxyhydrocarbyl" means a straight or branched chain hydrocarbyl group containing 3 to 12 carbon atoms substituted with both a hydroxyl group and an amino or substituted amino group, preferably: 2-amino-3-hydroxypropyl, 3-amino-2-hydroxypropyl, 2-amino-4-hydroxybutyl, 2-amino-3-hydroxybutyl, 3-amino-2-hydroxybutyl, 4-amino-2-hydroxybutyl.
2. The invention provides the biological activity of the amino-carbon carbohydrate compounds, mainly alpha-glycosidase inhibition activity and hypoglycemic activity in animal bodies, and suggests that the compounds can be used as hypoglycemic activity candidates.
3. The invention provides a synthesis method of amino carbon sugar compounds, which takes P-protected 3-deoxy-1-carbonyl as a raw material, obtains protected 3-deoxy-1-amino carbon sugar through reductive amination reaction, and finally obtains the amino carbon sugar through deprotection. The protecting group P is benzyl, substituted phenylmethyl, preferably benzyl protecting group. In the reductive amination, the organic amines H used2The R group in NR is the same as the above target, and the reducing agent used is LiBH4、NaBH4、KBH4、LiBH3CN、NaBH3CN、KBH3CN、NaBH(OAc)3(ii) a The solvent used for reductive amination is an alcoholic solvent, preferably methanol, ethanol, or any combination thereof; or ethereal solvents such as diethyl ether, tetrahydrofuran, 1, 4-dioxane, 1, 2-dimethoxyethane, or any combination thereof; or any combination of alcoholic and ethereal solvents; at the time of deprotectionThe protection of benzyl and substituted phenylmethyl is removed by a catalytic hydrogenation method of palladium, nickel, ruthenium and rhodium, and the used solvent is water, an alcoholic solvent or any combination thereof, preferably methanol, ethanol and isopropanol; an ethereal solvent or any combination thereof, preferably tetrahydrofuran, 1, 2-dimethoxyethane; in order to improve the activity of the catalyst, hydrochloric acid, formic acid and acetic acid can be added into the system to improve the deprotection reaction efficiency.
Figure BDA0002011850060000031
4. The invention provides a stereo and position selective synthesis method of an important intermediate 12, wherein the intermediate is a high-functionalization intermediate which is not reported and protects polyhydroxy, and is particularly suitable for constructing carbosugar with a novel framework or used as a fragment for constructing a building block of carbon glucoside; as mentioned above, the protecting group P is benzyl, substituted arylmethyl, preferably benzyl protecting group; 1, 4-Michelal addition of Hydride, wherein a reducing agent sodium hydrosulfite can be selected, and a double bond reduction method combining palladium, nickel, ruthenium and rhodium catalysts with hydrogen can also be selected; the solvent is water, alcoholic solvent or their arbitrary combination preferably methanol, ethanol, isopropanol; an ethereal solvent or any combination thereof, preferably tetrahydrofuran, 1, 2-dimethoxyethane.
Figure BDA0002011850060000032
5. According to the invention, murine oligosaccharidase alpha-sucrase and alpha-maltase are selected as test objects, the inhibition activity of main target objects on the two enzymes is systematically tested, and the result shows that part of the target objects show good inhibition activity on the alpha-sucrase, the action of the target objects is equivalent to that of a commercially available drug Voglibose, and the target objects also have inhibition effect on the alpha-maltase.
6. And selecting a target substance with better enzyme inhibition activity, and performing a mouse in-vivo glucose tolerance test, wherein the result shows that the activity of the target substance is equivalent to that of Voglibose, and the target substance can be used as a candidate structure to further screen the hypoglycemic drug.
The invention belongs to the field of pharmacy, and relates to a 3-deoxy-5-hydroxy-1-amino carbon carbohydrate compound, and selective synthesis and application thereof.
The invention provides amino carbonhydrate with more stable chemical structure and biological characteristics, the target has the structural characteristics of 3-deoxidation, namely 3-H-5-OH-1-amino carbonhydrate, and is a novel compound with highly functionalized rings, the compound has obvious alpha-glycosidase inhibition activity and in vivo obvious hypoglycemic activity, and the research has important significance for further searching for novel hypoglycemic drugs.
Drawings
FIG. 1 is a graph of the effect of samples on blood glucose curves and the area under the curves after sucrose loading in ICR mice.
Detailed Description
In the specification, the skeletons of the intermediate and the target are treated as carbon sugar skeletons during naming, and the naming numbers thereof are used for replacing-CH of-O-in a glucose ring by simulating the naming number method of glucose2The position is the 5 α -position, which is also a numbering and naming method that is frequently found in the literature; however, the target is a polysubstituted amino alcohol structure, according to the systematic naming method of organic chemistry, a cyclohexyl ring is taken as a framework, alcohol is taken as a starting point of a serial number, the amino in the structure is at a 5-position, and the original 5 alpha-position is a 6-position. The two designations are different and are described herein to avoid confusion.
The invention is further illustrated, but not limited, by the following specific examples.
Detailed Description
Preparation of (2S,4S,5S) -2, 4-dibenzyloxy-5-benzyloxymethyl-5-hydroxy-cyclohexanone (12)
Example 1 a: under an ice-water bath, 4.88g (11.0mmol) of Compound 14, 0.20g of 10% Pd/C, and Na2CO30.24g and MeOH 100mL were vigorously stirred for an atmospheric catalytic hydrogenation for 2.0 h. Filtering, and adding 1.0M NaH into filtrate2PO4/Na2HPO4The buffer solution was diluted to 100mL, and the mixture was concentrated under reduced pressure to recover methanol. The residue was extracted with ethyl acetate and dried over anhydrous sodium sulfate. After concentration, the crude product is separated by column chromatography to obtain 3.04g of white solid 12, and the yield is 62.0%. m.p. of 104 to 106 ℃, [ 2 ]α]D 20＝+82.88(c 1.0,CHCl3).
1H NMR(600MHz,CDCl3):δ7.29–7.17(m,15H),4.80(d,J＝11.9Hz,1H),4.57(d,J＝11.5Hz,1H),4.41–4.38(m,4H),3.94(dd,J＝11.6Hz,4.7Hz,1H),3.83(dd,J＝12.7Hz,6.1Hz,1H),3.56(d,J＝8.7Hz,1H),3.10(d,J＝8.7Hz,1H),2.65(d,J＝14.7,1H),2.42-2.39(m,1H),2.36(d,J＝14.6,1H),2.07(q,J＝12.2Hz,1H).
13C NMR(150MHz,CDCl3):δ206.19,137.95,137.79,137.68,128.60,128.18,128.11,128.07,128.00,127.96,77.96,77.02,74.03,73.54,73.10,72.05,71.97,45.75,32.62.
HR–MS:calcd.for C28H30O5Na+469.1985,found 469.1996.
Example 1 b: under similar conditions, 0.25g of 10% Ru/C was substituted for Pd/C in example 1a, giving 2.89g, 59.0% yield, based on 12 after similar workup.
Example 1 c: under similar conditions, 0.40g of Raney/Ni (W-2) was substituted for Pd/C in example 1a, and 2.40g of 12 was obtained in a yield of 49.0% after similar workup.
Example 1 d: under the protection of argon and electromagnetic stirring, 4.45g (10.0mmol) of compound 14 is counted and NaHCO is counted318.5g、Na2S2O4A mixture of 28.0g, 100mL of 1, 4-dioxane and 100mL of water was reacted at 80 ℃ for 4.0 h. Adjusting the pH value to 5-6 with 1.0mole/L hydrochloric acid. The solvent was recovered by concentration under reduced pressure, and the residue was extracted with EtOAc and dried over anhydrous sodium sulfate. The crude product obtained after concentration was separated by column chromatography to obtain 1.87g of a white solid 12 in a yield of 42.0%.
Example 1 e: the reaction was carried out under similar conditions using ethanol instead of methanol in example 1a, and similar workup gave 2.70g of 12 in 55.0% yield.
Example 1 f: the reaction was carried out under similar conditions using tetrahydrofuran in place of methanol in example 1a to give 3.10g in terms of 12 after similar workup in a yield of 63.0%.
Example 1 g: the reaction was carried out under similar conditions using 1, 2-dimethoxyethane instead of methanol in example 1a, and after similar workup, 2.85g based on 12 was obtained in a yield of 58.0%.
2. Preparation of key intermediate 13
2.1(1S,2S,4R,5S) -2, 4-dibenzyloxy-1-benzyloxymethyl-5-phenethylamino-1-cyclohexanol (13a)
Example 2 a: under the condition of ice-water bath, 223.0mg (0.5mmol) of 12 meters and 0.19mL (1.5mmol) of beta-phenylethylamine are added into 20mL of ethanol in batches, 55.0mg (1.5mmol) of sodium borohydride is added, after the reaction is carried out for 3.0h, the ethanol is evaporated under reduced pressure, the residue is diluted by 50mL of dichloromethane, 50mL of saturated ammonium chloride is washed, and the organic layer is dried by anhydrous sodium sulfate. After concentration, the crude product was isolated by column chromatography to give 142.7mg as a white solid 13a in 51.8% yield. m.p 142-144 ℃, [ alpha ]]D 20＝–16.59(c 1.0,CHCl3).
