阅读说明：本技术 一种异羟肟酸类衍生物及其制备方法和应用 (hydroxamic acid derivative and preparation method and application thereof ) 是由 王玉成 游学甫 王菊仙 杜潇楠 王明华 朱梅 张国宁 于 2019-09-19 设计创作，主要内容包括：本发明涉及酶抑制剂技术领域,尤其涉及一种异羟肟酸类衍生物及其制备方法和应用。本发明提供的异羟肟酸类衍生物中的异羟肟酸基团与LpxC酶活性区域中的活性锌离子螯合,且含有与LpxC酶中的疏水通道结合的疏水侧链,上述两个方面内容保证了异羟肟酸类衍生物对LpxC具有较好的杀菌活性和较低的毒性；本发明还提供了所述异羟肟酸类衍生物的制备方法,所述制备方法反应时间短,收率高。(The invention relates to the technical field of enzyme inhibitors, in particular to a hydroxamic acid derivative and a preparation method and application thereof. The hydroxamic acid group in the hydroxamic acid derivative is chelated with active zinc ions in an LpxC enzyme active area, and the hydroxamic acid derivative contains a hydrophobic side chain combined with a hydrophobic channel in the LpxC enzyme, so that the hydroxamic acid derivative has better bactericidal activity and lower toxicity to LpxC; the invention also provides a preparation method of the hydroxamic acid derivative, and the preparation method is short in reaction time and high in yield.)

1. A hydroxamic acid derivative having the structure of formula I:

In the formula I, X is

y is

Z is

Wherein when Y and Z are bothwhen X does not include

2. a hydroxamic acid derivative according to claim 1,

X is

y is

z is

3. a method for preparing hydroxamic acid derivatives according to claim 1 or 2, comprising the steps of:

mixing a compound with a structure shown in a formula II, a dess-martin oxidant and dichloromethane, and carrying out an oxidation reaction to obtain a compound with a structure shown in a formula III;

Mixing the compound with the structure shown in the formula III, triphenylphosphine, carbon tetrabromide and dichloromethane, and carrying out Corey-Fuchs reaction to obtain a compound with the structure shown in the formula IV;

The compound with the structure shown as the formula IV and Pd₂(dba)₃Mixing the compound with the structure shown in the formula a, triethylamine and N, N-dimethylformamide, and carrying out Sonogashira coupling reaction to obtain a compound with the structure shown in the formula V;

Mixing a compound with a structure shown in a formula V, tetrahydrofuran and a sodium hydroxide solution, and carrying out hydrolysis reaction to obtain a compound with a structure shown in a formula VI;

Mixing a compound with a structure shown in a formula VI, (S) -2-amino-3- (tert-butoxycarbonylamino) -3-methyl butyric acid methyl ester, diisopropylethylamine, 2- (7-oxybenzotriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate and N, N-dimethylformamide for condensation reaction to obtain a compound with a structure shown in a formula VII;

Mixing the compound with the structure shown in the formula VII, methanol and hydrogen chloride gas, and carrying out a de-Boc protection reaction to obtain a compound with the structure shown in the formula VIII;

mixing the compound with the structure shown in the formula VIII, hydroxylamine aqueous solution and isopropanol, and carrying out substitution reaction to obtain a compound with the structure shown in the formula I;

4. The method of claim 3, wherein the compound having the structure of formula II and the dess-martin oxidant are present in a molar ratio of 1: (1.0-1.2);

The temperature of the oxidation reaction is room temperature, and the time of the oxidation reaction is 2-8 h.

5. The method of claim 3, wherein the compound having the structure of formula iii, triphenylphosphine and carbon tetrabromide are present in a molar ratio of 1: (3.8-4.2): (1.8-2.2);

The temperature of the Corey-Fuchs reaction is-20 to-78 ℃.

6. The method according to claim 3, wherein the compound having the structure of formula IV, Pd₂(dba)₃The mol ratio of the compound with the structure shown in the formula a to triethylamine is 1: (0.02-0.04): (1.8-2.2): (2.8-3.2);

the temperature of the Sonogashira coupling reaction is 75-85 ℃, and the time of the Sonogashira coupling reaction is 6-10 h.

