CN105330590B - The preparation method of sitafloxacin five-membered ring side chain intermediate - Google Patents

The preparation method of sitafloxacin five-membered ring side chain intermediate Download PDF

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CN105330590B
CN105330590B CN201510672240.0A CN201510672240A CN105330590B CN 105330590 B CN105330590 B CN 105330590B CN 201510672240 A CN201510672240 A CN 201510672240A CN 105330590 B CN105330590 B CN 105330590B
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reaction
sitafloxacin
hours
side chain
preparation
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CN105330590A (en
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邱俊
王冰洋
钟娟
汪清国
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Guangzhou Langqi Biotechnology Co.,Ltd.
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Guangzhou Langqi Pharmaceutical Science And Technology Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/54—Spiro-condensed

Abstract

The present invention relates to a kind of preparation methods of sitafloxacin five-membered ring side chain intermediate, include the following steps：The ketone carbonyl of raw material 1 is reacted in the presence of ammonium acetate or ammonium chloride with sodium cyanoborohydride or three acetic acid sodium borohydrides, the amidocarbonylation of products therefrom is restored with Lithium Aluminium Hydride, the free amine group of reduzate is reacted with di-tert-butyl dicarbonate in the presence of base, the phenethyl of products therefrom formic acid or formates reduction in the presence of palladium carbon remove to get the sitafloxacin side chain intermediate (product 5).This method reaction condition is mild, low for equipment requirements, safe preparation process, and stereoselectivity is good, and source chemicals are cheap and easy to get, and manufacturing cost is low.

