CN102250033A - Preparation method for novel chiral auxiliary of synthetic imipenem antibiotic - Google Patents
Preparation method for novel chiral auxiliary of synthetic imipenem antibiotic Download PDFInfo
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- CN102250033A CN102250033A CN2011101396375A CN201110139637A CN102250033A CN 102250033 A CN102250033 A CN 102250033A CN 2011101396375 A CN2011101396375 A CN 2011101396375A CN 201110139637 A CN201110139637 A CN 201110139637A CN 102250033 A CN102250033 A CN 102250033A
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Abstract
The invention relates to a preparation method for products in the field of medical chemistry, specifically relates to a preparation method for a novel chiral auxiliary of a synthetic imipenem antibiotic. The preparation method for the novel chiral auxiliary of the synthetic imipenem antibiotic is characterized in that: the method comprises the following steps that: a) trichloromethyl chloroformate and a compound (I) are subjected to an acylation reaction to obtain a compound (II); b) the compound (II) reacts with trimethyl-1-chlorosilane to activate an amino on the compound (II), followed by reacting with 2-bromo propionyl bromide to obtain the end product (III). The preparation method provided by the present invention has the following advantages that: the prepared product has good quality and high yield; the raw materials has characteristics of low cost, cheap price, availability and low toxicity; the production steps are simple, the reaction conditions are mild, such that the safe production is easy to be realized; the products are easy to be separated, the post treatment is simple, the three waste discharging is less.
Description
(1) technical field
The present invention relates to the preparation method of medical chemistry field product, the preparation method of the antibiotic novel chiral prothetic group of the southern class of particularly a kind of synthetic training.
(2) background technology
Penem-like pharmaceutical was come out the eighties in 20th century, was the β-Nei Xiananleikangshengsu of complete synthesis carbapenems New-type wide-spectrum, was the class new antibiotic that antimicrobial spectrum is the widest up to now, anti-microbial activity is very strong.The resistant organism problem is increasingly serious in recent years, has antibiotic formulations now, comprises the cephalosporin new drug of some new listing, and is powerless to the infection that methicillin-resistant gold Portugal bacterium (MRSA) causes.Penem-like pharmaceutical is extremely outstanding in the effect of clinical anti-MRSA, " last line of defense " that is called as anti-severe infection of 21 century, therefore playing the part of the key player of anti-clinical severe infection last line of defense, making such medicine increase rapidly in the whole world and domestic usage quantity.
The penem-like pharmaceutical that has gone on the market in the whole world had seven to first penem-like pharmaceutical of Merck company " imipenum " since Japan's listing in 1985.Be followed successively by by the arrangement of listing time: imipenum (1985), panipenem (1994), meropenem (nineteen ninety-five), Faropenem (1997), ertapenem (2002), biapenem (2002) and the doripenem in U.S. new listing in 2006, other has a plurality of kinds or compound in research and development.Training southern class is the complete synthesis chiral drug of a class, so its chiral configuration and stereoselectivity have extremely important influence to antimicrobial spectrum and anti-microbial activity.
(3) summary of the invention
The present invention is in order to remedy the deficiencies in the prior art; the preparation method of the antibiotic novel chiral prothetic group of the southern class of synthetic training that a kind of production stage is simple and direct, raw materials cost is low is provided; be 3-(2-bromine propionyl)-4; 4-dimethyl-1; the preparation method of 3-oxazolidine-2-ketone, this compound structure is as follows:
The present invention is achieved through the following technical solutions:
The preparation method of the antibiotic novel chiral prothetic group of the southern class of a kind of synthetic training is characterized in that: comprise the steps:
A) by superpalite and compound (I)
Obtain compound (II) through acylation reaction
B) compound (II) activates the amino on the compound (II) with trimethylammonium-1-chlorosilane reaction, obtains final product (III) with the 2 bromo propionyl bromide reaction again after the amino activation
Reaction scheme is as follows:
Concrete steps are:
A) superpalite and compound (I) 2-amino-2-methyl-1-propanol acidylate Cheng Huan under alkaline condition, thin-layer chromatography detect, and react completely to compound (I).With ethyl acetate extraction and concentrated, add the stirring solvent crystallization, filter, dry, obtain compound (II);
B) with compound (II) in toluene or ethylene dichloride with the reaction of trimethylammonium-1-chlorosilane, dripping alkali liquid simultaneously, thin-layer chromatography detects, and reacts completely to compound (II).The gained reaction solution is added 2 bromo propionyl bromide react, simultaneously dripping alkali liquid.The reaction after-filtration, washing is concentrated into dried oily matter.In oily matter, add recrystallisation solvent, stirred crystallization, filter, dry final product (III).
