CN103086955B - Preparation method of 3-amino-4-alkoxyimino piperidine - Google Patents

Preparation method of 3-amino-4-alkoxyimino piperidine Download PDF

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CN103086955B
CN103086955B CN201310053240.3A CN201310053240A CN103086955B CN 103086955 B CN103086955 B CN 103086955B CN 201310053240 A CN201310053240 A CN 201310053240A CN 103086955 B CN103086955 B CN 103086955B
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stirring reaction
alkali
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CN103086955A (en
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郭慧元
刘明亮
刘秉全
魏增泉
刘开湘
李素杰
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Zhejiang Hong Kang Pharmaceutical Chemical Co ltd
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Institute of Medicinal Biotechnology of CAMS
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Abstract

The invention relates to a preparation method of 3-amino-4-alkoxyimino piperidine. More particularly, the preparation method provided by the invention comprises the following steps: performing nucleophilic addition reaction on ethyl 3-aminopropionate hydrochloride and acrylonitrile in the presence of alkali; treating with di-tert-butyl dicarbonate to obtain ethyl N-tert-butoxycarbonyl-3-(2-cyanoethyl)aminopropionate; performing cyclization in the presence of strong alkali to obtain 1-N-tert-butoxycarbonyl-3-cyano-4-piperidone, and performing oximation to obtain 1-N-tert-butoxycarbonyl-3-cyano-4-alkoxyimino piperidine; sequentially performing cyano hydrolysis and Hofmann degradation reaction on the latter to obtain 1-N-tert-butoxycarbonyl-3-amino-4-alkoxyimino piperidine; and finally, performing deprotection to obtain the 3-amino-4-alkoxyimino piperidine and salt thereof.

Description

The preparation method of 3-amino-4-alcoxyl imido grpup piperidines
Technical field
The invention belongs to medication chemistry production field, relate to a kind of preparation method of 3-amino-4-alcoxyl imido grpup piperidines.Specifically, the present invention, taking 3-alanine carbethoxy hydrochloride and vinyl cyanide as starting raw material, makes 3-amino-4-alcoxyl imido grpup piperidines and salt thereof through 7 steps reactions such as nucleophilic additions successively.
Background technology
3-amino-4-alcoxyl imido grpup piperidines is the important pharmaceutical-chemical intermediate of a class occurring in recent years, is mainly used in the antibacterial and tuberculosis candidate compound (ZL 200710145608.3 of synthesizing new quinolone; PCT/CN 2008/001526; ZL 201010156815.0).Document discloses the laboratory synthetic method of two these class intermediates so far.Wherein, literature method one is taking 1-benzyl-4-oxo-piperidine-3-carboxylic acid, ethyl ester as starting raw material, obtain 3-amino-4-alcoxyl imido grpup piperidines [Acta Pharmaceutica Sinica, 2008,43 (8): 819-827] through 9 step reactions such as carbonyl reduction, ester aminolysis, Hofmann degradeds successively.But in this preparation method, have the aftertreatment of 3 step reactions need to use chromatographic column isolation technique, the 7th step oxidizing reaction adopts Jones reagent (CrO 3+ H 2sO 4) there is heavy metal contamination, therefore be not suitable for suitability for industrialized production.
Literature method one:
Literature method two is taking pyridine as starting raw material, makes 3-amino-4-methoxyimino piperidines (Bioorg. Med. Chem. Lett. 2007,17,4523-4526) through 12 steps reactions such as quaternized, reduction.But this preparation method exists: 1) alkali of epoxy compounds (ammoniacal liquor) catalysis ring-opening reaction causes this step yield very low because of non-selectivity, use subsequently must be through column chromatographic isolation and purification after tertbutyloxycarbonyl (Boc) protection amino.In addition, first oximate and de-Boc protecting group salt-forming reaction also need through column chromatographic isolation and purification after completing; 2) adopt pyridine-SO 3-DMSO system oxidation hydroxyl, the dimethyl sulphide of generation stench, the problems such as serious environment pollution, therefore be also not suitable for suitability for industrialized production.
