CN102249972A - Method for synthesizing novel chiral lateral chain of meropenem - Google Patents
Method for synthesizing novel chiral lateral chain of meropenem Download PDFInfo
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- CN102249972A CN102249972A CN2011101396360A CN201110139636A CN102249972A CN 102249972 A CN102249972 A CN 102249972A CN 2011101396360 A CN2011101396360 A CN 2011101396360A CN 201110139636 A CN201110139636 A CN 201110139636A CN 102249972 A CN102249972 A CN 102249972A
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Abstract
The invention relates to a method for synthesizing an intermediate of meropenem, in particular to a method for synthesizing a novel chiral lateral chain of meropenem. The method for synthesizing the novel chiral lateral chain of meropenem is characterized by comprising the following steps of: (a) synthesizing a compound (III) by taking a compound (I) and a compound (II) as raw materials; (b) preparing a compound (IV) from the compound (III); (c) synthesizing a compound (V) by the compound (IV); (d) finally generating a final product (VII) by the compound (V) and the compound (VI). The method for synthesizing the novel chiral lateral chain of meropenem, provided by the invention, has beneficial effects as follows: the structure of the product is novel, the optical purity is high and the gradation of tone is good; the raw materials are cheap and easy to be obtained; compared with the traditional p-nitrobenzyl chloroformate, the allyl chloroformate has low price; and the reaction operation is simplified and the reaction conditions are moderate.
Description
(1) technical field
The present invention relates to the synthetic method of meropenem intermediate, particularly a kind of synthetic method of meropenem novel chiral side chain.
(2) background technology
Meropenem (meropenem) is complete synthesis carbapenem antibiotic, and Pharmaceutical Co., Ltd at first succeeds in developing by SUMITOMO CHEMICAL, and at first in Italy go on the market with trade(brand)name " Merrem " (U.S. flat) January nineteen ninety-five.
Meropenem is as tribactams, has has a broad antifungal spectrum, outstanding advantage that anti-microbial activity is strong.Play antibiotic, germicidal action by suppressing synthesizing of bacteria cell wall, all responsive to gram positive organism, gram-negative bacteria, especially gram-negative bacteria being had very strong anti-microbial activity, is the very few at present Broad spectrum antibiotics product that can treat various infectious diseases.
Meropenem is stable to most of β-Nei Xiananmeis, this compares with cynnematin has great advantage, therefore there is not cross resistance with third generation cephalosporin, and owing to have methyl on 1 of its chemical structure, make it stable to dehydropeptidase of kidney, need not share enzyme inhibitors, adverse reaction rate is low, be suitable for treating severe infection.Chang Zuowei severe infection and based on the mixed infection of G-bacterium, multi-drug resistant bacteria infects, zymogenic bacteria infects choice drug clinically.
Meropenem is a chiral drug, and its chiral side chain has extremely important influence to antimicrobial spectrum and anti-microbial activity.At present in the industrial production, producer both at home and abroad adopts old explained hereafter meropenem, and meropenem (VIII) is by parent nucleus MAP(IX) and side chain H(X) two portions are formed by connecting.
The synthetic of side chain H is raw material with nitrobenzyl chloroformate ester, thioacetic acid potassium etc., has problems such as optical purity is not high, look differential.When being used to produce meropenem, needing to use the noble metal catalyst pressure hydration at last and slough PNZ protecting group on the side chain H, condition is relatively harsh, be difficult for realizing safety in production, and the meropenem look level of producing is relatively poor.