Used alkali is oxyhydroxide, carbonate or the supercarbonate of potassium or sodium in the step a).
The crystallization solvent for use is one or more in isopropyl ether, normal hexane, the hexanaphthene in the step a).
In the step b) molar weight of used trimethylammonium-1-chlorosilane be compound (II) molar weight 0.2-1.5 doubly.
Employed alkali lye is diisopropyl ethyl amine, triethylamine, Tributylamine, pyridine or 2-picoline in the step b).
Recrystallisation solvent is one or more in acetonitrile, ethyl acetate, ethanol, methyl alcohol, the Virahol in the step b).
The present invention selects the activation of trimethylammonium-1-chlorosilane amino, not only reaction conditions gentleness, safety, and also protection and acidylate two-step reaction realized treating different things alike, and makes processing step simplify greatly, reduced the generation of the three wastes simultaneously.
The preparation method's of the antibiotic novel chiral prothetic group of the synthetic southern class of training of the present invention beneficial effect is: and the novel chiral prothetic group " 3-(2-bromine propionyl)-4; 4-dimethyl-1; 3-oxazolidine-2-ketone " to be used to train the antibiotic chirality of southern class synthetic, compare with other chirality prothetic group, have novel structure, stereoselectivity advantages of higher; Good product quality, the yield height of preparation; Raw materials cost is low, and is cheap and easy to get and poison little; Production stage is simple and direct and reaction conditions is gentle, is easy to realize safety in production; Product is easily separated, convenient post-treatment, and " three wastes " discharging is few.
(4) embodiment
Embodiment 1:
Should synthesize the preparation method of the antibiotic novel chiral prothetic group of the southern class of training, adopt following steps:
A) in the 1000mL reaction flask, add 500mL water, stir adding 120g sodium hydroxide down, stir molten clear.Reduce to room temperature, add 2-amino-2-methyl-1-propanol 60mL, temperature control 20-30 ℃, drip superpalite 60mL, dropwised in about 3 hours.Temperature control is to 20-30 ℃, continues reaction 3 hours, and thin-layer chromatography detects, and reacts completely to 2-amino-2-methyl-1-propanol.Divide 3 extractions with the 600mL ethyl acetate, use ethyl acetate 200mL at every turn, static layering 1 hour, combined ethyl acetate phase.The concentrating under reduced pressure dry ethyl acetate adds isopropyl ether 200mL, and stirred crystallization is cooled to-5 ℃, and temperature control 2 hours filters, with the cold isopropyl ether filter wash of 50mL cake, 30 ℃ of vacuum-drying 2 hours, 4,4-dimethyl-1,3-oxazolidine-2-ketone 65g, yield 90%;
Fusing point: 48-51 ℃;
B) in the 1000mL reaction flask, add 4,4-dimethyl-1,3-oxazolidine-2-ketone 65g, toluene 400mL, 60 ℃ the decompression and with water sepn, the time is 1 hour, is cooled to 15-20 ℃, add trimethylammonium-1-chlorosilane 20mL, stir and drip triethylamine 21mL down, finish for about 1 hour.Be warming up to 40-50 ℃, continue reaction 5 hours, thin-layer chromatography detects, to 4, and 4-dimethyl-1,3-oxazolidine-2-reactive ketone is complete.Be cooled to-5-0 ℃, drip 2 bromo propionyl bromide 70mL, dripped off in about 30 minutes, temperature control-5-0 ℃ of reaction 1 hour.Drip triethylamine 87mL, dripped off in about 1 hour, temperature control-5-0 ℃ was reacted 1 hour again.Filter, filter cake washes twice with 100mL toluene, and filtrate is evaporated to dried oily matter in 60 ℃, adding acetonitrile 400mL in oily matter, and stirred crystallization, stirred 2 hours by temperature control-10-5 ℃.Filter, with cold acetonitrile 50mL filter wash cake, dry 3-(2-bromine propionyl)-4,4-dimethyl-1,3-oxazolidine-2-ketone 120g, yield 85%, purity 99.1%.