1H NMR(400MHz,CDCl3):δ7.36–7.15(m,15H),7.17–7.02(m,5H),4.56–4.59(d,J＝12.0Hz,1H),4.26–4.45(m,2H),3.59(d,J＝8.6Hz,1H),3.40–3.46(m,1H),3.34–3.40(m,1H),3.23(d,J＝8.6Hz,1H),3.10–2.97(m,2H),2.80(dt,J＝12.4,5.9Hz,1H),2.62(dt,J＝13.6,7.6Hz,1H),2.53(dt,J＝11.0,7.4Hz,1H),2.08(dt,J＝12.4,4.7Hz,1H),1.98(t,J＝12.0Hz,1H),1.91(dd,J＝14.8,3.4Hz,1H),1.39(dd,J＝15.0,2.6Hz,1H).
13C NMR(100MHz,CDCl3):δ139.78,138.96,129.15,129.01,128.92,128.72,128.63,128.39,128.18,128.11,127.93,127.85,126.78,77.06,76.36,74.45,73.88,73.75,71.86,70.81,55.63,49.00,36.59,31.82,28.58.
HR-MS:calcd.for C36H41NO4H+552.3108,found 552.3137.
Example 2 b: under similar conditions with NaBH3CN 94.2mg (1.5mmol) was reacted instead of sodium borohydride in example 2a, to obtain 133.6mg in terms of 13a in a yield of 48.5% after similar post-treatment.
Example 2 c: under similar conditions with NaBH (OAc)3317.9mg (1.5mmol) were reacted instead of sodium borohydride in example 2a, similar workup gave 137.8mg of 13a, yield 50.0%.
Example 2 d: the reaction was carried out under similar conditions using THF instead of ethanol in example 2a, and similar work-up gave 124.1mg, yield 45.0%, of 13 a.
Example 2 e: the reaction was carried out under similar conditions by using 1, 4-dioxane instead of ethanol in example 2a, and after similar workup, 110.0mg of 13a was obtained in a yield of 40.0%.
2.2(1S,2S,4R,5S) -2, 4-dibenzyloxy-1-benzyloxymethyl-5- (2-hydroxy-1- (hydroxymethyl) ethylamino) -1-cyclohexanol (13b)
Example 2 f: under similar conditions, serinol is used to replace beta-phenylethylamine in the example 2a, the preparation method is the same as the example 2 a-2 e, white solid 13b is obtained, and the yield is 48.5-61.2%. [ alpha ] to]D 20＝+30.8(c 1.00,CHCl3).
1H NMR(400MHz,CDCl3):δ7.34–7.24(m,15H),4.61(dd,J＝11.7,1.9Hz,2H),4.50–4.42(m,4H),3.73–3.66(m,4H),3.58(d,J＝8.6Hz,1H),3.52–3.45(m,2H),3.33(d,J＝2.8,1H),3.25(d,J＝8.6Hz,1H),2.78(t,J＝3.9Hz,1H),2.20–2.17(m,1H),2.06(q,J＝12.0Hz,1H),1.91(dd,J＝15.1,2.8Hz,1H),1.49(dd,J＝15.1,2.4Hz,1H).
13C NMR(100MHz,CDCl3):δ138.67,138.45,138.08,128.62,128.42,128.35,128.02,127.94,127.81,127.78,127.67,127.62,76.18,75.77,74.32,73.42,71.42,70.35,65.01,61.17,56.60,51.91,32.21,27.93.
HR–MS:calcd.for C31H39NO6H+522.2850,found 522.2865.
2.3(1S,2S,4R,5S) -2, 4-dibenzyloxy-1-benzyloxymethyl-5- (2-hydroxyethyl) amino-1-cyclohexanol (13c)
Example 2 g: under similar conditions, ethanolamine is used to replace beta-phenylethylamine in example 2a, the preparation method is the same as that of examples 2a to 2e, white solid 13c is obtained, and the yield is 55.1-86.1%. [ alpha ] to]D 20＝+10.5(c 1.0,CHCl3).
1H NMR(400MHz,CDCl3):δ7.24–7.18(m,15H),4.51–4.36(m,6H),3.62–3.58(m,1H),3.53–3.51(m,2H),3.42–3.37(m,2H),3.19(d,J＝8.6Hz,1H),3.05(d,J＝2.8Hz,1H),2.80–2.77(m,1H),2.53–2.51(m,1H),2.11–2.08(m,1H),1.98(q,J＝12.1Hz,1H),1.87(dd,J＝15.0,J＝2.9Hz,1H),1.38(dd,J＝15.0,J＝2.4Hz,1H).
13C NMR(100MHz,CDCl3):δ138.74,138.46,138.13,128.57,128.34,128.26,128.01,127.88,127.74,127.72,127.58,127.52,76.31,75.80,74.22,73.33,71.37,70.47,61.25,55.05,49.20,31.26,28.06.
HR-MS:calcd.for C30H37NO5H+492.2744,found 492.2764.
2.4(1S,2S,4R,5S) -2, 4-dibenzyloxy-1-benzyloxymethyl-5- (3-hydroxypropyl) amino-1-cyclohexanol (13d)
Example 2 h: under similar conditions, 3-amino-1-propanol was used instead of β -phenylethylamine in example 2a, and the preparation method was the same as in examples 2a to 2e, to obtain white solid 13d with a yield of 49.3 to 69.3%. [ alpha ] to]D 20＝–4.6(c 1.00,H2O).
1H NMR(400MHz,D2O):δ3.99–3.94(m,1H),3.76–3.69(m,3H),3.51(s,2H),3.11(d,J 2.8Hz,1H,H5),3.01–2.95(m,1H),2.83–2.78(m,1H),2.06(dd,J 15.0,J＝4.2Hz,1H),1.98–1.87(m,2H),1.46(d,J 14.8Hz,1H).
13C NMR(100MHz,D2O):δ77.32,71.45,70.34,67.76,62.46,59.59,50.59,34.90,31.18.
HR-MS:calcd.for C9H19NO5H+222.1336,found 222.1331.
2.5(1S,2S,4R,5S) -2, 4-dibenzyloxy-1-benzyloxymethyl-5- (4-hydroxybutyl) amino-1-cyclohexanol (13e)
Example 2 i: under similar conditions, 4-aminobutanol was used in place of the β -phenylethylamine in example 2a, and the preparation method was the same as in examples 2a to 2e, to give 13e as a white solid with a yield of 49.5 to 65.0%. [ alpha ] to]D 20＝+7.1(c 1.00,CHCl3).
1H NMR(600MHz,CDCl3):δ7.37–7.24(m,15H),4.64–4.45(m,6H),3.63–3.56(m,3H),3.50–3.45(m,2H),3.26(d,J＝8.6Hz,1H),3.08(d,J＝3.1Hz,1H),2.83–2.78(m,1H),2.40–2.36(m,1H),2.17–2.14(m,1H),2.03(q,J＝12.1Hz,1H),1.94(dd,J＝15.0,3.2Hz,1H),1.59–1.51(m,3H),1.43(dd,J＝15.0,2.6Hz,1H).
13C NMR(150MHz,CDCl3):δ138.91,138.55,138.27,128.64,128.38,128.29,128.07,127.96,127.76,127.66,127.60,127.53,76.66,75.91,74.14,73.46,73.37,71.51,70.60,62.77,55.49,47.16,31.33,30.26,28.18,26.60.
HR-MS:calcd.for C32H41NO5H+520.3057,found 520.3079.
2.6(1S,2S,4R,5S) -2, 4-dibenzyloxy-1-benzyloxymethyl-5- (2- ((R) -1-hydroxypropyl) amino) -1-cyclohexanol (13f)
Example 2 j: under similar conditions, (R) -2-amino-1-propanol was used in place of the β -phenylethylamine in example 2a, and the preparation method was the same as in examples 2a to 2e, to obtain white solid 13f with a yield of 44.5 to 79.3%. [ alpha ] to]D 20＝–0.3(c 1.00,CHCl3).
1H NMR(400MHz,CDCl3):δ7.36–7.2(m,15H),4.63(d,J＝12.0Hz,1H),4.52–4.45(m,5H),3.90–3.86(m,1H),3.61(d,J＝8.6Hz,1H),3.51–3.44(m,2H),3.27(d,J＝8.6Hz,1H),3.10(d,J＝2.9Hz,1H),2.82(dd,J＝11.6,3.2Hz,1H),2.33(dd,J＝11.4,9.0Hz,1H),2.18–2.14(m,1H),2.06(q,J＝12.0Hz,1H),1.95(dd,J＝15.0,3.0Hz,1H),1.47(dd,J＝15.0,2.4Hz,1H),1.17(d,J＝6.2Hz,3H).