(3) summary of the invention
The present invention is in order to remedy the deficiencies in the prior art, the synthetic method of a kind of reaction conditions gentleness, optical purity of products height, meropenem novel chiral side chain that the look level is good is provided, i.e. (2S, 4S)-and the synthetic method of 4-benzoyl sulfo--2-dimethylamine carbonyl-1-allyloxycarbonyl tetramethyleneimine, this compound structure is as follows:
The present invention is achieved through the following technical solutions:
A kind of synthetic method of meropenem novel chiral side chain is characterized in that: comprise the steps:
A) with compound (I)
And compound (II)
Be raw material, synthetic compound (III)
B) by compound (III) preparation compound (IV)
C) by compound (IV) synthetic compound (V)
D) by compound (V) and compound (VI)
Generate final product (VII)
Synthetic route is:
Concrete steps are:
A) (2S, 4R)-4-Hydroxyproline and compound (II) allyl chlorocarbonate react under alkaline condition, alkali is oxyhydroxide, carbonate or the supercarbonate of potassium or sodium with compound (I).Reaction was at room temperature carried out 2-4 hour, water through acidifying, extraction, concentrate, toluene recrystallization and drying, compound (III), yield about 90%;
B) compound (III) reacts in organic solvent with methylsulfonyl chloride, and organic solvent is one or more in ethyl acetate, tetrahydrofuran (THF), methylene dichloride, ethylene dichloride, the acetonitrile, and 0-15 ℃ was reacted 2-3 hour down.Organic basess such as pyridine, diisopropyl ethyl amine and triethylamine are acid binding agent, and alkali number is slightly larger than the molar weight that generates acid;
C) step b) gained reaction solution is not treated, directly under alkaline condition with dimethylamine hydrochloride prepared in reaction compound (V), be reflected at and carried out under 0-15 ℃ 2-3 hour, organic basess such as pyridine, diisopropyl ethyl amine and triethylamine are acid binding agent;
D) compound (V) reacts under the high temperature reflux condition with compound (VI) and generates final product (VII): solvent for use is dimethyl sulfoxide (DMSO), dioxane, N, one or more in dinethylformamide, N,N-dimethylacetamide, the toluene.100-150 ℃ of down reaction 3-6 hour, crude product is a solvent recrystallization with in hexanaphthene, normal hexane, ethyl acetate, the sherwood oil one or more.
Starting compound in the step d) (VI) synthetic method is specially: be reflected under 20-60 ℃, with ethanol and methyl alcohol volume ratio is that the mixed solution of 1:1 is a solvent, with the thiobenzoic acid is raw material, reacts 1-2 hour promptly with potassium hydroxide, salt of wormwood or saleratus vigorous stirring.
The synthetic method of meropenem novel chiral side chain of the present invention by (2S, 4R)-the 4-oxyproline 1,2, introduce new functional group respectively in 3 functional groups of 4-position, and keep highly single-minded steric configuration.
The beneficial effect of the synthetic method of meropenem novel chiral side chain of the present invention is: the synthesis technique of having developed a kind of meropenem novel chiral side chain, the new production process that is used for meropenem, with the intermediate of this product as the preparation meropenem, constant product quality, yield height; Raw material is cheap and easy to get, and the more traditional nitrobenzyl chloroformate ester of allyl chlorocarbonate is cheap; Simplified operation, step b) and c) realized the method for the treatment of different things alike; Optical purity of products height, look level are good, the reaction conditions gentleness.
(4) embodiment
Embodiment 1:
The synthetic method of this meropenem novel chiral side chain, adopt following steps:
A) compound (III) is synthetic:
22.4 g sodium hydroxide are dissolved in the 280 mL water, are cooled to 25 ℃, and adding 33g (2S, 4R)-4-Hydroxyproline, in 25 ℃ of insulations.The 33.7mL allyl chlorocarbonate is dissolved in the 231 mL methylene dichloride, splashes in the above-mentioned solution, 25 ℃ of following stirring reaction 2h.After the layering with water layer with the 100mL washed with dichloromethane, wash 2 times.Water layer is transferred to about pH=1, and with the 200mL ethyl acetate extraction, the ethyl acetate layer anhydrous magnesium sulfate drying filters, be evaporated to dried, oily matter.In oily matter, add 280mL toluene, stirred crystallization, filter the 48.9g solid, yield 90%.
m.p.=90.8-91.8℃，[α]
D 25=?-81.5°(c=1,?MeOH)。
1H-NMR (300MHz, DMSO-d6) δ: 12.6 (s, 1H, COOH), 5.9 (m, 1H ,=CH), 5.05-5.35 (m, 2H ,=CH
2), 5.1 (s, 1H ,-OH), 4.5 (m, 2H, O-CH
2), 4.1-4.3 (m, 2H, CH-OH and CH-COOH), 3.3-3.5 (m, 2H, N-CH
2), 1.95-2.15 (m, 2H, CH
2-CHOH);
B) compound (IV) is synthetic:
Add 48.9g compound (III) and 1000mL methylene dichloride, 41.5mL pyridine in the 2000mL four-hole bottle, moltenly be cooled to 0 ℃ after clearly.Add the 63mL methylsulfonyl chloride, drip the 154.4mL pyridine afterwards, maintain the temperature at 0-15 ℃ of reaction 3 hours;
C) compound (V) is synthetic:
In step b) gained reaction solution, add the 54g dimethylamine hydrochloride fast, then drip the 300mL pyridine, keep 0-15 ℃ of reaction 3 hours.After reaction finished, the adding massfraction was 10% NaCl aqueous solution 300mL in reaction solution, stirs layering, and organic layer stirs layering with the hydrogen chloride solution 600mL washing of 1mol/L; Organic layer stirs layering with the NaOH solution 300mL washing of 1mol/L; Organic layer is that 10% NaCl aqueous solution 1200mL divides 2 washings with massfraction, stirs layering.The organic layer dried over mgso, suction filtration, be evaporated to dried, oily liquids 66.3g, yield 91%.