Fusing point: 72-73 ℃.
IR?(KBr):?3030,?1775,?1709,?1370,?1310,?1183,?1105,?1069,?760,?702cm-1;?1H–NMR?(CDCl3)?δ:?1.58?(3H,?S),?1.60(3H,?S),?1.81(3H,?d,?J=6.8Hz),?4.06(2H,?S),?5.74(1H,?q,?J=6.8Hz)。
Embodiment 2:
Should synthesize the preparation method of the antibiotic novel chiral prothetic group of the southern class of training, adopt following steps:
A) in the 1000mL reaction flask, add 500mL water, stir and add 120g sodium hydroxide down, stirs molten clearly, reduce to room temperature.Add 2-amino-2-methyl-1-propanol 60mL, temperature control 20-30 ℃, drip superpalite 60mL, dropwised in about 3 hours, temperature control continues reaction 2 hours to 20-30 ℃, and thin-layer chromatography detects, and reacts completely to 2-amino-2-methyl-1-propanol.With 600mL ethyl acetate extraction 3 times, use ethyl acetate 200mL, static layering 1 hour, combined ethyl acetate phase at every turn.The concentrating under reduced pressure dry ethyl acetate adds hexanaphthene 200mL, stirred crystallization.Be cooled to-5 ℃, temperature control 2 hours filters, with the cold hexanaphthene filter wash of 50mL cake.30 ℃ of vacuum-drying 2 hours, 4,4-dimethyl-1,3-oxazolidine-2-ketone 67g, yield 93%;
Fusing point: 49-52 ℃;
B) in the 1000mL reaction flask, add 4,4-dimethyl-1,3-oxazolidine-2-ketone 65 g, ethylene dichloride 400mL, 60 ℃ the decompression and with water sepn, the time is 1 hour, is cooled to 15-20 ℃, add trimethylammonium-1-chlorosilane 20mL, stir and drip triethylamine 21mL down, finish for about 1 hour.Be warming up to 40-50 ℃, continue reaction 5 hours, thin-layer chromatography detects, to 4, and 4-dimethyl-1,3-oxazolidine-2-reactive ketone is complete.Be cooled to-5-0 ℃, drip 2 bromo propionyl bromide 70mL, dripped off in about 30 minutes, temperature control-5-0 ℃ of reaction 1 hour.Drip triethylamine 87mL, dripped off in about 1 hour, temperature control-5-0 ℃ was reacted 1 hour again.Filter, filter cake washes twice with the 100mL ethylene dichloride, and filtrate is evaporated to dried oily matter in 80 ℃, adding acetonitrile 400mL in oily matter, and stirred crystallization, stirred 2 hours by temperature control-10-5 ℃.Filter, with cold acetonitrile 50mL filter wash cake, dry 3-(2-bromine propionyl)-4,4-dimethyl-1,3-oxazolidine-2-ketone 114g, yield 81%, purity 98.6%.
Fusing point: 72-73 ℃.