13C NMR(100MHz,CDCl3):δ138.85,138.53,138.20,128.63,128.40,128.32,128.07,127.93,127.81,127.79,127.63,127.57,76.45,75.84,74.22,73.44,73.40,71.45,70.52,67.34,55.63,55.20,31.52,28.16,21.80.
HR-MS:calcd.for C31H39NO5H+506.2901,found 506.2921.
2.7(1S,2S,4R,5S) -2, 4-dibenzyloxy-1-benzyloxymethyl-5- (2- ((S) -1-hydroxypropyl) amino) -1-cyclohexanol (13g)
Example 2 k: the procedure of examples 2a to 2e was followed using (S) -2-amino-1-propanol instead of beta-phenylethylamine in example 2a under similar conditions to give white solid 13g, yield 45.8-72.3%. [ alpha ] to]D 20＝–24.9(c 1.00,CHCl3).
1H NMR(400MHz,CDCl3):δ7.36–7.25(m,15H),4.64–4.44(m,6H),3.90–3.86(m,1H),3.62(d,J＝8.6Hz,1H),3.51–3.45(m,2H),3.26(d,J＝8.6Hz,1H),3.12(d,1H),2.65(dd,J＝12.3,7.3Hz,1H),2.52(dd,J＝12.3,3.3Hz,1H),2.20–2.14(m,1H),2.05(q,J＝12.0Hz,1H),1.93(dd,J＝15.0,3.0Hz,1H),1.47(dd,J＝15.0,2.5Hz,1H),1.15(d,J＝6.3Hz,3H).
13C NMR(100MHz,CDCl3):δ138.83,138.51,138.18,128.63,128.38,128.30,128.06,127.95,127.76,127.61,127.55,76.52,75.85,74.15,73.42,73.37,71.52,70.56,66.06,54.80,54.38,31.44,27.99,20.78.
HR-MS:calcd.for C31H39NO5H+506.2901,found 506.2933.
2.8(1S,2S,4R,5S) -2, 4-dibenzyloxy-1-benzyloxymethyl-5- (2- ((R) -1-hydroxybutyl) amino) -1-cyclohexanol (13h)
Example 2 l: under similar conditions, (R) -2-amino-1-butanol was used instead of beta-phenylethylamine in example 2a, and the preparation method was the same as in examples 2a to 2e, to obtain a white solid for 13h with a yield of 47.4 to 62.3%. [ alpha ] to]D 20＝+2.9(c 1.00,CHCl3).
1H NMR(400MHz,CDCl3):δ7.28–7.18(m,15H),4.58–4.38(m,6H),3.68(dd,J 11.5,J 3.4Hz,1H),3.56(d,J 8.7,J 3.2Hz,1H),3.45–3.33(m,3H),3.23(d,J 3.1Hz,1H),3.18(d,J 8.6Hz,1H),2.51–2.49(m,1H),2.13–2.10(m,1H),1.95(q,J＝12.1,1H),1.79(d,J 14.9,J 3.0Hz,1H,),1.46–1.38(m,3H),0.85(t,J＝7.4Hz,3H).
13C NMR(100MHz,CDCl3):δ138.81,138.49,137.88,128.70,128.41,128.34,128.07,127.86,127.82,127.66,127.61,76.25,75.87,73.94,73.57,73.40,71.59,70.45,61.21,57.62,52.28,32.67,27.52,25.51,10.93.
HR-MS:calcd.for C32H41NO5H+520.3057,found 520.3078.
2.9(1S,2S,4R,5S) -2, 4-dibenzyloxy-1-benzyloxymethyl-5- (2- ((S) -1-hydroxybutyl) amino) -1-cyclohexanol (13i)
Example 2 m: under similar conditions, (S) -2-amino-1-butanol was used in place of β -phenylethylamine in example 2a, and the preparation method was the same as in examples 2a to 2e, to obtain white solid 13i with a yield of 47.8 to 55.1%. [ alpha ] to]D 20＝+18.7(c 1.00,CHCl3).
1H NMR(400MHz,CDCl3):δ7.26–7.17(m,15H),4.57–4.37(m,6H),3.56–3.50(m,2H),3.45–3.38(m,3H),3.20(d,J＝8.4Hz,1H),2.55–2.54(m,1H),2.12–2.08(m,1H),2.00–1.89(m,2H),1.44–1.33(m,3H),0.83(t,J 6.0Hz,3H).
13C NMR(100MHz,CDCl3):δ138.77,138.46,137.97,128.61,128.39,128.32,127.98,127.93,127.76,127.63,127.59,127.56,76.18,75.85,74.32,73.42,73.40,71.49,70.43,64.82,58.97,52.93,32.35,27.91,23.46,10.18.
HR-MS:calcd.for C32H41NO5H+520.3057,found 520.3080.
2.10(1S,2S,4R,5S) -2, 4-dibenzyloxy-1-benzyloxymethyl-5- (3- ((R) -1, 2-dihydroxypropyl) amino) -1-cyclohexanol (13j)
Example 2 n: under similar conditions, (R) -3-amino-1, 2-dipropanol is used to replace beta-phenylethylamine in example 2a, the preparation method is the same as that of examples 2a to 2e, white solid 13j is obtained, and the yield is 57.8-63.0%. [ alpha ] to]D 20＝–8.1(c 1.00,CHCl3).
1H NMR(400MHz,CDCl3):δ7.36–7.24(m,15H),4.60–4.40(m,6H),3.98(s,4H),3.75–3.73(m,1H),3.58(d,J＝8.6Hz,1H),3.53–3.41(m,4H),3.25(d,J＝8.6Hz,1H),3.08(d,J＝2.6Hz,1H),2.76(dd,J＝12.2,6.7Hz,1H),2.50(dd,J＝12.1,3.2Hz,1H),2.18–2.13(m,1H),2.04(q,J＝12.0Hz,1H),1.92(dd,J＝15.1,3.0Hz,1H),1.44(dd,J＝15.0,2.2Hz,1H).
13C NMR(100MHz,CDCl3):δ138.58,138.41,138.16,128.62,128.41,128.35,128.14,127.93,127.82,127.77,127.66,76.25,75.85,74.39,73.38,73.26,71.62,70.51,70.23,64.68,55.13,49.50,31.09,28.07.
HR-MS:calcd.for C32H41NO5H+520.3057,found 520.9078.
2.11(1S,2S,4R,5S) -2, 4-dibenzyloxy-1-benzyloxymethyl-5- (3- ((S) -1, 2-dihydroxypropyl) amino) -1-cyclohexanol (13k)
Example 2 o: under similar conditions, (S) -3-amino-1, 2-dipropanol is used to replace beta-phenylethylamine in example 2a, the preparation method is the same as that of examples 2a to 2e, white solid 13k is obtained, and the yield is 37.8-46.1%. [ alpha ] to]D 20＝–18.4(c 1.00,CHCl3).
1H NMR(400MHz,CDCl3):δ7.33–7.24(m,15H),4.62–4.43(m,6H),3.74–3.70(m,1H),3.58–3.54(m,2H),3.48–3.41(m,3H),3.27(d,J＝8.6Hz,1H),3.07(d,J＝2.9Hz,1H),2.84(dd,J＝11.5,3.7Hz,1H),2.40(dd,J＝11.4,8.4Hz,1H),2.17–2.13(m,1H),2.08–1.93(m,2H),1.42(dd,J＝15.0,2.3Hz,1H).
13C NMR(100MHz,CDCl3):δ138.61,138.40,138.10,128.63,128.41,128.36,128.10,127.93,127.83,127.78,127.67,76.17,75.83,74.43,73.38,73.34,71.47,71.20,70.49,65.21,55.60,49.98,31.11,28.11.
HR-MS:calcd.for C31H39NO6H+522.2850,found 522.2882.
2.12(1S,2S,4R,5S) -2, 4-dibenzyloxy-1-benzyloxymethyl-5- ((R) -2-hydroxy-2-phenylethyl) amino-1-cyclohexanol (13l)
Example 2 p: under similar conditions, (R) -2-amino-1-phenylethylamine was used in place of the β -phenylethylamine in example 2a, and the preparation method was the same as in examples 2a to 2e, to obtain 13l of a white solid with a yield of 57.8 to 66.8%. [ alpha ] to]D 20＝–21.3(c 1.00,CHCl3).