Literature method two:
In order to overcome the existing defect of above-mentioned prior art, the inventor conducts extensive research, and explores and put into practice out a kind of new preparation process of 3-amino-4-alcoxyl imido grpup piperidines.Compared with existing literature method, this preparation method reactions steps is (totally 7 steps) still less, and related each step post-reaction treatment is routine operation, can meet industrial requirement, to saving production cost and protection of the environment has realistic meaning.
Summary of the invention
The object of the present invention is to provide a kind of class 3-amino-4-alcoxyl imido grpup piperidine compounds being represented by general formula (I) and the preparation method of salt thereof.Described method is suitable for large-scale production, simple to operate, environmental protection.
Wherein:
R represent methylidene, ethyl;
The salt of formula (I) compound comprises hydrochloride and mesylate.
For this reason, the invention provides the preparation method of a kind of formula (I) compound and salt thereof, described method steps is as follows:
1) there is nucleophilic addition with vinyl cyanide (III) in alanine carbethoxy hydrochloride (II) under alkali exists, and obtains (IV), (IV) with two dimethyl dicarbonate butyl ester (Boc 2o) process to obtain N-tertbutyloxycarbonyl-3-(2-cyano ethyl) alanine ethyl ester (V), (V) under highly basic exists, cyclization obtains 1-N-tertbutyloxycarbonyl-3-cyano group-4-piperidone (VI);
2) (VI) obtain 1-N-tertbutyloxycarbonyl-3-cyano group-4-alkoxyimino piperidines (VII) by alcoxyl amine hydrochlorate oximate under alkali exists, (VII) under weak base exists, obtain 1-N-tertbutyloxycarbonyl-3-formamido group-4-alkoxyimino piperidines (VIII) by cyan-hydrolysis;
3) (VIII) obtain 1-N-tertbutyloxycarbonyl-3-amino-4-alkoxyimino piperidines (IX) through Hofmann DeR, (IX) obtain 3-amino-4-alkoxyimino piperidines (I) with sour deprotection.
Preparation method of the present invention, chemical equation is as follows:
Wherein:
R represent methylidene, ethyl;
Wherein, in step 1), formula (II) compound is dissolved in protic solvent (as methyl alcohol, ethanol), add alkali (as sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus), stir 0.5-2 hour at 10-50 DEG C, add formula (III) compound, stirring reaction 3-8 hour at-10-50 DEG C, obtains formula (IV) compound, adds Boc2O, stirring reaction 1-5 hour at 30-50 DEG C, obtains formula (V) compound; Wherein, formula (II) compound
With the mol ratio of alkali, formula (III) compound and Boc2O be 1:0.5-2:1-1.5:1-1.2, at highly basic (as NaH, CH3ONa or C2H5ONa) exist under, formula (V) compound is dissolved in non-polar solvent (as toluene or dimethylbenzene), stirring reaction 2-10 hour at room temperature to 110 DEG C, obtains formula (VI) compound; Wherein, the mol ratio of formula (V) compound and highly basic is 1:1-2.
Wherein, step 2) in, alcoxyl amine hydrochlorate is dissolved in protic solvent (as methyl alcohol, ethanol), add alkali (as sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus), under room temperature, stir 0.5-2 hour, add formula (VI) compound, stirring reaction 3-8 hour at-10-50 DEG C, obtain formula (VII) compound, wherein, the mol ratio of formula (VI) compound and alcoxyl amine hydrochlorate and alkali is 1:1-1.5:1.1-3.Formula (VII) compound is dissolved in dimethyl sulfoxide (DMSO) (DMSO), adds weak base (as sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus) and hydrogen peroxide (H 2o 2) ,-5-40 DEG C of stirring reaction 10-36 hour, obtains formula (VIII) compound, and wherein, the mol ratio of formula (VII) compound weak base and hydrogen peroxide is 1:0.3-1:1.1-2.
Wherein, in step 3), formula (VIII) compound is dissolved in aprotic solvent (as acetonitrile, methylene dichloride), add hypohalite (as clorox, the sodium hypobromite) aqueous solution ,-15 DEG C under room temperature, stirring reaction 10-30 hour, obtains formula (IX) compound; Wherein, the mol ratio of formula (VIII) compound and hypohalite is 1:1.5-3.0; Formula (IX) compound is dissolved in aprotic solvent (as acetonitrile, methylene dichloride), add acid (as concentrated hydrochloric acid/pass into dry hydrogen chloride gas, methylsulfonic acid),-10 DEG C under room temperature, stirring reaction 1-4 hour, obtains hydrochloride or the mesylate of formula (I) compound.Adjust pH8 with alkali aqueous solution, obtain formula (I) compound; Wherein, formula (IV) compound and sour mol ratio are 1:1.5-4.