Embodiment 3:
Should synthesize the preparation method of the antibiotic novel chiral prothetic group of the southern class of training, adopt following steps:
A) add 500mL water in the 1000mL reaction flask, stir and add 120g sodium hydroxide down, stirs molten clearly, reduce to room temperature, add 2-amino-2-methyl-1-propanol 60mL, temperature control 20-30 ℃, dropping superpalite 60mL dropwised in about 3 hours.Temperature control is to 20-30 ℃, continues reaction 4 hours, and thin-layer chromatography detects, and reacts completely to 2-amino-2-methyl-1-propanol.With 600mL ethyl acetate extraction 3 times, use ethyl acetate 200mL, static layering 1 hour, combined ethyl acetate phase at every turn.The concentrating under reduced pressure dry ethyl acetate adds hexanaphthene 200mL, stirred crystallization.Be cooled to-5 ℃, temperature control 2 hours filters, with the cold hexanaphthene filter wash of 50mL cake, 30 ℃ of vacuum-drying 2 hours, 4,4-dimethyl-1,3-oxazolidine-2-ketone 67g, yield 93%;
Fusing point: 48-50 ℃;
B) in the 1000mL reaction flask, add 4,4-dimethyl-1,3-oxazolidine-2-ketone 65g, toluene 400mL, 60 ℃ the decompression and with water sepn, the time is 1 hour.Be cooled to 15-20 ℃, add trimethylammonium-1-chlorosilane 20mL, stir and drip Tributylamine 35mL down, finish for about 1 hour.Be warming up to 40-50 ℃, continue reaction 5 hours, thin-layer chromatography detects, to 4, and 4-dimethyl-1,3-oxazolidine-2-reactive ketone is complete.Be cooled to-5-0 ℃, drip 2 bromo propionyl bromide 70mL, dripped off in about 30 minutes, temperature control-5-0 ℃ of reaction 1 hour.Drip triethylamine 87mL, dripped off in about 1 hour, temperature control-5-0 ℃ was reacted 1 hour again.Filter, filter cake washes twice with 100mL toluene, and filtrate is evaporated to dried oily matter in 60 ℃; in oily matter, add ethanol 400mL; stirred crystallization, temperature control-10-5 ℃ 2 hours, filter; with cold ethanol 50mL filter wash cake; dry 3-(2-bromine propionyl)-4,4-dimethyl-1,3-oxazolidine-2-ketone 107g; yield 76%, purity 99.0%.
Fusing point: 72-73 ℃.
Claims (7)
1. the preparation method of the antibiotic novel chiral prothetic group of the synthetic southern class of training is characterized in that: comprise the steps:
A) by superpalite and compound (I)
Obtain compound (II) through acylation reaction
B) compound (II) activates the amino on the compound (II) with trimethylammonium-1-chlorosilane reaction, obtains final product (III) with the 2 bromo propionyl bromide reaction again after the amino activation
Reaction scheme is as follows:
2. the preparation method of the antibiotic novel chiral prothetic group of the southern class of synthetic training according to claim 1 is characterized in that: comprise the steps:
A) superpalite and compound (I) acidylate Cheng Huan under alkaline condition, thin-layer chromatography detect, and react completely to compound (I), with ethyl acetate extraction and concentrate, add the stirring solvent crystallization, filter, oven dry, obtain compound (II);
B) compound (II) is reacted with trimethylammonium-1-chlorosilane in toluene or ethylene dichloride, dripping alkali liquid simultaneously, thin-layer chromatography detects, and reacts completely to compound (II), the gained reaction solution is added 2 bromo propionyl bromide to react, dripping alkali liquid is reacted after-filtration simultaneously, washing, be concentrated into dried oily matter, in oily matter, add crystal solution, stirred crystallization, filter, dry final product (III).
3. the preparation method of the antibiotic novel chiral prothetic group of the southern class of synthetic training according to claim 2 is characterized in that: used alkali is oxyhydroxide, carbonate or the supercarbonate of potassium or sodium in the step a).