1H NMR(600MHz,CDCl3):δ7.37–7.24(m,20H),4.80(dd,J＝9.1,2.4Hz,1H),4.63(d,J＝12.0Hz,1H),4.51–4.47(m,3H),4.44(s,2H),3.61(d,J＝8.6Hz,1H),3.50–3.45(m,2H),3.26(d,J＝8.6Hz,1H),3.09(d,J＝2.9Hz,1H),3.01(dd,J＝11.8,2.8Hz,1H),2.57(dd,J＝11.6,9.4Hz,1H),2.18–2.14(m,1H),2.11–2.04(m,1H),1.92(dd,J＝15.0,3.1Hz,1H),1.45(dd,J＝15.0,2.5Hz,1H).
13C NMR(150MHz,CDCl3):δ142.72,138.86,138.50,138.23,128.63,128.58,128.39,128.32,128.07,127.89,127.85,127.77,127.62,127.56,125.97,76.51,75.88,74.23,73.56,73.41,73.35,71.43,70.47,55.39,55.32,31.54,28.19.
HR-MS:calcd.for C36H41NO5H+568.3057,found 568.3092.
2.13(1S,2S,4R,5S) -2, 4-dibenzyloxy-1-benzyloxymethyl-5- ((S) -2-hydroxy-2-phenylethyl) amino-1-cyclohexanol (13m)
Example 2 q: under similar conditions, (S) -2-amino-1-phenylethylamine in example 2a was replaced by (S) -2-amino-1-phenylethylamine, and the preparation method was the same as in examples 2a to 2e, whereby 13m of a white solid was obtained with a yield of 60.8 to 93.9%. [ alpha ] to]D 20＝+0.6(c 1.00,CHCl3).
1H NMR(400MHz,CDCl3):δ7.38–7.26(m,15H),4.70–4.45(m,6H),3.64(d,J＝8.6Hz,1H),3.52–3.44(m,2H),3.27(d,J＝8.6Hz,1H),3.12(d,J＝2.0Hz,1H),2.82–2.76(m,1H),2.40(s,1H),2.19–2.14(m,1H),2.08–1.96(m,2H),1.48–1.41(m,3H),1.37–1.26(m,3H),0.88(t,J＝7.3Hz,3H).
13C NMR(100MHz,CDCl3):δ139.03,138.63,138.32,128.65,128.38,128.29,128.07,127.94,127.80,127.66,127.60,127.49,127.10,75.96,74.07,73.53,73.38,71.52,70.61,55.47,54.23,38.15,31.42,31.38,31.31,28.29,26.67,26.15,25.99.
HR-MS:calcd.for C32H41NO4H+504.3108,found 504.3143.
2.14(1S,2S,4R,5S) -2, 4-dibenzyloxy-1-benzyloxymethyl-5- (2- ((S) -1-hydroxy-3-methylbutyl) amino) -1-cyclohexanol (13n)
Example 2 r: under similar conditions, (S) -2-amino-3-methylbutanol was used instead of β -phenylethylamine in example 2a, and the preparation method was the same as in examples 2a to 2e, to obtain white solid 13n with a yield of 40.8 to 57.2%. [ alpha ] to]D 20＝–24.9(c 1.00,CHCl3).
1H NMR(400MHz,CDCl3):δ7.36–7.25(m,15H),4.64–4.44(m,6H),3.90–3.86(m,1H),3.62(d,J＝8.6Hz,1H),3.51–3.45(m,2H),3.26(d,J＝8.6Hz,1H),3.12(d,1H),2.65(dd,J＝12.3,7.3Hz,1H),2.52(dd,J＝12.3,3.3Hz,1H),2.20–2.14(m,1H),2.05(q,J＝12.0Hz,1H),1.93(dd,J＝15.0,3.0Hz,1H),1.47(dd,J＝15.0,2.5Hz,1H),1.15(d,J＝6.3Hz,3H).
13C NMR(100MHz,CDCl3):δ138.83,138.51,138.18,128.63,128.38,128.30,128.06,127.95,127.76,127.61,127.55,76.52,75.85,74.15,73.42,73.37,71.52,70.56,66.06,54.80,54.38,31.44,27.99,20.78.
HR-MS:calcd.for C31H39NO5H+506.2901,found 506.2933.
2.15(1S,2S,4R,5S) -2, 4-dibenzyloxy-1-benzyloxymethyl-5- (cyclohexylmethyl) amino) -1-cyclohexanol (13o)
Example 2 s: under similar conditions, the preparation method is the same as the examples 2a to 2e by replacing beta-phenylethylamine in the example 2 with cyclohexylmethylamine, so that a white solid 13o is obtained, and the yield is 50.8-67.8%. [ alpha ] to]D 20＝–18.4(c 1.00,CHCl3).
1H NMR(400MHz,CDCl3):δ7.33–7.24(m,15H),4.62–4.43(m,6H),3.74–3.70(m,1H),3.58–3.54(m,2H),3.48–3.41(m,3H),3.27(d,J＝8.6Hz,1H),3.07(d,J＝2.9Hz,1H),2.84(dd,J＝11.5,3.7Hz,1H),2.40(dd,J＝11.4,8.4Hz,1H),2.17–2.13(m,1H),2.08–1.93(m,2H),1.42(dd,J＝15.0,2.3Hz,1H).
13C NMR(100MHz,CDCl3):δ138.61,138.40,138.10,128.63,128.41,128.36,128.10,127.93,127.83,127.78,127.67,76.17,75.83,74.43,73.38,73.34,71.47,71.20,70.49,65.21,55.60,49.98,31.11,28.11.
HR-MS:calcd.for C31H39NO6H+522.2850,found 522.2882.
2.16(1S,2S,4R,5S) -2, 4-dibenzyloxy-1-benzyloxymethyl-5-benzylamino-1-cyclohexanol (13p)
Example 2 t: in analogous conditions, benzylamine was used instead of example 2The preparation method of beta-phenylethylamine in a is the same as that of the examples 2 a-2 e, and white solid 13p is obtained, and the yield is 30.8-43.3%. [ alpha ] to]D 20＝–7.0(c 1.00,CHCl3).
1H NMR(400MHz,CDCl3):δ7.35–7.25(m,15H),4.65–4.46(m,6H),3.63(d,J＝8.6Hz,1H),3.50–3.44(m,2H),3.28(d,J＝8.6Hz,1H),2.98(d,J＝2.5Hz,1H),2.39(s,3H),2.18-2.13(m,1H),2.07–1.96(m,2H),1.43(dd,J＝14.9,2.1Hz,1H).
13C NMR(100MHz,CDCl3):δ138.99,138.64,138.28,128.66,128.40,128.32,128.13,127.98,127.79,127.69,127.61,127.56,76.69,76.02,74.19,73.57,73.41,71.53,70.60,57.56,34.26,30.77,28.17.
HR-MS:calcd.for C29H35NO4H+462.2639,found 462.2667.
2.17(1S,2S,4R,5S) -2, 4-dibenzyloxy-1-benzyloxymethyl-5-methylamino-1-cyclohexanol (13q)
Example 2 u: under similar conditions, methylamine is used to replace beta-phenylethylamine in the example 2a, the preparation method is the same as the examples 2 a-2 e, white solid 13q is obtained, and the yield is 34.8-40.0%. [ alpha ] to]D 20＝+14.5(c 1.00,CHCl3).
1H NMR(400MHz,CDCl3):δ7.33–7.21(m,20H),4.64(d,J＝12.0Hz,1H),4.51–4.47(m,3H),4.35(dd,J＝25.7,12.0,2H),4.01(d,J＝13.1Hz,1H),3.68(d,J＝8.6Hz,1H),3.51(dd,J＝11.6,3.4Hz,2H),3.46–3.41(m,1H),3.32(d,J＝8.6Hz,1H),3.18(d,J＝3.0Hz,1H),2.18–2.11(m,1H),2.08–2.03(m,2H),1.48(dd,J＝15.0,2.4Hz,1H).
13C NMR(100MHz,CDCl3):δ139.15,138.98,138.62,138.17,128.65,128.60,128.48,128.40,128.30,128.07,127.89,127.79,127.60,127.52,127.44,76.54,76.00,74.16,73.55,73.43,71.51,70.42,53.80,51.07,31.18,28.23.
HR-MS:calcd.for C35H39NO4H+538.2952,found 538.2978.
2.18(1S,2S,4R,5S) -2, 4-dibenzyloxy-1-benzyloxymethyl-5-butylamino-1-cyclohexanol (13R)
Example 2 v: under similar conditions, butylamine is used to replace beta-phenylethylamine in example 2a, and the preparation method is the same as in examples 2 a-2 e, so that white solid 13r is obtained, and the yield is 34.3-40.9%. [ alpha ] of]D 20＝+0.6(c 1.00,CHCl3).