The invention has the advantages that: as the new preparation process of 3-amino-4-alcoxyl imido grpup piperidines, process choice of the present invention is reasonable, taking inexpensive alanine carbethoxy hydrochloride and vinyl cyanide as starting raw material, reactions steps is less, related each step post-reaction treatment is routine operation, avoid the pollution problem of post lock out operation and heavy metal, thereby can greatly reduce production costs.Technique of the present invention has satisfactory stability and circulation ratio, is suitable for large-scale production.
Embodiment
In the following example, will more specifically explain the present invention.
Embodiment 1,1-N-tertbutyloxycarbonyl-3-cyano group-4-piperidone
In 2000mL there-necked flask, add 3-alanine carbethoxy hydrochloride (153.5g, 1mol) and ethanol (850mL), under room temperature mechanical stirring molten clear after, add sodium hydroxide (41.5g, 1mol), stirring at room temperature 0.5 hour.Be heated to 50 DEG C (interior temperature, lower same), drip ethanol (150 mL) solution of vinyl cyanide (66mL, 1mol).Drip and finish (1 hour), continue to stir under equality of temperature, TLC follows the tracks of reaction and finishes for approximately 4 hours.
As above after the reaction mixture of gained slightly cold (~ 40 DEG C), drip wherein two dimethyl dicarbonate butyl ester (218.25g, ethanol (150mL) solution (temperature≤50 DEG C during this time) 1mol), drip and finish (~ 1 hour), continue to stir in 40-45 DEG C, TLC follows the tracks of reaction and finishes for approximately 3 hours.Be down to room temperature, elimination insolubles (inorganic salt), filtrate decompression is concentrated.In oily resistates, add distilled water (400mL), after fully stirring, with ethyl acetate extraction (300mL × 3), united extraction liquid, the saturated NaCl aqueous solution (300mL × 2) washing, anhydrous Na 2sO 4dry.Filter, filtrate decompression is concentrated, obtains N-tertbutyloxycarbonyl-3-(2-cyano ethyl) alanine ethyl ester (light yellow oil, 248g, 92%). 1H?NMR?(400MHz,?CDCl 3)?δ?(ppm):?4.23?(2H,?q,?J?=?6.7?Hz),?3.37?(4H,?m),?3.21?(2H,?q,?J?=?6.7Hz),?2.65?(2H,?q,?J?=?6.7?Hz),?1.38?(9H,?s),?1.26?(3H,?t,?J?=?6.7?Hz).?MS-ESI?(m/z)：271?(M+H) +.
In 2000mL there-necked flask, add sodium hydride (46.8g, 1.17mol) and dry toluene (900mL), under mechanical stirring and reflux (110 DEG C), drip dry toluene (300mL) solution of N-tertbutyloxycarbonyl-3-(2-cyano ethyl) alanine ethyl ester (243g, 0.9mol).Drip and finish (1.5 hours), equality of temperature continues to stir, and TLC follows the tracks of reaction and finishes approximately 1 hour.Be down to room temperature, under the cooling and abundant stirring of ice-water-bath, in reaction mixture, drip successively ethanol (50mL) and distilled water (500 mL).Stratification, divides and removes toluene layer, after toluene wash for water layer (300mL × 2), adjusts pH6 with acetic acid, with ethyl acetate extraction (300mL × 3), united extraction liquid, and the saturated NaCl aqueous solution (400mL) washing, anhydrous Na 2sO 4dry.Filter, filtrate decompression is concentrated, obtains 1-N-tertbutyloxycarbonyl-3-cyano group-4-piperidone (yellow oil, 191g, 95%). 1h NMR (400MHz, CDCl 3) δ (ppm): 6.82 (1H, s), 4.16-4.18 (2H, m), 3.56-3.59 (2H, m), 2.34-2.36 (2H, m), 1.47 (9H, s). MS-ESI (m/z): 223 (M-H) +.