7. the method of claim 3, wherein the molar ratio of the compound having the structure of formula v to the sodium hydroxide in the sodium hydroxide solution is 1: (8-12);

The temperature of the hydrolysis reaction is room temperature, and the time of the hydrolysis reaction is 6-10 hours.

8. A process according to claim 3, wherein the compound having the structure of formula vi, methyl (S) -2-amino-3- (tert-butoxycarbonylamino) -3-methylbutyrate, diisopropylethylamine and 2- (7-oxybenzotriazole) -N, N' -tetramethyluronium hexafluorophosphate are present in a molar ratio of 1: (1.1-1.3): (3.8-4.2): (1.1-1.3);

The temperature of the condensation reaction is room temperature, and the time of the condensation reaction is 3-8 h.

9. The method according to claim 3, wherein the molar ratio of the compound having the structure represented by formula VIII to hydroxylamine in the aqueous hydroxylamine solution is 1: (18-22).

10. Use of the hydroxamic acid derivative according to claim 1 or 2 or the hydroxamic acid derivative prepared by the preparation method according to any one of claims 3 to 9 for inhibiting UDP-3-O- (R-hydroxytetradecanoyl) -N-acetylglucosaminyl deacetylase.

Technical Field

The invention relates to the technical field of enzyme inhibitors, in particular to a hydroxamic acid derivative and a preparation method and application thereof.

background

Super bacteria and human are in mutual game and continuously struggle. Starting in the 30's when freming found penicillin, the first antibiotics were born, but bacteria likewise began to evolve and struggle. Today, bacterial resistance is becoming increasingly severe, and development of new antibiotics is relatively delayed. About 70 million people die from drug-resistant bacteria infection every year around the world, 23 million newborns die because of the death, if novel antibiotics cannot be developed to control the spread of the superbacteria, and the number of the death caused by the bacterial infection around the world is estimated to reach about 1000 ten thousand in 2050, which is the highest point of all diseases.

UDP-3-O (R-hydroxytetradecanoyl) -N-acetamido glucose deacetylase (LpxC) is a key enzyme for catalyzing and synthesizing the main component lipid A of outer membrane lipopolysaccharide of gram-negative bacteria, has high homology in the gram-negative bacteria, has no common sequence with various enzymes of mammals (including human), and can kill some gram-negative bacteria due to deletion or over-expression of the LpxC, so that the LpxC becomes a brand-new target of an anti-gram-negative bacteria drug with development prospect.

Over the past 20 years, scientists have designed and synthesized various types of LpxC inhibitors, and despite the excellent preclinical data of many reported compounds, there remains a need for new LpxC inhibitors that not only have bactericidal activity against gram-negative bacteria, but also have acceptable toxicity or tolerance.

Disclosure of Invention

The invention aims to provide a hydroxamic acid derivative, and a preparation method and application thereof, wherein the hydroxamic acid derivative has better bactericidal activity and lower toxicity to LpxC.

In order to achieve the above object, the present invention provides the following technical solutions:

The invention provides a hydroxamic acid derivative, which has a structure shown in a formula I:

in the formula I, X is

y is

Z is

wherein when Y and Z are bothWhen X does not include

Preferably, the first and second liquid crystal materials are,

X is

y is

z is

the invention also provides a preparation method of the hydroxamic acid derivative, which comprises the following steps:

Mixing a compound with a structure shown in a formula II, a dess-martin oxidant and dichloromethane, and carrying out an oxidation reaction to obtain a compound with a structure shown in a formula III;

mixing the compound with the structure shown in the formula III, triphenylphosphine, carbon tetrabromide and dichloromethane, and carrying out Corey-Fuchs reaction to obtain a compound with the structure shown in the formula IV;

The compound with the structure shown as the formula IV and Pd₂(dba)₃Mixing the compound with the structure shown in the formula a, triethylamine and N, N-dimethylformamide, and carrying out Sonogashira coupling reaction to obtain a compound with the structure shown in the formula V;

Mixing a compound with a structure shown in a formula V, tetrahydrofuran and a sodium hydroxide solution, and carrying out hydrolysis reaction to obtain a compound with a structure shown in a formula VI;