1H NMR(400MHz,CDCl3):δ7.38–7.26(m,15H),4.70–4.45(m,6H),3.64(d,J＝8.6Hz,1H),3.52–3.44(m,2H),3.27(d,J＝8.6Hz,1H),3.12(d,J＝2.0Hz,1H),2.82–2.76(m,1H),2.40(s,1H),2.19–2.14(m,1H),2.08–1.96(m,2H),1.48–1.41(m,3H),1.37–1.26(m,3H),0.88(t,J＝7.3Hz,3H).
13C NMR(100MHz,CDCl3):δ139.03,138.63,138.32,128.65,128.38,128.29,128.07,127.94,127.80,127.66,127.60,127.49,127.10,75.96,74.07,73.53,73.38,71.52,70.61,55.47,54.23,38.15,31.42,31.38,31.31,28.29,26.67,26.15,25.99.
HR-MS:calcd.for C32H41NO4H+504.3108,found 504.3143.
2.19(1S,2S,4R,5S) -2, 4-dibenzyloxy-1-benzyloxymethyl-5-isopropylamino-1-cyclohexanol (13S)
Example 2 w: under similar conditions, isopropylamine is used to replace beta-phenylethylamine in example 2a, and the preparation method is the same as that of examples 2a to 2e, so that white solid 13s is obtained, and the yield is 54.3-46.1%. [ alpha ] to]D 20＝+183.2(c 1.00,CHCl3).
1H NMR(400MHz,CDCl3):δ7.38–7.23(m,15H),4.65(d,J＝12.0Hz,1H),4.56–4.45(m,5H),3.65(d,J＝8.6Hz,1H),3.52–3.43(m,2H),3.32(d,J＝2.9Hz,1H),3.27(d,J＝8.6Hz,1H),2.94–2.91(m,J＝6.3Hz,1H),2.16–2.12(m,1H),2.04(q,J＝12.0Hz,1H),1.90(dd,J＝14.9,3.3Hz,1H),1.43(dd,J＝14.9,2.6Hz,1H),1.08(dd,J＝16.4,6.4Hz,6H).
13C NMR(100MHz,CDCl3):δ139.06,138.67,138.19,128.65,128.39,128.29,128.04,127.93,127.79,127.63,127.48,76.44,76.07,74.02,73.65,73.41,71.49,70.32,51.35,45.64,32.16,28.26,24.41,21.67.
HR-MS:calcd.for C31H39NO4H+490.2952,found 490.2978.
2.20(1S,2S,4R,5S) -2, 4-dibenzyloxy-1-benzyloxymethyl-5- (2-methoxyethyl) amino-1-cyclohexanol (13t)
Example 2 x: under similar conditions, 2-methoxyethylamine was used in place of β -phenylethylamine in example 2a, and the preparation method was the same as in examples 2a to 2e, to obtain 13t of a white solid with a yield of 44.3 to 53.8%. [ alpha ] to]D 20＝+58.9(c 1.00,CHCl3).
1H NMR(400MHz,CDCl3):δ7.37–7.23(m,15H),4.64(d,J＝12.1Hz,1H),4.55–4.45(m,5H),3.63(d,J＝8.6Hz,1H),3.54–3.38(m,4H),3.31(s,3H),3.28(d,J＝8.6,1H),3.15(d,J＝2.8Hz,1H),2.96–2.91(m,1H),2.68–2.62(m,1H),2.18–2.11(m,1H),2.08–2.02(m,1H)1.94(dd,J＝15.0,3.0Hz,1H),1.44(dd,J＝15.0,2.4Hz,1H).
13C NMR(100MHz,CDCl3):δ139.00,138.62,138.22,128.59,128.37,128.28,128.05,127.88,127.76,127.58,127.49,76.48,75.99,74.12,73.52,73.38,71.56,71.43,70.33,58.92,54.69,46.88,31.34,28.25.
HR-MS:calcd.for C31H39NO5H+506.2901,found 506.2921.
2.21(1S,2S,4R,5S) -2, 4-dibenzyloxy-1-benzyloxymethyl-5- (3-methoxypropyl) amino-1-cyclohexanol (13u)
Example 2 y: under similar conditions, 3-methoxypropylamine was used instead of β -phenylethylamine in example 2a, and the preparation method was the same as in examples 2a to 2e, to obtain 13u as a white solid with a yield of 54.3 to 60.0%. [ alpha ] to]D 20＝+1.7(c 1.00,H2O).
1H NMR(600MHz,D2O):δ3.93–3.90(m,1H),3.68(dd,J＝9.9,5.6Hz,1H),3.55–3.51(m,2H),3.49(d,J＝2.5Hz,2H),3.33(s,3H),2.99(s,1H),2.86–2.82(m,1H),2.64–2.60(m,1H),1.99(d,J＝14.6Hz,1H),1.93–1.87(m,2H),1.82–1.74(m,2H),1.39(d,J＝14.2Hz,1H).
13C NMR(100MHz,D2O):δ76.92,73.43,70.85,68.84,67.70,60.93,60.43,47.05,34.71,30.28,28.28.
HR-MS:calcd.for C11H23NO5H+250.1649,found 250.1649.
3. Preparation of target 11
3.1(1S,2S,4R,5S) -1-hydroxymethyl-5- (2-phenylethyl) amino-1, 2, 4-cyclohexanetriol (11a)
Example 3 a: under hydrogen, 52.0mg (0.10mmol) of 13a, 50.0mg of 10% Pd/C in 10.0mL of 20% formic acid anhydride in methanol was catalytically hydrogenated for 24 h. After filtration, formic acid and methanol were distilled off under reduced pressure, the residue was diluted with a small amount of water and separated by column chromatography on a cationic resin (Dowex 50 W.times.8-200), eluting with water and aqueous ammonia in this order, and the aqueous ammonia layer was concentrated under reduced pressure and lyophilized to give 20.0mg of a white solid 11a with a yield of 71.0%. m.p 145-147 deg.C, [ alpha ]]D 20＝+2.9(c 1.00,H2O).
1H NMR(600MHz,D2O):δ7.17–7.06(m,5H),3.65–3.62(m,1H),3.5(q,J＝6.4Hz,1H),3.38(d,J＝10.9Hz,1H),3.29(d,J＝10.9Hz,1H),2.95–2.92(m,1H),2.83(s,1H),2.72–2.63(m,3H),1.89(dd,J＝14.8,3.2Hz,1H),1.76–1.74(m,2H),1.23(d,J＝14.4Hz,1H).
13C NMR(100MHz,D2O):δ140.83,129.74,129.56,127.32,75.65,70.16,69.77,66.84,59.21,49.70,37.03,34.80,30.84.
HR-MS:calcd.for C10H21NO6Na+304.1519,found 304.1513.
Example 3 b: the preparation of Pd/C as in example 3a was carried out in a similar manner to example 3a except that 50.0mg of 10% Ru/C was used instead of Pd/C, whereby 18.3mg of white solid 11a was obtained in a yield of 65.0%.
Example 3 c: the preparation was carried out in a similar manner to example 3a except that 60.0mg of Raney Ni (W-2) was used in place of Pd/C in example 3a, and 14.1mg of a white solid (11a) was obtained with a yield of 50.0%.
Example 3 d: the procedure of example 3a was carried out under similar conditions except that the methanol solution of 20% anhydrous formic acid in example 3a was replaced with the methanol solution of 20% anhydrous acetic acid to give 20.0mg of white solid 11a in a yield of 71.0%.
Example 3 e: the procedure of example 3a was carried out under similar conditions, using a THF solution of 20% anhydrous formic acid instead of the methanol solution of 20% anhydrous formic acid of example 3a, to give 18.3mg, yield 65.0%, of white solid 11 a.
3.2(1S,2S,4R,5S) -1- (hydroxymethyl) -5- (2-hydroxy-1- (hydroxymethyl) ethylamino) -1,2, 4-cyclohexanetriol (11b)
Example 3 f: 52.0mg (0.10mmol) of 13b, the preparation method is the same as that of examples 3a to 3e, and the yield is 61.0 to 81.0%. [ alpha ] to]D 20＝+11.8(c 1.00,H2O).
1H NMR(600MHz,D2O):δ1.40(d,J＝22.1,1H),1.94–1.90(m,2H),2.00(dd,J＝22.3,5.6Hz,1H),2.90–2.87(m,1H),3.19(s,1H),3.49(s,2H),3.71–3.57(m,5H),3.94–3.89(m,1H).
13C NMR(100MHz,D2O):δ74.47,68.90,68.03,65.11,61.84,58.68,56.28,53.64,32.04,29.47.
HR-MS:calcd.for C10H21NO6H+252.1442,found 252.1436.
3.3(1S,2S,4R,5S) -1-hydroxymethyl-5- (2-hydroxyethyl) amino-1, 2, 4-cyclohexanetriol (11c)
Example 3 g: 52.0mg (0.10mmol) of 13c, the preparation method is the same as that of examples 3a to 3e, and the yield is 71.0 to 85.8%. [ alpha ] to]D 20＝–4.6(c 1.00,H2O).