4. the preparation method of the antibiotic novel chiral prothetic group of the southern class of synthetic training according to claim 2 is characterized in that: the crystallization solvent for use is one or more in isopropyl ether, normal hexane, the hexanaphthene in the step a).
5. the preparation method of the antibiotic novel chiral prothetic group of the southern class of synthetic training according to claim 2 is characterized in that: in the step b) molar weight of used trimethylammonium-1-chlorosilane be compound (II) molar weight 0.2-1.5 doubly.
6. the preparation method of the antibiotic novel chiral prothetic group of the southern class of synthetic training according to claim 2 is characterized in that: employed alkali lye is diisopropyl ethyl amine, triethylamine, Tributylamine, pyridine or 2-picoline in the step b).
7. the preparation method of the antibiotic novel chiral prothetic group of the southern class of synthetic training according to claim 2 is characterized in that: recrystallisation solvent is one or more in acetonitrile, ethyl acetate, ethanol, methyl alcohol, the Virahol in the step b).
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| CN2011101396375A CN102250033A (en) | 2011-05-27 | 2011-05-27 | Preparation method for novel chiral auxiliary of synthetic imipenem antibiotic |
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS61275267A (en) * | 1985-03-29 | 1986-12-05 | メルク エンド カムパニ− インコ−ポレ−テツド | Enantioselective manufacture of 1-beta-methylcarbapenem antibiotic intermediate |
| JPS6310765A (en) * | 1986-01-27 | 1988-01-18 | Sumitomo Pharmaceut Co Ltd | Novel beta-lactam derivative and production thereof |
| JPH02262568A (en) * | 1989-03-31 | 1990-10-25 | Sumitomo Chem Co Ltd | Production of oxazolidine-2-one derivative |
| JP2003012656A (en) * | 2001-06-26 | 2003-01-15 | Sumitomo Chem Co Ltd | Method for producing 3-(2-bromopropionyl)-4,4- dimethyloxazolidin-2-one |
| CN1948312A (en) * | 2006-03-14 | 2007-04-18 | 深圳市海滨制药有限公司 | Preparation method of meluopeinan |
-
2011
- 2011-05-27 CN CN2011101396375A patent/CN102250033A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS61275267A (en) * | 1985-03-29 | 1986-12-05 | メルク エンド カムパニ− インコ−ポレ−テツド | Enantioselective manufacture of 1-beta-methylcarbapenem antibiotic intermediate |
| JPS6310765A (en) * | 1986-01-27 | 1988-01-18 | Sumitomo Pharmaceut Co Ltd | Novel beta-lactam derivative and production thereof |
| JPH02262568A (en) * | 1989-03-31 | 1990-10-25 | Sumitomo Chem Co Ltd | Production of oxazolidine-2-one derivative |
| JP2003012656A (en) * | 2001-06-26 | 2003-01-15 | Sumitomo Chem Co Ltd | Method for producing 3-(2-bromopropionyl)-4,4- dimethyloxazolidin-2-one |
| CN1948312A (en) * | 2006-03-14 | 2007-04-18 | 深圳市海滨制药有限公司 | Preparation method of meluopeinan |
Non-Patent Citations (1)
| Title |
|---|
| YOSHIO ITO等: "A HIGHLY STEREOSELECTIVE SYNTHESIS OF A KEY INTERMEDIATE OF lB-METHYLCARBAPENEMS EMPLOYING THE REFORMATSKY REACTION OF 3-(2-BROMOPROPIONYL)-2-OXAZOLIDONE DERIVATIVES", 《TETRAHEDRON LETTERS》, vol. 28, no. 52, 31 December 1987 (1987-12-31), pages 6625 - 6628, XP000650048, DOI: doi:10.1016/S0040-4039(00)96930-2 * |
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Application publication date: 20111123 |