Mixing a compound with a structure shown in a formula VI, (S) -2-amino-3- (tert-butoxycarbonylamino) -3-methyl butyric acid methyl ester, diisopropylethylamine, 2- (7-oxybenzotriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate and N, N-dimethylformamide for condensation reaction to obtain a compound with a structure shown in a formula VII;

Mixing the compound with the structure shown in the formula VII, methanol and hydrogen chloride gas, and carrying out a de-Boc protection reaction to obtain a compound with the structure shown in the formula VIII;

mixing the compound with the structure shown in the formula VIII, hydroxylamine aqueous solution and isopropanol, and carrying out substitution reaction to obtain a compound with the structure shown in the formula I;

preferably, the molar ratio of the compound having the structure shown in formula II to the dess-martin oxidant is 1: (1.0-1.2);

The temperature of the oxidation reaction is room temperature, and the time of the oxidation reaction is 2-8 h.

Preferably, the compound with the structure shown in the formula III, triphenylphosphine and carbon tetrabromide have a molar ratio of 1: (3.8-4.2): (1.8-2.2);

The temperature of the Corey-Fuchs reaction is-20 to-78 ℃.

Preferably, the compound having the structure shown in formula IV and Pd₂(dba)₃The mol ratio of the compound with the structure shown in the formula a to triethylamine is 1: (0.02-0.04): (1.8-2.2): (2.8-3.2);

The temperature of the Sonogashira coupling reaction is 75-85 ℃, and the time of the Sonogashira coupling reaction is 6-10 h.

Preferably, the molar ratio of the compound having the structure shown in formula v to the sodium hydroxide in the sodium hydroxide solution is 1: (8-12);

The temperature of the hydrolysis reaction is room temperature, and the time of the hydrolysis reaction is 6-10 hours.

Preferably, the compound having the structure shown in formula VI, the molar ratio of (S) -2-amino-3- (tert-butoxycarbonylamino) -3-methyl butanoic acid methyl ester, diisopropylethylamine and 2- (7-oxybenzotriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate is 1: (1.1-1.3): (3.8-4.2): (1.1-1.3);

The temperature of the condensation reaction is room temperature, and the time of the condensation reaction is 3-8 h.

Preferably, the molar ratio of the compound having the structure represented by formula viii to hydroxylamine in the aqueous hydroxylamine solution is 1: (18-22).

the invention also provides application of the hydroxamic acid derivative in the technical scheme or the hydroxamic acid derivative prepared by the preparation method in the technical scheme in inhibiting UDP-3-O- (R-hydroxytetradecanoyl) -N-acetylglucosaminyl deacetylase.

the invention provides a hydroxamic acid derivative with a structure shown as a formula I, wherein a hydroxamic acid group in the hydroxamic acid derivative is chelated with active zinc ions in an LpxC enzyme active area and contains a hydrophobic side chain combined with a hydrophobic channel in the LpxC enzyme, and the two aspects ensure that the hydroxamic acid derivative has better bactericidal activity and lower toxicity on LpxC;

The invention also provides a preparation method of the hydroxamic acid derivative, and the preparation method is short in reaction time and high in yield.

Detailed Description

The invention provides a hydroxamic acid derivative, which has a structure shown in a formula I:

In the formula I, X is

Y is

Z is

Wherein when Y and Z are bothWhen X does not includeIn the present invention, X is preferablyY is preferablyZ is preferably

In the present invention, the hydroxamic acid derivative is more preferably N- ((S) -3-amino-1- (hydroxyamino) -3-methyl-1-oxobut-2-yl) -4- (((1R, 2S) -2-methoxycyclopentyl) but-1, 3-diyn-1-yl) benzamide, (S) -N- (3-amino-1- (hydroxyamino) -3-methyl-1-oxobut-2-yl) -4- ((4-nitrophenyl) but-1, 3-diyn-1-yl) piperazine-1-carboxamide or (S) -N- (3-amino-1- (hydroxyamino) -3-methyl-1- Oxobut-2-yl) -2-hydroxy-4- ((4- (piperidin-1-ylmethyl) phenyl) but-1, 3-diyn-1-yl) benzamide.