1H NMR(400MHz,D2O):δ3.99–3.94(m,1H),3.76–3.69(m,3H,H2),3.51(s,2H),3.11(d,J＝2.8Hz,1H),3.01–2.95(m,1H),2.83–2.78(m,1H),2.06(dd,J＝15.0,J＝4.2Hz,1H),1.98–1.87(m,2H),1.46(d,J＝14.8Hz,1H).
13C NMR(100MHz,D2O):δ77.32,71.45,70.34,67.76,62.46,59.59,50.59,34.90,31.18.
HR-MS:calcd.for C9H19NO5H+222.1336；found 222.1331.
3.4(1S,2S,4R,5S) -1-hydroxymethyl-5- (3-hydroxypropyl) amino-1, 2, 4-cyclohexanetriol (11d)
Example 3 h: 52.0mg (0.10mmol) based on 13d, the preparation method is the same as that of examples 3a to 3e, and the yield is 51.0 to 69.8%. [ alpha ] to]D 20＝–3.0(c 1.00,H2O).
1H NMR(400MHz,D2O):δ4.01–3.99(m,1H),3.76–3.69(m,3H),3.54(s,2H),3.18(s,1H),3.06–3.02(m,1H),2.87–2.81(m,1H),2.10(dd,J＝15.1,J＝4.6Hz,1H),1.98–1.90(m,2H),1.85–1.82(m,2H),1.53(d,J＝15.2Hz,1H).
13C NMR(100MHz,D2O):δ74.44,68.54,67.06,65.00,59.70,57.16,43.70,32.13,29.88,28.14.
HR-MS:calcd.for C10H21NO5H+236.1492,found 236.1486.
3.5(1S,2S,4R,5S) -1-hydroxymethyl-5- (4-hydroxybutyl) amino-1, 2, 4-cyclohexanetriol (11e)
Example 3 i: 52.0mg (0.10mmol) of 13e, the preparation method is the same as that of examples 3a to 3e, and the yield is 55.0 to 76.7%. [ alpha ] to]D 20＝–0.1(c 1.00,H2O).
1H NMR(400MHz,D2O):δ4.02–3.98(m,1H),3.74(dd,J＝9.9,4.8Hz,1H),3.61(t,J＝6.2Hz,2H),3.52(s,2H),3.22(d,J＝3.5Hz,1H),3.03–2.97(m,1H),2.86–2.80(m,1H),2.10(dd,J＝15.1,4.8Hz,1H),2.00–1.86(m,2H),1.68–1.60(m,5H).
13C NMR(100MHz,D2O):δ77.11,71.12,69.47,67.64,63.96,59.80,48.57,34.80,31.47,30.66,26.52.
HR-MS:calcd.for C11H23NO5Na+272.1468,found 272.1476.
3.6(1S,2S,4R,5S) -1-hydroxymethyl-5- (((R) -2-hydroxypropyl) amino) -1,2, 4-cyclohexanetriol (11f)
Example 3 j: 52.0mg (0.10mmol) in terms of 13f, the preparation method being the same as in examples 3a to 3e, the yield being 45.0 to 55.0%. [ alpha ] to]D 20＝–0.8(c 1.00,H2O).
1H NMR(400MHz,D2O):δ4.02–3.95(m,2H),3.72(dd,J＝10.0,5.0Hz,1H),3.51(s,2H),3.16(d,J＝3.1Hz,1H),2.99(dd,J＝12.3,3.6Hz,1H),2.66(dd,J＝12.1,8.7Hz,1H),2.08(dd,J＝15.1,4.6Hz,1H),1.99–1.87(m,2H),1.52(d,J＝14.4Hz,1H),1.20(d,J＝6.4Hz,3H).
13C NMR(400MHz,D2O):δ77.27,71.27,69.87,68.52,67.67,60.29,55.81,34.83,31.04,22.76.
HR-MS:calcd.for C10H21NO5H+236.1492,found 236.1484.
3.7(1S,2S,4R,5S) -1-hydroxymethyl-5- (((S) -1-hydroxypropyl) amino) -1,2, 4-cyclohexanetriol (11g)
Example 3 k: 52.0mg (0.10mmol) of 13g, the preparation method is the same as that of examples 3a to 3e, and the yield is 55.0 to 79.2%. [ alpha ] to]D 20＝+11.3(c 1.00,H2O).
1H NMR(400MHz,D2O):δ4.06–3.98(m,2H),3.73(dd,J＝10.8,4.7Hz,1H),3.53(s,J＝1.2Hz,2H),3.24(d.J＝3.28Hz,1H),2.92–2.90(m,2H),2.12(dd,J＝15.4,4.1Hz,1H),2.03–1.98(m,1H),1.93–1.84(m,1H),1.54(d,J＝13.4Hz,1H),1.21(d,J＝6.4Hz,3H).
13C NMR(100MHz,D2O):δ77.26,71.22,69.72,67.85,67.35,60.11,55.39,34.87,30.68,22.58.
HR-MS:calcd.for C10H21NO5H+236.1492,found 236.1478.
3.8(1S,2S,4R,5S) -1-hydroxymethyl-5- (2- ((R) -1-hydroxybutyl) amino) -1,2, 4-cyclohexanetriol (11h)
Example 3 l: 52.0mg (0.10mmol) in 13h, the preparation method is the same as in examples 3a to 3e, and the yield is 45.0-53.2%. [ alpha ] to]D 20＝+2.8(c 1.00,H2O).
1H NMR(400MHz,D2O):δ3.98(s,1H),3.74(s,2H),3.62(d,J＝10.4,1H),3.52(s,2H),3.35(s,1H),2.96(s,1H),2.05(d,J＝13.4Hz,1H),1.96–1.52(m,5H),0.95(t,J＝6.9Hz,3H).
13C NMR(100MHz,D2O):δ77.32,71.27,69.79,67.79,62.02,60.19,57.20,34.80,31.59,26.23,12.34.
HR-MS:calcd.for C11H23NO5Na+272.1468,found 272.1480.
3.9(1S,2S,4R,5S) -1-hydroxymethyl-5- (2- ((S) -1-hydroxybutyl) amino) -1,2, 4-cyclohexanetriol (11i)
Example 3 m: 52.0mg (0.10mmol) of 13i, the preparation method is the same as that of examples 3a to 3e, and the yield is 45.8 to 59.3%. [ alpha ] to]D 20＝+15.7(c 1.00,H2O).
1H NMR(400MHz,D2O):δ3.99–3.96(m,1H),3.73–3.71(m,2H),3.58(dd,J＝11.6,7.1Hz,1H),3.51(s,2H),3.32(s,1H),2.95(s,1H),2.06–1.96(m,2H),1.91–1.83(m,1H),1.64–1.63(m,1H),1.53–1.48(m,2H),0.89(t,J＝7.3Hz,3H).
13C NMR(100MHz,D2O):δ74.32,68.51,67.14,65.00,61.99,57.23,54.27,31.96,28.69,20.68,8.56.
HR-MS:calcd.for C11H23NO5Na+272.1468,found 272.1474
3.10(1S,2S,4R,5S) -1-hydroxymethyl-5- (((R) -2, 3-dihydroxypropyl) amino) -1,2, 4-cyclohexanetriol (11j)
Example 3 n: 52.0mg (0.10mmol) of 13j, the preparation method is the same as that of examples 3a to 3e, and the yield is 47.8 to 59.4%. [ alpha ] to]D 20＝+15.7(c 1.00,H2O).
1H NMR(400MHz,D2O):δ3.99–3.96(m,1H),3.73–3.71(m,2H),3.58(dd,J＝11.6,7.1Hz,1H),3.51(s,2H),3.32(s,1H),2.95(s,1H),2.06–1.96(m,2H),1.91–1.83(m,1H),1.64–1.63(m,1H),1.53–1.48(m,2H),0.89(t,J＝7.3Hz,3H).
13C NMR(100MHz,D2O):δ74.32,68.51,67.14,65.00,61.99,57.23,54.27,31.96,28.69,20.68,8.56.
HR-MS:calcd.for C11H23NO5Na+272.1468,found 272.1474.
3.11(1S,2S,4R,5S) -1-hydroxymethyl-5- ((S) -2, 3-dihydroxypropyl) amino) -1,2, 4-cyclohexanetriol (11k)
Example 3 o: 52.0mg (0.10mmol) of 13k, the preparation method is the same as that of examples 3a to 3e, and the yield is 37.8 to 41.7%. [ alpha ] to]D 20＝–11.2(c 1.00,H2O).