Description

The preparation method of sitafloxacin five-membered ring side chain intermediate
Technical field
The present invention relates to pharmacy and the field of chemical synthesis, more particularly to a kind of sitafloxacin five-membered ring side chain intermediate Preparation method.
Background technology
Entitled 7- [(7S) -7- amino -5- azaspiros [2.4] hept- of sitafloxacin (sitafloxacin hydrate) chemistry 5- yls] the fluoro- 1- of the chloro- 6- of -8- [(1R, 2S)-cis-2- fluorine cyclopropyl]-Isosorbide-5-Nitrae-dihydro -4- oxo -3- quinoline carboxylic acids are first One broad spectrum quinolone class antimicrobial of pharmacy Sankyo Co., Ltd (Daiichi Sankyo) exploitation, its clinical monohydrate, For treating serious refractory infectious diseases.
Sitafloxacin due in structure containing there are one cis- fluorine cyclopropylamine group, and it is special with good pharmacokinetics Property, and adverse reaction can be mitigated, the more most of similar drugs of antibacterial activity in vitro are remarkably reinforced.Sitafloxacin is not only notable The antibacterial activity to gram positive bacteria is enhanced, and also there is antibacterial to the bacterial strain for many resistance to fluoroquinolones being clinically separated Activity.About sitafloxacin antibacterial activity in vitro studies have shown that sitafloxacin has broad-spectrum antibacterial action, not only to the blue the moon of leather Property bacterium has antibacterial activity, and to gram positive bacteria (methicillin-resistant staphylococcus aureus, methicillin-resistant epidermis grape ball Bacterium), anaerobic bacteria (including bacteroides fragilis) and mycoplasma, Chlamydia etc. there is stronger antibacterial activity, to it is many it is clinical often See that the bacterial strain of resistance to fluoroquinolones also has good bactericidal effect.Sitafloxacin oral absorption is good, bioavailability is more than 70%, group It is wide to knit distribution, the drug concentration in Various Tissues outside central nervous system is above serum drug level, therefore, Xi Tasha Star is expected to become the important of the single or mixed cell infection such as treatment respiratory tract, urogenital tract, abdominal cavity and skin soft tissue Drug.
The structural formula of sitafloxacin is as follows：
Wherein, side chain A is chiral molecules by the intermediate introducing with lower structure, the intermediate.
The existing synthetic method of the intermediate mainly has following two：
In above two synthetic method, the first be by azido compound intermediate, although this method yield compared with Height, but azido compound is easy explosion, and there are security risk, this risk is especially prominent in large-scale production；Second of side The shortcomings that method is that then hydro-reduction introduces chiral nitrogen-atoms again by hydroxylamine hydrochloride and ketone carbonyl condensation, this method is choosing Selecting property is poor, and yield is low, causes cost high.
Invention content
Based on this, the purpose of the present invention is to provide a kind of preparation methods of sitafloxacin five-membered ring side chain intermediate, should Method safety is efficient, cost is relatively low.
Realize that foregoing invention purpose specific technical solution is as follows：
A kind of preparation method of sitafloxacin side chain intermediate, includes the following steps：
(1) raw material 1 reacts in the presence of ammonium acetate or ammonium chloride with sodium cyanoborohydride or three acetic acid sodium borohydrides, will Ketone carbonyl reduction amination obtains intermediate 2；
(2) intermediate 2 is reacted with Lithium Aluminium Hydride, and amidocarbonylation is restored to obtain intermediate 3；
(3) intermediate 3 reacts in the presence of organic base with di-tert-butyl dicarbonate, obtains amino and is protected by tertbutyloxycarbonyl The intermediate 4 of shield；
(4) intermediate 4 obtains product 5 in the presence of palladium-carbon with formic acid or formic acid reactant salt, reduction removing phenethyl；
The structural formula of the raw material, intermediate and product is as follows：
In wherein some embodiments, the reaction dissolvent of step (1) is C1-C4Alcohol, reaction temperature are -5 DEG C -25 DEG C, reaction Time is 1-16 hours, and the molar ratio of raw material 1, ammonium acetate and sodium cyanoborohydride is 1:4-6:1-2.