Embodiment 2,1-N-tertbutyloxycarbonyl-3-carbamyl-4-methoxyimino piperidines
Tri-mouthfuls of reaction flasks of 2000mL add methoxamine hydrochloride (50.1g, 0.6mol) and methyl alcohol (400mL), room temperature mechanical stir molten clear after, add sodium hydroxide (25g, 0.6mol), stirring at room temperature 0.5 hour, add 1-tertbutyloxycarbonyl-3-cyano group-4-piperidone (112g, methyl alcohol (400mL) solution 0.5mol), is heated to 50 DEG C of stirrings, and TLC follows the tracks of reaction and finishes approximately 3 hours.Be down to room temperature, elimination insolubles (sodium-chlor), filtrate decompression is concentrated, in resistates, add distilled water (250mL), after fully stirring, with ethyl acetate extraction (200mL × 3), united extraction liquid, by the saturated NaCl aqueous solution (250mL) washing, anhydrous Na 2sO 4dry.Filter, filtrate decompression is concentrated, under fully stirring, by in slow gained resistates impouring ether (1000mL), continue to stir 0.5 hour elimination insolubles, concentrated (recovery ether) final vacuum of filtrate is dry, obtain 1-tertbutyloxycarbonyl-3-cyano group-4-methoxyimino piperidines (yellow oil, 120g, 95%). 1h NMR (400 MHz, DMSO-d 6) δ (ppm): 4.48 (1H, s), 4.25 (1H, m), 4.04 (1H, m), 3.84 (3H, s), 3.14 (1H, brs), 2.93 (1H, brs), 2.41 (2H, m), 1.42 (9H, s). MS-ESI (m/z): 254 (M+H) +.
In 1000mL there-necked flask, add dimethyl sulfoxide (DMSO) (DMSO, 300mL) and 1-tertbutyloxycarbonyl-3-cyano group-4-methoxyimino piperidines (7,114g, 0.45mol), under room temperature, fully stir and moltenly add anhydrous K after clear 2cO 3(25g, 0.18mol), ice-water-bath is cooled to 13-15 DEG C, drips hydrogen peroxide (77mL, 0.675mol), drips and finishes (approximately 0.5 hour), and stirring at room temperature reaction is spent the night, and TLC follows the tracks of reaction and finishes.Add distilled water (350mL), after fully stirring, extract (120mL × 7) by ethyl acetate, united extraction liquid, the saturated NaCl aqueous solution (300mL) washing, anhydrous Na 2sO 4dry.Filter, the concentrated oily matter that to obtain of filtrate decompression, add appropriate ether molten clear after, refrigerator cold-storage spends the night.Filter, filter cake is washed with ether, is dried to obtain 1-N-tertbutyloxycarbonyl-3-carbamyl-4-methoxyimino piperidines (white solid, 89.1g, yield 72%), mp:131-133 DEG C. 1h NMR (400 MHz, DMSO-d 6) δ (ppm): 7.18 (2H, s), 4.19-4.10 (1H, brs), 4.00-3.92 (1H, m), 3.84 (1H, s), 3.72 (3H, s), 3.11 (1H, m), 2.61-2.53 (1H, m), 2.24 (1H, brs), 1.42 (1H, s), 1.38 (9H, s). MS-ESI (m/z): 294 (M+Na) +.
In like manner, can obtain 1-N-tertbutyloxycarbonyl-3-carbamyl-4-ethoxy imino piperidines. 1H?NMR?(400?MHz,?DMSO-d 6)?δ?(ppm):?7.22?(2H,?s),?4.32(2H,?q,?J?=?6.8?Hz),?4.23-4.15?(1H,?brs),?4.03-3.96?(1H,?m),?3.80?(1H,?s),?3.11?(1H,?m),?2.58?(1H,?m),?2.19?(1H,?brs),?1.52?(1H,?s),?1.37?(9H,?s),?1.23?(3H,?J?=?6.8?Hz).?MS-ESI?(m/z):?286?(M?+?H) +.