the invention also provides a preparation method of the hydroxamic acid derivative, which comprises the following steps:

Mixing a compound with a structure shown in a formula II, a dess-martin oxidant and dichloromethane, and carrying out an oxidation reaction to obtain a compound with a structure shown in a formula III;

mixing the compound with the structure shown in the formula III, triphenylphosphine, carbon tetrabromide and dichloromethane, and carrying out Corey-Fuchs reaction to obtain a compound with the structure shown in the formula IV;

the compound with the structure shown as the formula IV and Pd₂(dba)₃Mixing the compound with the structure shown in the formula a, triethylamine and N, N-dimethylformamide, and carrying out Sonogashira coupling reaction to obtain a compound with the structure shown in the formula V;

mixing a compound with a structure shown in a formula V, tetrahydrofuran and a sodium hydroxide solution, and carrying out hydrolysis reaction to obtain a compound with a structure shown in a formula VI;

mixing a compound with a structure shown in a formula VI, (S) -2-amino-3- (tert-butoxycarbonylamino) -3-methyl butyric acid methyl ester, diisopropylethylamine, 2- (7-oxybenzotriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate and N, N-dimethylformamide for condensation reaction to obtain a compound with a structure shown in a formula VII;

Mixing the compound with the structure shown in the formula VII, methanol and hydrogen chloride gas, and carrying out a de-Boc protection reaction to obtain a compound with the structure shown in the formula VIII;

Mixing the compound with the structure shown in the formula VIII, hydroxylamine aqueous solution and isopropanol, and carrying out substitution reaction to obtain a compound with the structure shown in the formula I;

In the present invention, all the raw material components are commercially available products well known to those skilled in the art unless otherwise specified.

The compound with the structure shown in the formula II, the dess-martin oxidant and dichloromethane are mixed for oxidation reaction to obtain the compound with the structure shown in the formula III.

In the present invention, when X isy isthe invention is preferably achieved byPreparing the compound with the structure shown in the formula II.

when X isY isIn this case, the specific preparation process of the compound having the structure shown in formula ii is preferably as shown in formula 1:

In the present invention, the specific preparation process of the compound having the structure shown in formula ii is preferably: AAgOTf (12.8g, 50mmol), fluorinating agent Selectfluor (8.9g,25mmol) and a solution of potassium fluoride (3.9g,66mmol) in ethyl acetate (30mL) were mixed under an argon atmosphere at room temperature, and then added(6.5g, 50mmol) and trifluoromethyltrimethylsilane (7.1g, 50mmol), reacted for 8h, filtered, and concentrated to give the crude product, which was chromatographed on silica gel (PE: EA: 20:1 to 10:1) to give(4.3g，43％)。

When X isY isthe invention is preferably achieved byPreparing the compound with the structure shown in the formula II.

In the present invention, the specific preparation process of the compound having the structure shown in formula ii is preferably as shown in formula 2:

In the present invention, the specific preparation process of the compound having the structure shown in formula ii is preferably:

Acetamide (1.0g,17mmol),(7.3g,51mmol) and dichloro (pentamethylcyclopentadienyl) iridium (III) dimer (0.3g, 0.4mmol) were mixed and charged into a microwave reaction tube, and microwave-reacted at 130 ℃ for 3 hours. Cooled to room temperature and water (10mL) was added. Extracting with ethyl acetate (the dosage ratio of the ethyl acetate to the water is preferably 1 (1.0-1.5)) for 3 times, combining organic phases, drying with anhydrous sodium sulfate, filtering and concentrating to obtain a crude product. Purification using silica gel column chromatography (DCM: MeOH ═ 20:1) gave compound 3(0.9g, 30%).