In wherein some embodiments, the C1-C4Alcohol is methanol or ethyl alcohol.
In wherein some embodiments, the reaction dissolvent of step (2) is tetrahydrofuran, and reaction temperature is -5 DEG C -65 DEG C, instead It is 1-14 hours between seasonable, the molar ratio of intermediate 2 and Lithium Aluminium Hydride is 1:1-1.2.
In wherein some embodiments, the reaction dissolvent of step (3) is dichloromethane, and reaction temperature is -5 DEG C -30 DEG C, instead It is 1-8 hours between seasonable, the molar ratio of intermediate 3 and di-tert-butyl dicarbonate is 1:1-1.2.
In wherein some embodiments, the reaction dissolvent of step (4) is ethyl alcohol, back flow reaction 2-10 hour, intermediate 4 and The molar ratio of formic acid or formates is 1:4-5.
In wherein some embodiments, the reaction temperature of step (1) is -5 DEG C -5 DEG C, and the reaction time is 12-16 hours； The reaction temperature of step (2) is -5 DEG C -5 DEG C, and the reaction time is 10-14 hours；The reaction temperature of step (3) is 15 DEG C -30 DEG C, Reaction time is 2-4 hours；The reaction of step (4) is back flow reaction 3-5 hours.
In wherein some embodiments, step (1) is reacted under conditions of pH value is 4.5-6.5.
In wherein some embodiments, step (3) described organic base is the mixing of triethylamine and p- dimethylamino naphthyridine Object.
In wherein some embodiments, step (4) described formates is ammonium formate/sodium formate.
The preparation method of sitafloxacin side chain intermediate of the present invention has the advantages that：Reaction condition temperature With it is low for equipment requirements；The stereoselectivity of reaction is good；Source chemicals are cheap and easy to get, and manufacturing cost is low；It avoids using Azide The dangerous higher reagent/raw material such as object and hydrogen is closed, the security risk and production cost in preparation process are reduced.
Specific implementation mode
With reference to specific embodiment, the present invention is described further.
The preparation of raw material 1：
(1) bromination of substituted cyclopropane keto acid ethyl ester
7 grams of substituted cyclopropane keto acid ethyl esters are dissolved in 40 milliliters of absolute ethyl alcohols, bromine 1.2 is slowly added dropwise at 0 DEG C and works as Amount, reacts 1 hour, the reaction was complete, and reaction is quenched with 20 milliliters of saturated aqueous sodium thiosulfates, adds 60 at room temperature after adding Milliliter water dilution, after lower layer's product is separated, 40 milliliters of ethyl acetate of water phase extract three times, with 40 after extract liquor merging Milliliter saturated common salt washing is primary, is dried with anhydrous magnesium sulfate, is concentrated after filtering, concentrate is used column chromatography (mobile phase For petroleum ether:Ethyl acetate=30:1) 7.2g grams of product, yield are obtained：80%.
(2) cyclopropane bromide keto acid ethyl ester prepares raw material 1 with (R) -1- phenylethylamine condensations
1.0 grams of cyclopropane bromide keto acid ethyl esters are dissolved in 80 milliliters of tetrahydrofurans, are added dropwise at 0 DEG C (R)-of 1.1 equivalents Then the triethylamine of 1- phenylethylamines and 1.1 equivalents reacts 2 hours at room temperature.Add 100 milliliters of water, with 40 milliliters of acetic acid second Ester extracts three times, then primary with 40 milliliters of saturated common salt washings, is dried with anhydrous magnesium sulfate, is concentrated to dryness after filtering.It places It is completely converted into final product overnight.Sterling 0.62g, yield 60% are obtained after purification.1HNMR(CDCl3, 400 Μ Η z)：δ1.81(d, 3H, J=7.2Hz), 1.4-1.74 (m, 4H), 3.48 (d, 1H, J=17.5Hz), 3.88 (d, 1H, J=17.5Hz), 5.81 (q, 1H, J=7.2Hz), 7.34 (s, 1H).
1 reduction amination of raw material prepares intermediate 2：