Embodiment 3, N-tertbutyloxycarbonyl-3-amino-4-methoxyimino piperidines
In 1000mL there-necked flask, add 1-N-tertbutyloxycarbonyl-3-carbamyl-4-methoxyimino piperidines (27.1g; 0.1mol) and acetonitrile (600mL); room temperature mechanical stirs molten clear; ice-water bath is cooled to about 0-5 DEG C; drip freshly prepd sodium hypobromite solution (253 mL, 0.18mol), drip and finish (approximately 1 hour); stirring at room temperature reaction is spent the night, and TLC follows the tracks of reaction and finishes.Stratification, point water-yielding stratum (lower floor).PH6.5 is adjusted with acetic acid in upper strata (acetonitrile layer), concentrating under reduced pressure, adding distil water (50mL) in gained oily resistates, adjust pH3 with 6N HCl solution again, wash the aqueous solution and the merging of above-mentioned water layer after (30mLx2) by ethyl acetate, use 6N NaOH solution to adjust pH9, with ethyl acetate extraction (150mLx6) united extraction liquid, wash (300mL), anhydrous Na with the saturated NaCl aqueous solution 2sO 4dry.Filter, concentrating under reduced pressure obtains N-tertbutyloxycarbonyl-3-amino-4-methoxyimino piperidines (yellow oil, 15.8g, 65%). 1h NMR (400 MHz, DMSO-d 6) δ (ppm): 4.09-4.02 (1H, m), 3.74 (3H, s), 3.57 (1H, m), 3.31-3.25 (1H, m), 3.11 (1H, s), 2.99-2.92 (1H, brs), 2.71-2.66 (1H, m), 1.98 (1H, brs), 1.38 (9H, s). MS-ESI (m/z): 244 (M+H) +.
In like manner, can obtain N-tertbutyloxycarbonyl-3-amino-4-ethoxy imino piperidines. 1H?NMR?(400?MHz,?DMSO-d 6)?δ?(ppm):?4.46?(?1H,?m),?4.27?(2H,?q,?J?=?6.8?Hz),?4.01?(1H,?m),?3.71-3.57?(2H,?m,),?3.31(1H,?t,?J?=?12?Hz),?3.23-3.14?(1H,?m),?2.45-2.38?(1H,?m),1.40?(9H,?s),?1.28?(3H,?t,?J?=?6.8?Hz).?MS-FAB?(m/z):?258?(M?+?1) +.
Embodiment 4,3-amino-4-methoxy imino phenylpiperidines dihydrochloride
In 250mL there-necked flask, add N-tertbutyloxycarbonyl-3-amino-4-methoxyimino piperidines (12.1g, 0.05mol) and methylene dichloride (100mL), stirring at room temperature molten clear after, pass into dry HCl gas to TLC demonstration raw material point disappearance (about 1-2 hour), separate out white solid therebetween, then under room temperature, continue to stir 2-3 hour.Be evaporated to dryly, in gained solid, add ethyl acetate (100mL), fully stir 1 hour.Filter, dried solid recrystallizing methanol, room temperature vacuum-drying, obtains 3-amino-4-methoxy imino phenylpiperidines dihydrochloride (white solid, 6.1g, yield 56%), mp:224-226 DEG C. 1h NMR (400 MHz, D 2o) δ (ppm): 4.40-4.48 (1H, m), 4.00-4.02 (1H, m), 3.96 (3H, s), 3.70-3.65 (1H, m), 3.61-3.57 (1H, m), 3.35-3.29 (1H, m), 3.24-3.18 (1H, m), 2.45-2.38 (1H, m). MS-FAB (m/z): 144 (M+1) +.
In like manner, can obtain 3-amino-4-ethoxy imido grpup piperidines dihydrochloride. 1H?NMR(400?MHz,?D 2O)?δ?(ppm):?4.41?(1H,?m),?4.02?(1H,?m),?4.23?(2H,?q,?J?=?6.6?Hz),?3.68-3.61?(2H,?m),?3.27?(1H,?t,?J?=?12?Hz),?3.21-3.17?(1H,?m),?2.43?(1H,?m),?1.32?(3H,?t,?J?=?6.6?Hz).?MS-FAB?(m/z):?158?(M?+?1) +.