When X isy isThe invention is preferably achieved bypreparing the compound with the structure shown in the formula II。

In the present invention, the specific preparation process of the compound having the structure shown in formula ii is preferably as shown in formula 3:

in the present invention, the specific preparation process of the compound having the structure shown in formula ii is preferably:

d- (+) -Camphorsulfonic acid (0.9g,4mol) was added to a solution of pyrrolidine (0.7g,10mmol) in toluene (10mL), stirred at room temperature for 1 minute, and added(4.3g,25mmol) and ruthenium-NHC complex (0.1mmol) and stirred at 120 ℃ for 10h, cooled to room temperature, added with water (the amount ratio of the water to the toluene is preferably 1 (1.0 to 1.5)), extracted with ethyl acetate (the amount ratio of the water to the ethyl acetate is preferably 1 (1.0 to 1.5)) for preferably 3 times, the organic phases combined, dried over anhydrous sodium sulfate, filtered, concentrated to give a crude product, and purified by silica gel column chromatography (PE: EA 20:1 to 10:1) to give compound 3(0.8g, 37%).

When the compound having the structure shown in the formula II has a structure other than the three cases, the compound is preferably obtained from a commercially available product or prepared according to a preparation method disclosed in the prior art.

In the present invention, the molar ratio of the compound having the structure represented by formula ii to the dess-martin oxidant is preferably 1: (1.0 to 1.5), more preferably 1: (1.2-1.3); the dosage ratio of the compound with the structure shown in the formula II to the dichloromethane is preferably 1g (15-30) mL, more preferably 1g: (18-28) mL, most preferably 1g: (21-25) mL.

In the present invention, the mixing is preferably: under the condition of-10 ℃, the compound with the structure shown in the formula II is firstly mixed with dichloromethane to obtain a dichloromethane solution of the compound with the structure shown in the formula II, and then the dess-martin oxidant is added in batches (in the adding process, because the temperature rise phenomenon occurs, the temperature of a reaction system can be kept between-7 ℃ and-10 ℃ by controlling the adding speed).

In the present invention, the oxidation reaction is preferably carried out under stirring, and the stirring is not particularly limited, and may be carried out by a process known to those skilled in the art; the temperature of the oxidation reaction is preferably room temperature, and the time of the oxidation reaction is preferably 2-8 h, and more preferably 4-6 h.

after the oxidation reaction is completed, the invention preferably carries out post-treatment on the product system after the reaction, and the post-treatment process is preferably as follows: after the product system is moved to an ice bath, a saturated sodium thiosulfate aqueous solution and a saturated sodium bicarbonate aqueous solution are sequentially added for quenching reaction, the mixture is filtered (solid is removed), the mixture is kept stand for layering, the obtained water phase is extracted three times by dichloromethane, the organic phases are combined, the obtained organic phase is dried by anhydrous sodium sulfate, and after filtration and reduced pressure concentration, the mixture is separated and purified by silica gel column chromatography (eluent is petroleum ether: ethyl acetate ═ 20: 1).

after a compound with a structure shown in a formula III is obtained, mixing the compound with the structure shown in the formula III, triphenylphosphine, carbon tetrabromide and dichloromethane, and carrying out Corey-Fuchs reaction to obtain a compound with a structure shown in a formula IV; in the present invention, the compound having the structure represented by formula iii, triphenylphosphine, and carbon tetrabromide are preferably used in a molar ratio of 1: (3.8-4.2): (1.8-2.2), more preferably 1: (3.9-4.1): (1.9-2.1); the amount ratio of the compound having the structure represented by the formula iii to the first organic solvent is preferably 1g: (25-45) mL, more preferably 1g: (30-40) mL, most preferably 1g: (34-36) mL.

In the present invention, the mixing of the compound having the structure represented by formula iii, triphenylphosphine, carbon tetrabromide, and methylene chloride preferably comprises the steps of:

Mixing the compound with the structure shown in the formula III and a first part of first organic solvent to obtain a solution of the compound with the structure shown in the formula III;

Mixing triphenylphosphine and a second part of first organic solvent to obtain a solution of triphenylphosphine;

Mixing the carbon tetrabromide with a third portion of the first organic solvent to obtain a solution of carbon tetrabromide;

mixing the solution of carbon tetrabromide, the solution of triphenylphosphine and the solution of the compound with the structure shown in the formula III.

the proportion of the first part of the first organic solvent, the second part of the first organic solvent and the third part of the first organic solvent is not limited at all, and the corresponding solvents can be fully dissolved. The sum of the amounts of the first portion of the first organic solvent, the second portion of the first organic solvent and the third portion of the first organic solvent is the amount of the first organic solvent.