0.60 gram of raw material 1 is dissolved in 40 milliliter of 95% ethyl alcohol, the ammonium acetate of 5 equivalents is added, is added with stirring a small amount of acetic acid PH value is adjusted to 5.5, is cooled to 0 DEG C, then the sodium cyanoborohydride of 1.1 equivalents is added portionwise in reaction bulb.Reaction 14 hours Afterwards, add 20 milliliters of water that reaction is quenched.Three times with 40 milliliters of ethyl acetate extractions, after merging one is washed with 20 milliliters of saturated common salts Secondary, anhydrous magnesium sulfate drying is concentrated to dryness after filtering.Obtain 0.53 gram of the crude product of intermediate 2, crude product silica gel column chromatography (mobile phase is dichloromethane for purifying:Methanol=95:5) 0.48 gram of intermediate 2, yield 80%, are obtained.1HNMR(CDCl3, 400 Μ Ηz)：δ 0.6-1.3 (m, 4H), 1.40 (s, 2H), 1.52 (d, 3H, J=7.2Hz), 2.99 (dd, 1H, J=12.8Hz), 3.16-3.46 (m, 2H), 5.52 (q, 1H, J=7.2Hz), 7.30 (s, 5H).
The reduction of intermediate 2 prepares intermediate 3：
Above-mentioned 0.40 gram of intermediate 2 is dissolved in 40 milliliters of tetrahydrofuran solutions, 1.1 equivalents are added in three batches at 0 DEG C Lithium Aluminium Hydride, react 12 hours at room temperature, reaction be then quenched with water, extracted three times, then with 40 milliliters of ethyl acetate It washed once with 20 milliliters of saturated salt solutions, anhydrous magnesium sulfate drying is concentrated to dryness after filtering, obtains 0.33 gram of intermediate 3, produces Rate 88%.1HNMR(CDCl3, 400 Μ Η z)：δ 0.20-0.82 (m, 4H), 1.35 (d, 3H, J=6.5Hz), 1.6-2.0 (br M, 2H), 2.2-3.1 (m, 4H), 3.25 (q, 1H, J=6.5Hz), 3.5-3.9 (m, 1H), 7.28 (br s, 5H).
BOC protecting groups prepare intermediate 4 on the amino of intermediate 3：
Above-mentioned 0.30 gram of intermediate 3 is dissolved in 20 milliliters of dichloromethane, and p- the two of triethylamine and catalytic amount is added at room temperature The di-tert-butyl dicarbonate of 1.1 equivalents is then added in methylamino pyridine (DMAP), stirs 3 hours.Then with 10 milliliter 10% Acetic acid washes twice, and is washed once with 10 milliliters of saturated sodium bicarbonate solutions, and after anhydrous magnesium sulfate drying, solvent is evaporated off in filtering. To 0.37 gram of intermediate 4, yield：88%, optical value (CHCl3,10mg/mL),[a]D 25=-16 °, dr>90%, ee>97%.1HNMR(CDCl3, 400 Μ Η z)：δ 0.4-0.9 (m, 4 Η), 1.36 (d, 3 Η, J=7.2 Η z), 1.44 (s, 9H), 2.43 (dq, 2H, J=10.2Hz, J=5.6Hz), 3.24 (q, 1H, J=7.2Hz), 3.6-4.0 (m, 1H), 4.5-5.1 (br, 1H), 7.28(s,5H)。
Intermediate 4 removes phenethyl and prepares product 5：
Above-mentioned 0.37 gram of intermediate 4 is dissolved with 20 milliliter of 95% ethyl alcohol, be added 4 equivalents ammonium formate solid and 0.5 gram 5% Palladium-carbon.Then it is heated to reflux 4 hours, cooled and filtered removes solid, washed once with a small amount of ethyl alcohol.Then it removes under reduced pressure Solvent.Obtain 0.28 gram of the crude product of final product.The crude product is dissolved in 20 milliliters of ethyl acetate, then with 20 milliliter 10% Aqueous citric acid solution washs three times, and water phase is adjusted to alkalinity with 20% sodium hydrate aqueous solution, then with 40 milliliters of dichloromethane Extraction three times, washed once with saturated salt solution, is filtered after anhydrous magnesium sulfate drying, solvent is evaporated off, obtains required final product 0.245 gram, yield 99%.1HNMR(CDCl3, 400 Μ Η z)：δ 0.4-1.0 (m, 4H), 1.42 (s, 9H), 2.72 (d, 1H, J= 10.2Hz), 2.92 (dd, 1H, J=10.8Hz, 3.6Hz), 3.01 (d, 1H, J=10.2Hz), 3.33 (dd, 1H, J= 10.8Hz,5.4Hz),3.5-3.91(m,1H),5.01-5.42(br,1H)。
Each technical characteristic of embodiment described above can be combined arbitrarily, to keep description succinct, not to above-mentioned reality It applies all possible combination of each technical characteristic in example to be all described, as long as however, the combination of these technical characteristics is not deposited In contradiction, it is all considered to be the range of this specification record.
Several embodiments of the invention above described embodiment only expresses, the description thereof is more specific and detailed, but simultaneously It cannot therefore be construed as limiting the scope of the patent.It should be pointed out that coming for those of ordinary skill in the art It says, without departing from the inventive concept of the premise, various modifications and improvements can be made, these belong to the protection of the present invention Range.Therefore, the protection domain of patent of the present invention should be determined by the appended claims.