In like manner, can obtain 3-amino-4-methoxy imino phenylpiperidines dimethanesulfonate. 1H?NMR(400?MHz,?D 2O)?δ?(ppm):?4.43?(1H,?m),?3.98?(1H,?m),?3.87?(3H，s),?3.76-3.69?(1H,?m),?3.63-3.55?(1H,?m),?3.31?(1H,?m),?3.20?(1H,?m),?2.39?(1H,?m),?2.31?(6H,?s).?MS-FAB?(m/z):?144?(M?+?1) +.
Embodiment 5,3-amino-4-methoxy imino phenylpiperidines
3-amino-4-methoxy imino phenylpiperidines dihydrochloride (2.15g, 0.01mol) water-soluble (25mL), ice-water bath is cooled to about 0-5 DEG C, adjusts pH8 with 0.5% the NaOH aqueous solution, extracts continuously with methylene dichloride.Extracting solution, after activated carbon decolorizing, is used anhydrous Na 2sO 4dry.Filter, concentrating under reduced pressure obtains 3-amino-4-methoxyimino piperidines (yellow oil, 1.22 g, 85%). 1H?NMR?(300?MHz,?DMSO-d 6)?δ?(ppm):?4.45-4.50?(1H,?m),?4.01-3.97?(4H,?m),?3.70-3.65?(1H,?m),?3.59-3.53?(1H,?m),?3.34-3.28?(1H,?m),?3.23-3.15?(1H,?m),?2.46-2.37?(1H,?m).?mp:?178-181℃.?MS-FAB?(m/z):?144(M?+?H)? +.
In like manner, can obtain 3-amino-4-ethoxy imido grpup piperidines. 1H?NMR(400?MHz,?DMSO-d? 6)?δ?(ppm):?4.45?(1H,m),?4.25?(2H,?q,?J?=?6.8?Hz),?3.95?(1H,?m),?3.69-3.57?(2H,?m),?3.29?(1H,?t,?J?=?12?Hz),?3.22-3.15?(1H,?m),?2.46-2.37?(1H,?m),?1.28?(3H,?t,?J?=?6.8?Hz).?MS-FAB?(m/z):?158?(M?+?1) +。

Claims (7)

1. a preparation method for formula (I) compound,
Wherein: R represent methylidene, ethyl; It is characterized in that, preparation process comprises the following steps:
1) there is nucleophilic addition with vinyl cyanide (III) in alanine carbethoxy hydrochloride (II) under alkali exists, and obtains (IV), (IV) with two dimethyl dicarbonate butyl ester (Boc 2o) process to obtain N-tertbutyloxycarbonyl-3-(2-cyano ethyl) alanine ethyl ester (V), (V) under highly basic exists, cyclization obtains 1-N-tertbutyloxycarbonyl-3-cyano group-4-piperidone (VI);
2) (VI) obtain 1-N-tertbutyloxycarbonyl-3-cyano group-4-alkoxyimino piperidines (VII) by alcoxyl amine hydrochlorate oximate under alkali exists, (VII) under weak base exists, obtain 1-N-tertbutyloxycarbonyl-3-formamyl-4-alkoxyimino piperidines (VIII) by cyan-hydrolysis;
3) (VIII) obtain 1-N-tertbutyloxycarbonyl-3-amino-4-alkoxyimino piperidines (IX) through Hofmann DeR, (IX) obtain 3-amino-4-alkoxyimino piperidines (I) with sour deprotection;
2. preparation method according to claim 1, is characterized in that, wherein, step 1) in, formula (II) compound is dissolved in protic solvent, adds alkali, stirs 0.5-2 hour at 10-50 DEG C, add formula (III) compound, stirring reaction 3-8 hour at-10-50 DEG C, obtains formula (IV) compound, adds Boc2O, stirring reaction 1-5 hour at 30-50 DEG C, obtains formula (V) compound; Wherein, the mol ratio of formula (II) compound and alkali, formula (III) compound and Boc2O is 1:0.5-2:1-1.5:1-1.2, under highly basic exists, formula (V) compound is dissolved in non-polar solvent, stirring reaction 2-10 hour at room temperature to 110 DEG C, obtains formula (VI) compound; Wherein, the mol ratio of formula (V) compound and highly basic is 1:1-2.