In the present invention, a specific process of mixing the solution of carbon tetrabromide, the solution of triphenylphosphine, and the solution of the compound having the structure represented by formula iii is preferably: and (2) dropwise adding a triphenylphosphine solution into the carbon tetrabromide solution at-20 ℃ under the protection of argon, stirring to react for 30min, cooling to-78 ℃, continuously dropwise adding a compound solution with a structure shown in a formula III, and stirring to react for 30 min. The invention does not have any special limitation on the dropping, and the dropping process known by the technicians in the field can be adopted; the stirring is not particularly limited in the present invention, and the stirring may be performed by a procedure well known to those skilled in the art.

In the invention, the triphenylphosphine has the function of attacking carbon tetrabromide to abstract a bromide ion in the reaction process to generate phosphonium ion and bromoform anion; the generated phosphonium ions are subjected to nucleophilic substitution by bromoform anions generated simultaneously to form dibromomethylene phosphorus ylide, then dibromomethylene carbon and aldehyde carbonyl are subjected to nucleophilic addition, and the formed amphoteric intermediate is cyclized to form oxyphosphate and oxetane, so that triphenylphosphine oxide and dibromoolefin are further eliminated.

In the present invention, the Corey-Fuchs reaction is preferably carried out under stirring conditions, and the stirring is not particularly limited in the present invention, and may be carried out by a process well known to those skilled in the art; the temperature of the Corey-Fuchs reaction is preferably-20 to-78 ℃, and more preferably-60 to-70 ℃; in the invention, the Corey-Fuchs reaction time is preferably 20-40 min, and more preferably 25-35 min. In the present invention, the Corey-Fuchs reaction time is based on the completion of the dropwise addition of the solution of the compound having the structure shown in formula III.

After the Corey-Fuchs reaction is completed, the post-treatment of the obtained product system is preferably carried out in the invention, and the post-treatment preferably comprises the following steps: and (3) heating the product system to room temperature, carrying out reduced pressure distillation to remove the solvent, dissolving in 40% ethanol solution, adding n-hexane, violently stirring for 10min, standing for layering, taking the n-hexane layer, and concentrating under reduced pressure, wherein the n-hexane layer is directly used for the next reaction without purification.

after obtaining the compound with the structure shown in the formula IV, the invention uses the compound with the structure shown in the formula IV and Pd₂(dba)₃mixing the compound with the structure shown in the formula a, triethylamine and N, N-Dimethylformamide (DMF), and carrying out Sonogashira coupling reaction to obtain a compound with the structure shown in the formula V;

In the invention, the compound with the structure shown in formula IV and Pd₂(dba)₃The molar ratio of the compound having the structure represented by formula a to triethylamine is preferably 1: (0.02-0.04): (1.8-2.2): (2.8-3.2), more preferably 1: (0.025-0.035): (1.9-2.1): (2.96-3.1); the dosage ratio of the compound with the structure shown in the formula IV to DMF is preferably 1g: (10-18) mL, more preferably 1g: (12-16) mL, most preferably 1g: (13-15) mL.

in the present invention, the mixing is preferably performed under an argon atmosphere, and the mixing is not particularly limited in the present invention, and may be performed by a mixing process well known to those skilled in the art.

in the present invention, the Sonogashira coupling reaction is preferably carried out under stirring, and the stirring is not particularly limited in the present invention, and may be carried out by a procedure well known to those skilled in the art. In the invention, the temperature of the Sonogashira coupling reaction is preferably 75-85 ℃, and more preferably 78-82 ℃; the time of the Sonogashira coupling reaction is preferably 6-10 h, and more preferably 8-19 h.

In the present invention, the Pd₂(dba)₃Is a catalyst, the triethylamine acts as an acid-binding agent, and the DMF acts as a solvent.

After the Sonogashira coupling reaction is completed, the invention preferably performs post-treatment on the obtained product system, wherein the post-treatment preferably comprises: ethyl acetate was added to the reaction system, which was washed with water three times, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by silica gel column chromatography (eluent was petroleum ether: ethyl acetate in a volume ratio of 80: 1).