1H NMR(400MHz,D2O):δ4.04–3.99(m,1H),3.94–3.89(m,1H),3.73(dd,J＝10.3,4.8Hz,1H),3.68–3.64(m,2H),3.61–3.56(m,2H),3.52(s,2H),3.23(d,J＝2.48Hz,1H),3.15(dd,J＝11.9,2.8Hz,1H),2.80(dd,J＝11.9,8.5Hz,1H),2.11(dd,J＝15.2,4.5Hz,1H),2.02–1.92(m,2H),1.88(d,J＝11.0Hz,1H).
13C NMR(100MHz,D2O):δ77.32,72.15,71.28,69.70,67.79,66.73,60.65,51.70,34.88,30.94.
HR-MS:calcd.for C10H21NO6H+252.1442,found 252.1444.
3.12(1S,2S,4R,5S) -1-hydroxymethyl-5- ((R) -2-hydroxy-2-phenylethyl) amino-1, 2, 4-cyclohexanetriol (11l)
Example 3 p: 52.0mg (0.10mmol) in terms of 13l, the preparation method is the same as in examples 3a to 3e, and the yield is 39.8 to 50.4%. [ alpha ] to]D 20＝–15.3(c 1.00,H2O).
1H NMR(400MHz,D2O):δ7.45–7.39(m,5H),4.93(dd,J＝8.4,4.4Hz,1H),3.99–3.97(m,1H),3.70(dd,J＝10.4,4.7Hz,1H),3.49(s,2H),3.22(d,J＝13.2Hz,2H),3.01(t,J＝9.4Hz,1H),2.06(dd,J＝15.0,4.3Hz,1H),1.98–1.83(m,2H),1.51(d,J＝15.0Hz,1H).
13C NMR(100MHz,D2O):δ143.64,131.64,131.19,128.87,77.19,74.24,71.24,69.82,67.66,60.38,55.51,34.80,31.12.
HR-MS:calcd.for C15H23NO5H+298.1649,found 298.1647.
3.13(1S,2S,4R,5S) -1-hydroxymethyl-5- ((S) -2-hydroxy-2-phenylethyl) amino-1, 2, 4-cyclohexanetriol (11m)
Example 3 q: 52.0mg (0.10mmol) of 13m, the preparation method is the same as that of examples 3a to 3e, and the yield is 61.8 to 71.2%. [ alpha ] to]D 20＝+24.3(c 1.00,H2O).
1H NMR(400MHz,D2O):δ7.47–7.39(m,5H),4.94(dd,J＝8.1,4.2Hz,1H),3.98–3.94(m,1H),3.71–3.67(m,1H),3.50(s,2H),3.21–3.16(m,2H),3.02(dd,J＝12.4,3.8Hz,1H),2.08(dd,J＝15.0,3.1Hz,1H),1.98–1.81(m,2H),1.48(d,J＝14.7Hz,1H).
13C NMR(100MHz,D2O):δ143.56,131.48,130.98,128.78,77.09,73.68,71.18,69.95,67.65,59.64,55.14,34.69,30.88.
HR-MS:calcd.for C15H23NO5H+298.1649,found 298.1643.
3.14(1S,2S,4R,5S) -1-hydroxymethyl-5- (2- ((S) -1-hydroxy-3-methylbutyl) amino) -1,2, 4-cyclohexanetriol (11n)
Example 3 r: 52.0mg (0.10mmol) based on 13n, the preparation method is the same as that of examples 3a to 3e, and the yield is 51.8 to 77.7%. [ alpha ] to]D 20＝–5.7(c 1.00,H2O).
1H NMR(400MHz,D2O):δ3.99–3.97(m,1H),3.77(dd,J＝11.8,4.0Hz,1H),3.70(dd,J＝10.4,4.9Hz,1H),3.58(dd,J＝11.7,7.9Hz,1H),3.51(s,2H),3.31(s,1H),2.85–2.83(m,1H),2.05–1.89(m,4H),1.46(d,J＝14.5Hz,1H),0.97(d,J＝6.9Hz,3H).0.88(d,J＝6.9Hz,3H).
13C NMR(100MHz,D2O):δ77.24,71.54,70.29,67.96,64.27,63.11,57.53,34.85,31.84,29.00,21.11,18.70.
HR–MS:calcd.for C12H25NO5H+264.1805,found 264.1814.
3.15(1S,2S,4R,5S) -1-hydroxymethyl-5- (cyclohexylmethyl) amino-1, 2, 4-cyclohexanetriol (11o)
Example 3 s: 52.0mg (0.10mmol) in 13o, the preparation method is the same as that of the examples 3a to 3e, and the yield is 21.8 to 31.7 percent. [ alpha ] to]D 20＝–3.7(c 1.00,H2O).
1H NMR(400MHz,D2O):δ4.00–3.97(m,1H),3.74(dd,J＝10.3,4.6Hz,1H),3.52(d,J＝5.0Hz,2H),3.16(d,J＝2.8Hz,1H),2.76(dd,J＝11.8,8.3Hz,1H),2.61(dd,J＝11.7,5.4Hz,1H),2.08(dd,J＝14.9,4.0Hz,1H),2.00–1.89(m,2H),1.77–1.53(m,7H),1.49–1.14(m,3H),1.02–0.94(m,2H).
13C NMR(100MHz,D2O):δ77.42,71.28,70.03,67.75,60.26,55.47,38.82,34.98,33.38,30.92,28.77,28.25,28.13.
HR-MS:calcd.for C14H27NO4H+274.2013,found 274.2023.
3.16(1S,2S,4R,5S) -1-hydroxymethyl-5-amino-1, 2, 4-cyclohexanetriol (11p)
Example 3 t: 52.0mg (0.10mmol) of 13p, the preparation method is the same as that of examples 3a to 3e, and the yield is 61.8-81.8%. [ alpha ] to]D 20＝+3.0(c 1.00,H2O).
1H NMR(400MHz,D2O):δ4.01–3.97(m,1H),3.73(dd,J＝10.1,4.8Hz,1H),3.52(s,2H),3.05(d,J＝4.3Hz,1H),2.54(s,3H),2.10(dd,J＝19.6,4.4Hz,1H),2.00–1.84(m,2H),1.52(dd,J＝15.2,2.4Hz,1H).
13C NMR(100MHz,D2O):δ77.20,71.32,69.74,67.82,61.64,34.91,30.45,22.88.
HR-MS:calcd.for C8H17NO4H+192.1230,found 192.1231.
3.17(1S,2S,4R,5S) -1-hydroxymethyl-5-methylamino-1, 2, 4-cyclohexanetriol (11q)
Example 3 u: 52.0mg (0.10mmol) in terms of 13q, the preparation method being the same as in examples 3a to 3e, the yield being 21.8 to 31.0%. [ alpha ] to]D 20＝–2.8(c 1.00,H2O).
1H NMR(400MHz,D2O):δ4.01–3.97(m,1H),3.73(dd,J＝10.1,4.8Hz,1H),3.52(s,2H),3.05(d,J＝4.3Hz,1H),2.54(s,3H),2.10(dd,J＝19.6,4.4Hz,1H),2.00–1.84(m,2H),1.52(dd,J＝15.2,2.4Hz,1H).
13C NMR(100MHz,D2O):δ77.20,71.32,69.74,67.82,61.64,34.91,30.45,22.88.
HR-MS:calcd.for C8H17NO4H+192.1230,found 192.1231.
3.18(1S,2S,4R,5S) -1-hydroxymethyl-5-butylamino-1, 2, 4-cyclohexanetriol (11R)
Example 3 v: 52.0mg (0.10mmol) in 13r, the preparation method is the same as that of the examples 3a to 3e, and the yield is 29.8 to 49.7 percent. [ alpha ] to]D 20＝–1.1(c 1.00,H2O).
1H NMR(400MHz,D2O):δ4.05–4.00(m,1H),3.75(dd,J＝10.0,4.7Hz,1H),3.53(d,J＝1.0Hz，2H),3.28(d,J＝3.9Hz,1H),3.08–2.01(m,1H),2.90–2.84(m,1H),2.12(dd,J＝15.2,4.7Hz,1H),2.01–1.89(m,2H),1.62–1.51(m,3H),1..39–1.31(m,2H),0.90(t,J＝7.4Hz,3H).
13C NMR(100MHz,D2O):δ77.08,71.02,69.02,67.67,59.98,48.56,34.18,31.35,30.41,22.18,15.74.
HR-MS:calcd.for C11H23NO4H+234.1700,found 234.1703.
3.19(1S,2S,4R,5S) -1-hydroxymethyl-5-isopropylamino-1, 2, 4-cyclohexanetriol (11S)
Example 3 w: 52.0mg (0.10mmol) in 13s, the preparation method is the same as in examples 3a to 3e, and the yield is 59.8 to 71.0%. [ alpha ] to]D 20＝+2.5(c 1.00,H2O).