3. preparation method according to claim 1, it is characterized in that, wherein, step 2) in, alcoxyl amine hydrochlorate is dissolved in protic solvent, add alkali, under room temperature, stir 0.5-2 hour, add formula (VI) compound, stirring reaction 3-8 hour at-10-50 DEG C, obtain formula (VII) compound, wherein, the mol ratio of formula (VI) compound and alcoxyl amine hydrochlorate and alkali is 1:1-1.5:1.1-3, formula (VII) compound is dissolved in dimethyl sulfoxide (DMSO), add weak base and hydrogen peroxide,-5-40 DEG C of stirring reaction 10-36 hour, obtain formula (VIII) compound, wherein, formula (VII) compound, the mol ratio of weak base and hydrogen peroxide is 1:0.3-1:1.1-2.
4. preparation method according to claim 1, is characterized in that, wherein, step 3) in, formula (VIII) compound is dissolved in aprotic solvent, adds the hypohalite aqueous solution,-15 DEG C under room temperature, stirring reaction 10-30 hour, obtains formula (IX) compound; Wherein, the mol ratio of formula (VIII) compound and hypohalite is 1:1.5-3.0; Formula (IX) compound is dissolved in aprotic solvent, adds acid ,-10 DEG C under room temperature, stirring reaction 1-4 hour, obtains hydrochloride or the mesylate of formula (I) compound, adjusts pH8 with alkali aqueous solution, obtains formula (I) compound; Wherein, formula (IV) compound and sour mol ratio are 1:1.5-4.
5. preparation method according to claim 2, it is characterized in that, wherein, step 1) in, formula (II) compound is dissolved in protic solvent and is selected from methyl alcohol, ethanol, add alkali to be selected from sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus, stirs 0.5-2 hour at 10-50 DEG C, add formula (III) compound, stirring reaction 3-8 hour at-10-50 DEG C, obtains formula (IV) compound, adds Boc2O, stirring reaction 1-5 hour at 30-50 DEG C, obtains formula (V) compound; Wherein, the mol ratio of formula (II) compound and alkali, formula (III) compound and Boc2O is 1:0.5-2:1-1.5:1-1.2, be selected from NaH at highly basic, under CH3ONa or C2H5ONa exist, formula (V) compound is dissolved in non-polar solvent and is selected from toluene or dimethylbenzene, stirring reaction 2-10 hour at room temperature to 110 DEG C, obtains formula (VI) compound; Wherein, the mol ratio of formula (V) compound and highly basic is 1:1-2.
6. preparation method according to claim 3, it is characterized in that, wherein, step 2) in, alcoxyl amine hydrochlorate is dissolved in protic solvent and is selected from methyl alcohol, ethanol, add alkali to be selected from sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus, under room temperature, stir 0.5-2 hour, add formula (VI) compound, stirring reaction 3-8 hour at-10-50 DEG C, obtain formula (VII) compound, wherein, the mol ratio of formula (VI) compound and alcoxyl amine hydrochlorate and alkali is 1:1-1.5:1.1-3, formula (VII) compound is dissolved in dimethyl sulfoxide (DMSO), add weak base to be selected from sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus and hydrogen peroxide,-5-40 DEG C of stirring reaction 10-36 hour, obtain formula (VIII) compound, wherein, formula (VII) compound, the mol ratio of weak base and hydrogen peroxide is 1:0.3-1:1.1-2.
7. preparation method according to claim 4, it is characterized in that, wherein, step 3) in, formula (VIII) compound is dissolved in aprotic solvent and is selected from acetonitrile, methylene dichloride, add hypohalite to be selected from clorox, the sodium hypobromite aqueous solution ,-15 DEG C under room temperature, stirring reaction 10-30 hour, obtains formula (IX) compound; Wherein, the mol ratio of formula (VIII) compound and hypohalite is 1:1.5-3.0; Formula (IX) compound is dissolved in aprotic solvent and is selected from acetonitrile, methylene dichloride, add acid to be selected from concentrated hydrochloric acid, methylsulfonic acid,-10 DEG C under room temperature, stirring reaction 1-4 hour, obtains hydrochloride or the mesylate of formula (I) compound, adjust pH8 with alkali aqueous solution, obtain formula (I) compound; Wherein, formula (IV) compound and sour mol ratio are 1:1.5-4.
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