After the compound with the structure shown in the formula V is obtained, the compound with the structure shown in the formula V, tetrahydrofuran and a sodium hydroxide solution are mixed for hydrolysis reaction to obtain the compound with the structure shown in the formula VI; in the present invention, the sodium hydroxide solution is preferably an aqueous sodium hydroxide solution; the dosage ratio of the sodium hydroxide to the water in the sodium hydroxide aqueous solution is preferably (0.15-0.25) g: 1mL, more preferably (0.18 to 0.22) g: 1 mL.

In the present invention, the mixing of the compound having the structure represented by formula v, tetrahydrofuran and a sodium hydroxide solution preferably includes the following steps:

And mixing the compound with the structure shown in the formula V with tetrahydrofuran to obtain a tetrahydrofuran solution of the compound with the structure shown in the formula V, and then mixing the tetrahydrofuran solution with a sodium hydroxide solution. The present invention does not limit the mixing in any particular way, and the mixing may be carried out by a process known to those skilled in the art.

In the present invention, the molar ratio of the compound having the structure represented by formula v to sodium hydroxide in the sodium hydroxide solution is preferably 1: (8-12), more preferably 1: (9-11); the ratio of the compound having the structure shown in formula V to tetrahydrofuran is preferably 1g: (15-40) mL, more preferably 1g: (20-30) mL, most preferably 1g: (35-37) mL.

In the present invention, the hydrolysis reaction is preferably carried out under stirring, and the stirring is not particularly limited in the present invention, and may be carried out by a procedure well known to those skilled in the art. In the invention, the temperature of the hydrolysis reaction is preferably room temperature, and the time of the hydrolysis reaction is preferably 6-10 h, and more preferably 8-9 h.

After the hydrolysis reaction is completed, the invention preferably carries out post-treatment on the obtained product system, wherein the post-treatment is preferably as follows: and (3) evaporating the product system under reduced pressure to remove the solvent, adding water, adjusting the pH to 2.0 by using 1mol/L hydrochloric acid, extracting by using ethyl acetate, combining organic phases, drying by using anhydrous sodium sulfate, filtering, and concentrating under reduced pressure, wherein the product system is directly used for the next reaction without purification.

After the compound with the structure shown in the formula VI is obtained, the compound with the structure shown in the formula VI, (S) -2-amino-3- (tert-butoxycarbonylamino) -3-methyl butyric acid methyl ester, diisopropylethylamine, 2- (7-oxide benzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate and N, N-dimethylformamide are mixed for condensation reaction to obtain the compound with the structure shown in the formula VII.

In the present invention, the mixing of the compound having the structure represented by formula vi, (S) -2-amino-3- (tert-butoxycarbonylamino) -3-methylbutanoic acid methyl ester, diisopropylethylamine, 2- (7-oxybenzotriazole) -N, N' -tetramethyluronium hexafluorophosphate, and N, N-dimethylformamide preferably comprises the steps of:

Mixing a compound with a structure shown in a formula VI, 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HATU) and DMF to obtain a mixed solution; the invention does not have any special limitation on the mixing, and the mixing can be carried out by adopting the process well known by the technical personnel in the field;

Adding (S) -2-amino-3- (tert-butoxycarbonylamino) -3-methylbutyrate methyl ester (Boc-S) and diisopropylethylamine to the mixed solution to mix; the adding mode of the invention is not limited in any way, and the adding mode known to the person skilled in the art can be adopted.

In the present invention, the molar ratio of the compound having the structure represented by formula VI, Boc-S, diisopropylethylamine and HATU is preferably 1: (1.1-1.3): (3.8-4.2): (1.1 to 1.3), more preferably 1: (1.15-1.25): (3.9-4.1): (1.15-1.25). In the present invention, the compound having the structure represented by formula VI and DMF are preferably used in a ratio of 1g: (15-30) mL, more preferably 1g: (17-28) mL, most preferably 1g: (20-25) mL.

In the present invention, the condensation reaction is preferably carried out under stirring, and the stirring is not particularly limited, and may be carried out by a procedure well known to those skilled in the art; the temperature of the condensation reaction is preferably room temperature, and the time of the condensation reaction is preferably 3-8 h, and more preferably 4-6 h.