Claims (5)

1. a kind of preparation method of sitafloxacin side chain intermediate, which is characterized in that include the following steps：
(1) ketone carbonyl reduction amination is obtained intermediate 2 by raw material 1 with sodium cyanoborohydride reaction in the presence of ammonium acetate；
(2) intermediate 2 is reacted with Lithium Aluminium Hydride, and amidocarbonylation is restored to obtain intermediate 3；
(3) intermediate 3 reacts in the presence of organic base with di-tert-butyl dicarbonate, obtains what amino was protected by tertbutyloxycarbonyl Intermediate 4；
(4) intermediate 4 obtains product 5 in the presence of palladium-carbon with formic acid or formic acid reactant salt, reduction removing phenethyl；
The structural formula of the raw material, intermediate and product is as follows：
The reaction dissolvent of step (1) is C1-C4Alcohol, reaction temperature are -5 DEG C -25 DEG C, and the reaction time is 1-16 hours, raw material 1, vinegar The molar ratio of sour ammonium and sodium cyanoborohydride is 1:4-6:1-2；
The reaction dissolvent of step (3) is dichloromethane, and reaction temperature is -5 DEG C -30 DEG C, and the reaction time is 1-8 hours, intermediate 3 Molar ratio with di-tert-butyl dicarbonate is 1:1-1.2；The organic base is the mixing of triethylamine and p- dimethylamino naphthyridine Object；
The reaction dissolvent of step (4) is ethyl alcohol, and back flow reaction 2-10 hours, intermediate 4 and the molar ratio of formic acid or formates are 1:4-5。
2. the preparation method of sitafloxacin side chain intermediate according to claim 1, which is characterized in that step (2) it is anti- It is tetrahydrofuran to answer solvent, and reaction temperature is -5 DEG C -65 DEG C, and the reaction time is 1-14 hours, and intermediate 2 rubs with Lithium Aluminium Hydride You are than being 1:1-1.2.
3. the preparation method of sitafloxacin side chain intermediate according to claim 1, which is characterized in that step (1) it is anti- It is -5 DEG C -5 DEG C to answer temperature, and the reaction time is 12-16 hours；The reaction temperature of step (2) is -5 DEG C -5 DEG C, and the reaction time is 10-14 hours；The reaction temperature of step (3) is 15 DEG C -30 DEG C, and the reaction time is 2-4 hours；The reaction of step (4) is reflux Reaction 3-5 hours.
4. according to the preparation method of claim 1-3 any one of them sitafloxacin side chain intermediates, which is characterized in that step (1) it is reacted under conditions of pH value is 4.5-6.5.
5. according to the preparation method of claim 1-3 any one of them sitafloxacin side chain intermediates, which is characterized in that step (4) formates is ammonium formate or sodium formate.
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CN105906545B (en) * 2016-05-06 2018-06-29 广州康瑞泰药业有限公司 A kind of preparation method for synthesizing sitafloxacin intermediate (7S) -5- azaspiros [2.4] heptane -7- carbamates
CN109232530B (en) * 2018-10-25 2020-05-22 苏州东瑞制药有限公司 Preparation method of sitafloxacin hydrate

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CN1040790A (en) * 1988-08-31 1990-03-28 第一制药株式会社 The preparation of spirocyclic compound
TW212179B (en) * 1991-05-28 1993-09-01 Daiichi Co Ltd
CN1580055A (en) * 2003-07-31 2005-02-16 上海新创医药科技有限公司 Quinolone carboxylic acid derivatives and their salts
CN101759629A (en) * 2009-12-22 2010-06-30 北大方正集团有限公司 Novel preparation method for sitafloxacin intermediate

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1037507A (en) * 1988-04-27 1989-11-29 第一制药株式会社 Optically active pyridone carboxylic acid derivatives
CN1040790A (en) * 1988-08-31 1990-03-28 第一制药株式会社 The preparation of spirocyclic compound
TW212179B (en) * 1991-05-28 1993-09-01 Daiichi Co Ltd
CN1580055A (en) * 2003-07-31 2005-02-16 上海新创医药科技有限公司 Quinolone carboxylic acid derivatives and their salts
CN101759629A (en) * 2009-12-22 2010-06-30 北大方正集团有限公司 Novel preparation method for sitafloxacin intermediate

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