1H NMR(400MHz,D2O):δ4.07–4.03(m,1H),3.78(dd,J＝9.8,4.6Hz,1H),3.55(s,2H),3.52–3.47(m,2H),2.13(dd,J＝15.2,4.9Hz,1H),2.02–1.98(m,1H),1.93–1.85(m,1H),1.68(dd,J＝15.1,2.4Hz,1H),1.28(dd,J＝17.7,6.5Hz,6H).
13C NMR(100MHz,D2O):δ77.12,70.85,68.41,67.62,57.44,50.84,34.07,30.45,22.72,20.76.
HR-MS:calcd.for C10H21NO6H+220.1543,found 220.1539.
3.20(1S,2S,4R,5S) -1-hydroxymethyl-5- (2-methoxyethyl) amino-1, 2, 4-cyclohexanetriol (11t)
Example 3 x: 52.0mg (0.10mmol) in terms of 13t, the preparation method is the same as in examples 3a to 3e, and the yield is 49.8 to 59.1%. [ alpha ] to]D 20＝–6.6(c 1.00,H2O).
1H NMR(600MHz,D2O):δ3.98–3.94(m,1H),3.70(dd,J＝15.2,7.7Hz,1H),3.64–3.60(m,2H),3.51(s,2H),3.37(s,3H),3.11(d,J＝4.4Hz,1H),3.08–2.84(m,2H),2.05(dd,J＝22.5,6.5Hz,1H),1.97–1.88(m,2H),1.47(d,J＝22.0Hz,1H).
13C NMR(100MHz,D2O):δ77.53,73.03,71.64,70.44,67.97,61.02,59.90,48.30,35.11,31.38.
HR-MS:calcd.for C10H21NO5H+236.1492,found 236.1491.
3.21(1S,2S,4R,5S) -1-hydroxymethyl-5- (3-methoxypropyl) amino-1, 2, 4-cyclohexanetriol (11u)
Example 3 y: 52.0mg (0.10mmol) of 13u, the preparation method is the same as that of examples 3a to 3e, and the yield is 55.8 to 60.9%. [ alpha ] to]D 20＝+1.7(c 1.00,H2O).
1H NMR(600MHz,D2O):δ3.93–3.90(m,1H),3.68(dd,J＝9.9,5.6Hz,1H),3.55–3.51(m,2H),3.49(d,J＝2.5Hz,2H),3.33(s,3H),2.99(s,1H),2.86–2.82(m,1H),2.64–2.60(m,1H),1.99(d,J＝14.6Hz,1H),1.93–1.87(m,2H),1.82–1.74(m,2H),1.39(d,J＝14.2Hz,1H).
13C NMR(100MHz,D2O):δ76.92,73.43,70.85,68.84,67.70,60.93,60.43,47.05,34.71,30.28,28.28.
HR-MS:calcd.for C11H23NO5H+250.1649,found 250.1649.
4. Activity test of α -glycosidase inhibitors:
example 4 a: the activity detection method of the alpha-glycosidase inhibitor comprises the following steps:
mouse intestinal α -glucosidase was prepared. The reaction mixture consisted of 100. mu.L of alpha-glucosidase and 80. mu.L of compound (pH 6.8 in 50mM phosphate buffer). After incubation at 37 ℃ for 10 min, 20. mu.L of sucrose (100 mg/ml) was added and the solution incubated for a further 30 min at 37 ℃. The reaction was terminated by incubation at 80-85 ℃ for 3 minutes. The amount of free glucose was measured by the glucose oxidase method. Positive controls were voglibose, miglitol and acarbose.
TABLE 1. results of activity test of alpha-glucosidase inhibitors
Figure BDA0002011850060000181
a: has no inhibitory activity
Example 4 b: effect of selected 5 samples on sucrose tolerance in normal ICR mice.
Healthy male ICR mice (20-22 g) were purchased from Beijing Wittingle laboratory animal technology, Inc. (Beijing, China). All mice were acclimated in a light and temperature controlled room for 3 days with random food and water. The mice were divided into 9 groups. Each group consisted of 8 animals. A single dose (2.0mg/kg) of test compound was administered orally to each mouse. Positive controls were voglibose, miglitol, acarbose (2.0 mg/kg). Each mouse was given 4.0g/kg sucrose solution (expressed as 0 min). Control mice were given equal amounts of distilled water and sucrose solution. Approximately 20 μ L of blood was collected from the tail vein for 0, 30, 60 and 120 minutes, respectively, and the blood glucose level was measured by the glucose oxidase method. Data are expressed as mean ± SD (mg/dL).
TABLE 2 influence of samples on blood glucose and area under the blood glucose curve after sucrose load in ICR mice
Figure BDA0002011850060000191
Note:*P<0.05,**P<0.01,***P<0.001vs Nor group,n＝8,means±SD.
FIG. 1. Effect of samples on blood glucose curves and areas under curves after sucrose loading in ICR mice (see attached figure)

Claims (7)

  1. A 3-deoxy-5-hydroxy-1-amino carbo-carbohydrate compound having the following general structural formula:
    Figure DEST_PATH_IMAGE002
    wherein said compound is characterized in that R is ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 2-methoxyethyl, 3-methoxypropyl, 4-methoxybutyl, 2-ethoxyethyl, 3-ethoxypropyl, 4-ethoxybutyl, 2, 3-dihydroxypropyl, 2-aminoethyl, 3-aminopropyl, 2-amino-3-hydroxypropyl, 3-amino-2-hydroxypropyl, 2-amino-4-hydroxybutyl, methyl, ethyl, isopropyl, 2-amino-4-hydroxybutyl, isobutyl, tert-butyl, n-pentyl, cyclopentyl, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopropylmethyl, 2-methoxyethyl, 3-methoxy-butyl, 4-ethoxybutyl, 2-dihydroxypropyl, 2-amino-2-amino-3-hydroxy-3-hydroxypropyl, 2-amino-4-hydroxybutyl, 2-hydroxy-butyl, 2-hydroxy-propyl, 2-hydroxy-2-amino-3-hydroxy-2-hydroxy-2-hydroxy-propyl, or-hydroxy-2-amino-2-amino-hydroxy-2-hydroxy-2-hydroxy-2-hydroxy-is present in a, 2-amino-3-hydroxybutyl, 3-amino-2-hydroxybutyl, 4-amino-2-hydroxybutyl.
  2. 2. A pharmaceutical composition comprising the 3-deoxy-5-hydroxy-1-aminocarboxylate compound according to claim 1 and a pharmaceutically acceptable carrier.
  3. 3. The process for the synthesis of 3-deoxy-5-hydroxy-1-aminocarbonyl sugars according to claim 1, characterized in that starting from the P-protected 3-deoxy-1-carbonyl, a reductive amination reaction is carried out to obtain the protected 3-deoxy-1-aminocarbonyl sugar, which is finally deprotected to obtain the protected group P, which is benzyl, R is as defined in claim 1:
    Figure DEST_PATH_IMAGE004
    Figure DEST_PATH_IMAGE006
    Figure DEST_PATH_IMAGE008
    。
  4. 4. the process as claimed in claim 3, wherein, in the reductive amination, the organic amine H used is2The R group in NR is the same as the above target, and the reducing agent used is LiBH4、NaBH4、KBH4、LiBH3CN、NaBH3CN、KBH3CN、NaBH(OAc)3(ii) a The solvent used for reductive amination is an alcoholic solvent, or an ethereal solvent, or any combination of the alcoholic solvent and the ethereal solvent, the alcoholic solvent is methanol, ethanol or any combination thereof, and the ethereal solvent is diethyl ether, tetrahydrofuran, 1, 4-dioxane, 1, 2-dimethoxyethane or any combination thereof; when in deprotection, palladium, nickel, ruthenium and rhodium catalytic hydrogenation methods are selected to remove the protection of benzyl, and the used solvent is water, alcoholic solvent or any combination thereof, and ethereal solvent or any combination thereof; in order to improve the activity of the catalyst, hydrochloric acid, formic acid and acetic acid can be added into the system to improve the deprotection reaction efficiency.
  5. 5. The method of claim 3, wherein compound 12 is synthesized via the synthetic route for compound 14, and the protecting group P is benzyl; 1, 4-Michelal addition selective reducing agent sodium hydrosulfite, or selective double bond reduction method combining palladium, nickel, ruthenium, rhodium catalyst and hydrogen, wherein the used solvent is water, methanol, ethanol, isopropanol or any combination thereof, tetrahydrofuran, 1, 2-dimethoxyethane or any combination thereof:
    Figure DEST_PATH_IMAGE009
    。
  6. 6. use of the 3-deoxy-5-hydroxy-1-aminocarboxylic acid compound of claim 1 or the pharmaceutical composition of claim 2 for the preparation of a hypoglycemic agent.
  7. 7. Use of compound 12 of claim 5 for the preparation of 3-deoxy-5-hydroxy-1-aminocarboxylic acid compound of claim 1.
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