[α]
D 25=-12.1°?(c=1,?CHCl3)。
1H-NMR?(300MHz,?CDCl
3)?δ:?5.9?(m,?1H,?=CH),?5.15-5.40?(m,?2H,?=CH
2),?5.2?(m,?1H,?CH-OMs),?4.85?(m,?1H,?CH-CON),?4.45-4.65?(m,?2H,?CH
2-O),?3.80-3.95?(m,?2H,?N-CH
2),?2.45-2.65?(m,?2H,?CH
2-CHOMs)；
Synthesizing of compound (VI):
Add 370mL methyl alcohol, 370mL ethanol and 51.4g thiobenzoic acid in the 1000mL four-hole bottle, add 23.4g potassium hydroxide, 50 ℃ of following vigorous stirring were reacted 2 hours.Reaction solution is concentrated into yellow solid, 200mL isopropyl ether washing, filter 59.0g thiobenzoic acid potassium, yield 98%;
D) final product (VII) is synthetic:
Add 66.3g compound (V), 1600mL dimethyl sulfoxide (DMSO) and 57.0g thiobenzoic acid potassium in the 2000mL four-hole bottle, nitrogen protection was reacted 5 hours down in 120 ℃.Reaction solution is cooled to 25-30 ℃, and adding 1600mL massfraction is 10% the NaCl aqueous solution, 850mL unsaturated carbonate aqueous solutions of potassium and 1000mL toluene.Stir layering, water layer extracts with 1000mL toluene; The combining methylbenzene layer washs with salt of wormwood saturated aqueous solution 1000mL.Organic layer washs 2 times again with the saturated NaCl solution washing of 6000mL.Anhydrous magnesium sulfate drying, 40 ℃ of concentrating under reduced pressure, crude product are dissolved under 30 ℃ in the 255mL ethyl acetate, add the crystallization of 400mL hexanaphthene.Temperature is slowly reduced to 10 ℃, and 10 ℃ were stirred 2 hours.Filter, filter cake is chilled to ethyl acetate-sherwood oil mixed solution (volume ratio 30:70) washing of 0 ℃ in advance with 70mL.Oven dry gets 63.8g final product (VII), yield 85%.
m.p.=100.7-101.5℃，[α]
D 25=?+1.5(c=1,?CHCl3)。
1H-NMR?(300MHz,?CDCl
3)?δ:?7.9-7.44?(m,?5H,?Ar-H),?5.9?(m,?1H?,=CH),?5.05-5.35?(m,?2H,?=CH
2),?4.79?(m,?1H,?CH-CON),?4.45-4.65?(m,?2H,?O-CH
2),?4.05-4.25?(m,?2H,?N-CH
2),?3.4-3.6?(m,?1H,?CH-S),?3.11-2.96 (m,?6H,?2CH
3),?2.50-2.95?(m,?2H,?CH
2-CHS)。
Embodiment 2:
The synthetic method of this meropenem novel chiral side chain, adopt following steps:
A) compound (III) is synthetic:
22.4g sodium hydroxide is dissolved in the 280mL water, is cooled to 25 ℃, and adding 33g (2S, 4R)-4-Hydroxyproline, in 25 ℃ of insulations.The 33.7mL allyl chlorocarbonate is dissolved in the 231mL methylene dichloride, splashes into above-mentioned solution, 25 ℃ of following stirring reaction 2h.After the layering with water layer with 100 mL washed with dichloromethane, wash 2 times.Water layer is transferred to about pH=1, with the 200mL ethyl acetate extraction, the ethyl acetate layer anhydrous magnesium sulfate drying.Filter, be evaporated to dried, oily matter.In oily matter, add 280mL toluene, stirred crystallization, filter the 48.9g solid, yield 90%;
B) compound (IV) is synthetic:
Add 48.9g compound (III), 1000mL methylene dichloride, 23.1mL triethylamine in the 2000mL four-hole bottle, moltenly be cooled to 0 ℃ after clear.Add the 63mL methylsulfonyl chloride, drip the 86mL triethylamine afterwards, maintain the temperature at 0-15 ℃ of reaction 2 hours;
C) compound (V) is synthetic:
In step b) gained reaction solution, add 54 g dimethylamine hydrochlorides fast, then drip the 167.5mL triethylamine, keep 0-15 ℃ of reaction 2 hours.After reaction finished, the adding massfraction was 10% NaCl aqueous solution 300mL in reaction solution, stirs layering.Organic layer stirs layering with the hydrogen chloride solution 600mL washing of 1mol/L; Organic layer stirs layering with the NaOH solution 300mL washing of 1mol/L; Organic layer is that 10% NaCl aqueous solution 1200mL divides 2 washings with massfraction, stirs layering.The organic layer anhydrous magnesium sulfate drying, suction filtration, and be evaporated to dried, oily liquids 64.4g, yield 89%;
Synthesizing of compound (VI):
Add 370mL methyl alcohol, 370mL ethanol and 51.4g thiobenzoic acid in the 1000mL four-hole bottle, add 19.0g potassium hydroxide, 50 ℃ of following vigorous stirring were reacted 2.5 hours.Reaction solution is concentrated into yellow solid, 200mL isopropyl ether washing, filter 59.4g thiobenzoic acid potassium, yield 99%;
D) final product (VII) is synthetic:
Add 64.4g compound (V), 1600mL N in the 2000mL four-hole bottle, dinethylformamide and 57.0g thiobenzoic acid potassium, nitrogen protection was reacted 6 hours down in 110 ℃.Reaction solution is cooled to 25-30 ℃, and the adding massfraction is 10% NaCl aqueous solution 1600mL, unsaturated carbonate aqueous solutions of potassium 850mL and 1000mL toluene, stirs layering.Water layer extracts with 1000mL toluene; The combining methylbenzene layer washs with salt of wormwood saturated aqueous solution 1000mL; Organic layer washs 2 times again with the saturated NaCl solution washing of 6000mL.Organic layer with anhydrous magnesium sulfate drying after, 40 ℃ of concentrating under reduced pressure.Crude product is dissolved under 30 ℃ in the 255mL ethyl acetate, adds the crystallization of 400mL hexanaphthene, and temperature is slowly reduced to 10 ℃, and 10 ℃ were stirred 2 hours.Filter, filter cake is chilled to ethyl acetate-normal hexane mixed solution (volume ratio 30:70) washing of 0 ℃ in advance with 70 mL.Oven dry gets 66.4g product (VII), yield 91%.
Embodiment 3:
The synthetic method of this meropenem novel chiral side chain, adopt following steps:
A) compound (III) is synthetic:
31.4g potassium hydroxide is dissolved in the 280mL water, is cooled to 20 ℃, and adding 33g (2S, 4R)-4-Hydroxyproline, in 20 ℃ of insulations.The 33.7mL allyl chlorocarbonate is dissolved in the 231 mL methylene dichloride, splashes into above-mentioned solution, 20 ℃ of following stirring reactions 2 hours.After the layering with water layer with the 100mL washed with dichloromethane, wash 2 times.Water layer is transferred to about pH=1, and with the 200mL n-butyl acetate extraction, the butylacetate layer is with anhydrous magnesium sulfate drying.Be evaporated to dried, oily matter, in oily matter, add 280mL toluene, stirred crystallization is filtered, the 49.3g solid, yield 91%;
B) compound (IV) is synthetic:
Add 49.3g compound (III), 1000mL ethylene dichloride, 23.2mL triethylamine in the 2000 mL four-hole bottles, moltenly be cooled to 0 ℃ after clear.Add the 63mL methylsulfonyl chloride, drip the 87mL triethylamine afterwards, maintain the temperature at 0-10 ℃ of reaction 3 hours;
C) compound (V) is synthetic:
In step b) gained reaction solution, add the 54g dimethylamine hydrochloride fast, then drip the 167.5mL triethylamine, keep 0-10 ℃ of reaction 2 hours.After reaction finished, the adding massfraction was 10% NaCl aqueous solution 300mL in reaction solution, stirs layering.Organic layer stirs layering with the hydrogen chloride solution 600mL washing of 1mol/L; Organic layer stirs layering with the NaOH solution 300mL washing of 1mol/L; Organic layer is that 10% NaCl aqueous solution 1200mL divides 2 washings with massfraction, stirs layering.The organic layer anhydrous magnesium sulfate drying filters; Be evaporated to dried, oily liquids 65.9g, yield 90%;
Synthesizing of compound (VI):
Add 370mL methyl alcohol, 370mL ethanol and 51.4g thiobenzoic acid in 1000 mL four-hole bottles, nitrogen protection adds the 33.9g saleratus down, and 50 ℃ of following vigorous stirring were reacted 1 hour.Reaction solution is concentrated into yellow solid, 200mL isopropyl ether washing, filter 57.5g thiobenzoic acid potassium, yield 95%;
D) final product (VII) is synthetic:
Add 65.9g compound (V), 1600mL dioxane and 57.0g thiobenzoic acid potassium in the 2000mL four-hole bottle, nitrogen protection was in 100 ℃ of boiling reactions 6 hours.Reaction solution is cooled to 25-30 ℃, and the adding massfraction is 10% NaCl aqueous solution 1600mL, saturated aqueous sodium carbonate 850mL and 1000mL toluene, stirs layering.Water layer extracts with 1000mL toluene, the combining methylbenzene layer.Organic layer washs 2 times again with the saturated NaCl solution washing of 6000 mL.Organic layer is with anhydrous magnesium sulfate drying, and 40 ℃ of concentrating under reduced pressure, crude product are dissolved under 30 ℃ in the 255mL ethyl acetate, adds the crystallization of 400mL sherwood oil.Temperature is slowly reduced to 10 ℃, stirs 2 hours.Filter, filter cake is chilled to ethyl acetate-sherwood oil mixed solution (volume ratio 30:70) washing of 0 ℃ in advance with 70mL.Oven dry gets 60g product (VII), yield 82%.