In the present invention, the HATU functions to activate a carboxyl group, and the diisopropylethylamine functions to activate an amino group.

After the condensation reaction is completed, the present invention preferably performs a post-treatment on the obtained product system, and the post-treatment preferably comprises the following steps: ethyl acetate was added to the reaction system, which was washed three times with 1.2mol/L aqueous lithium chloride solution, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and separated and purified by silica gel column chromatography (eluent was petroleum ether and ethyl acetate in a volume ratio of 2: 1).

after the compound with the structure shown in the formula VII is obtained, the compound with the structure shown in the formula VII, methanol and hydrogen chloride gas are mixed for Boc protection reaction, and the compound with the structure shown in the formula VIII is obtained.

in the present invention, it is preferable that the compound having a structure represented by the formula VII, methanol and a hydrogen chloride gas are mixed by mixing the compound having a structure represented by the formula VII with methanol and then introducing a hydrogen chloride gas. The present invention does not have any particular limitation on the mixing of the compound having the structure represented by formula VII and methanol, and the mixing may be performed by a process well known to those skilled in the art. In the invention, the introduction rate of the hydrogen chloride gas is preferably 0.5mL/s, and more preferably 1 mL/s; the introducing time of the hydrogen chloride gas is preferably 15-25 min, more preferably 18-22 min, and most preferably 20 min. In the invention, the introduction time of the hydrogen chloride is the time of the de-Boc protection reaction, and the temperature of the de-Boc protection reaction is preferably room temperature.

after the Boc protection removal reaction is completed, the obtained product system is preferably subjected to post-treatment, and the post-treatment is preferably performed by distilling off the solvent under reduced pressure to obtain a crude compound with a structure shown in a formula VIII. The crude compound having the structure shown in formula VIII is used in the next reaction without further purification.

After the compound with the structure shown in the formula VIII is obtained, the compound with the structure shown in the formula VIII, hydroxylamine aqueous solution and isopropanol are mixed for substitution reaction, and the compound with the structure shown in the formula I is obtained. In the present invention, the concentration of the hydroxylamine aqueous solution is preferably 16 to 17mmol/mL, and more preferably 16.5 to 16.8 mmol/mL.

in the present invention, the compound having the structure represented by the formula viii, the aqueous hydroxylamine solution and isopropanol are preferably mixed together after the compound having the structure represented by the formula viii and isopropanol are mixed together and then mixed with the aqueous hydroxylamine solution. The present invention does not limit the mixing in any particular way, and the mixing may be carried out by a process known to those skilled in the art.

in the present invention, the molar ratio of the compound having the structure represented by formula viii to hydroxylamine in the aqueous hydroxylamine solution is preferably 1: (18-22), more preferably 1: (19-21), most preferably 1: 20; the compound having the structure represented by formula VIII and isopropanol are preferably used in a ratio of 1g: (20-30) mL, more preferably 1g: (22-28) mL, most preferably 1g: (24-26) mL.

In the present invention, the substitution reaction is preferably carried out under stirring, and the stirring is not particularly limited in the present invention, and may be carried out by a procedure well known to those skilled in the art. The temperature of the substitution reaction is preferably room temperature, and the progress of the substitution reaction is preferably monitored by LCMS to determine whether the reaction is complete.

After the substitution reaction is finished, the product system obtained is preferably subjected to post-treatment, the post-treatment step is preferably to separate and purify the product system by using reverse phase HPLC (conditions: chromatographic column XDB-C18 column (21.2mm multiplied by 250mm, 7 mu m; mobile phase A: acetonitrile (containing 0.1% TFA), B: water (containing 0.1% TFA), gradient elution (0-40min: A5% -30%); column temperature 25 ℃, flow rate 10 mL/min; detection wavelength 280nm), and then the obtained product is frozen and dried.

The invention also provides application of the hydroxamic acid derivative in the technical scheme or the hydroxamic acid derivative prepared by the preparation method in the technical scheme in inhibiting UDP-3-O- (R-hydroxytetradecanoyl) -N-acetylglucosaminyl deacetylase.

The hydroxamic acid derivatives provided by the present invention, the preparation method and the application thereof are described in detail below with reference to examples, but they should not be construed as limiting the scope of the present invention.