Claims (8)
1. the synthetic method of a meropenem novel chiral side chain is characterized in that: comprise the steps:
A) with compound (I)
And compound (II)
Be raw material, synthetic compound (III)
B) by compound (III) preparation compound (IV)
C) by compound (IV) synthetic compound (V)
D) by compound (V) and compound (VI)
Generate final product (VII)
Synthetic route is:
2. the synthetic method of meropenem novel chiral side chain according to claim 1 is characterized in that: comprise the steps:
A) compound (I) and compound (II) are reacted under alkaline condition, room temperature reaction 2-4 hour, water through acidifying, extraction, concentrate, toluene recrystallization and drying, compound (III);
B) compound (III) reacts in organic solvent with methylsulfonyl chloride, and 0-15 ℃ was reacted 2-3 hour down;
C) step b) gained reaction solution is not treated, directly under alkaline condition with dimethylamine hydrochloride prepared in reaction compound (V), be reflected at and carried out under 0-15 ℃ 2-3 hour;
D) compound (V) reacts under the high temperature reflux condition with compound (VI) and generates final product (VII), and temperature of reaction is 100-150 ℃, reaction times 3-6 hour.
3. the synthetic method of meropenem novel chiral side chain according to claim 2, it is characterized in that: the synthetic method of compound (VI) is: under 20-60 ℃, with ethanol and methyl alcohol volume ratio is that the mixed solution of 1:1 is a solvent, with the thiobenzoic acid is raw material, reacts 1-2 hour promptly with potassium hydroxide, salt of wormwood or saleratus vigorous stirring.
4. the synthetic method of meropenem novel chiral side chain according to claim 2 is characterized in that: the alkali that uses in the step a) is oxyhydroxide, carbonate or the supercarbonate of potassium or sodium.
5. the synthetic method of meropenem novel chiral side chain according to claim 2 is characterized in that: organic solvent is one or more in ethyl acetate, tetrahydrofuran (THF), methylene dichloride, ethylene dichloride, the acetonitrile in the step b).
6. the synthetic method of meropenem novel chiral side chain according to claim 2 is characterized in that: use pyridine, diisopropyl ethyl amine or triethylamine to be acid binding agent step b) neutralization procedure c).
7. the synthetic method of meropenem novel chiral side chain according to claim 2, it is characterized in that: dipole solvent is dimethyl sulfoxide (DMSO), dioxane, N in the step d), in dinethylformamide, N,N-dimethylacetamide, the toluene one or more.
8. the synthetic method of meropenem novel chiral side chain according to claim 2 is characterized in that: the crude product for preparing in the step d) is a solvent recrystallization with in hexanaphthene, normal hexane, ethyl acetate, the sherwood oil one or more.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103113373A (en) * | 2013-03-11 | 2013-05-22 | 辽宁天华化工有限责任公司 | 1 beta-methyl carbapenem compound and synthetic process thereof |
| CN103113374A (en) * | 2013-03-11 | 2013-05-22 | 辽宁天华化工有限责任公司 | Carbapenem antibiotic and new synthetic process thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JP2955886B2 (en) * | 1990-12-18 | 1999-10-04 | 住友製薬株式会社 | Pyrrolidine derivative and method for producing the same |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103113373A (en) * | 2013-03-11 | 2013-05-22 | 辽宁天华化工有限责任公司 | 1 beta-methyl carbapenem compound and synthetic process thereof |
| CN103113374A (en) * | 2013-03-11 | 2013-05-22 | 辽宁天华化工有限责任公司 | Carbapenem antibiotic and new synthetic process thereof |
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Application publication date: 20111123 |