CN102775410A - Preparation method for tebipenem pivoxil - Google Patents
Preparation method for tebipenem pivoxil Download PDFInfo
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Abstract
The invention discloses a preparation method for tebipenem pivoxil shown as formula 1. The preparation method comprises the following step of performing the following reaction on a compound III and a compound IV in an organic solvent and water, with the action of (R1)3P and an organic base, under inert gas protection, wherein the volume ratio of the organic solvent and water is 1000 : 1-20 : 1; a reaction temperature is -40-50 DEG C; and R1 represents phenyl or C2-C8 alkyls. The preparation method is easy to operate, simple in post-treatment, with the product having high yield and high purity, and is suitable for industrialized production.
Description
Technical field
The present invention relates to the preparation method of a kind of tebipenem volt ester.
Background technology
Tebipenem volt ester is first oral carbapenem antibiotic in the world of Japanese Meiji Seika Kaisba company research and development, on August 26th, 2009 in Japanese Initial Public Offering.
A tebipenem volt ester (formula I) is the prodrug of tebipenem.A tebipenem volt ester is a broad spectrum antibiotic; All effective to gram-positive microorganism and Gram-negative bacteria; To staphylococcus, suis, streptococcus pneumoniae (comprising PRSP), catarrhalis (Blanc Han Shi) (comprising that beta lactamase produces bacterium); Hemophilus influenzae (comprising Ampicillin Trihydrate drug-resistant type hemophilus influenzae) etc. all has the anti-microbial effect of strong effect, particularly to causing children's otitis media, the bacterial classification of nasal sinusitis and pneumonia.To penicillium mould drug-resistant type streptococcus pneumoniae, the antimicrbial power of the pneumococcal antimicrbial power ratio of macrolide drug-resistant type oral property antimicrobial drug in the past is all strong.
Formula I
Report among the patent WO2004035539: with compound (III) is starting raw material, directly with side chain (formula II) condensation after, obtain tebipenem and lie prostrate ester.
Visible by above-mentioned patent, side chain (II) is the key intermediate of a synthetic tebipenem volt ester.
Having reported the compound method (like figure below) of side chain (formula II) in the document (Chem.Pharm.Bull.2006,54 (10) 1408~1411), is starting raw material with benzylamine and epoxy chloropropane; Change into Bunte salt 5 through the closed loop methylsulfonyl; With 2-methylthio group-4, obtain compound 7,7 after the reaction of 5-thiazoline quinoline and obtain compound (formula IV) in oxidation; Compound (IV) fracture cystine linkage obtains 3-sulfydryl-1-(1,3 thiazoline-2-yl) azetidine hydrochloride (II).
The document discovers in the product 10% oxidation products (IV) is arranged all the time when directly synthesizing side chain (II) by compound 7, and can't remove.Point out also among the patent JP9278776 that when disulphide (IV) directly obtained compound (II), purity (84.8%) content (86.7%) was generally lower.In order to address this problem, to obtain disulphide (IV) back fracture cystine linkage through oxidation and obtain compound (II).When synthetic compound (II), need to feed hydrogen chloride gas, equipment there is bigger corrosion; Because compound (II) is a hydrochloride, be prone to the moisture absorption simultaneously, preparation and preservation are not easy; When reacting, need add the organic bases more than the molar weight twice, increase production cost with parent nucleus (III).
Summary of the invention
Technical problem to be solved by this invention is the above-mentioned deficiency that exists in the above-mentioned existing method in order to overcome; And the preparation method of a kind of new tebipenem volt ester is provided; Wherein, Directly use the dimeric compounds (IV) of compound (II) to adopt the reaction of " treating different things alike " to prepare tebipenem ester (compound I) with compound (III), thus the tebipenem side chain (being compound I I) of having avoided using the very easily moisture absorption, preparation and preservation to be difficult for.Preparing method of the present invention is easy and simple to handle, and aftertreatment is simple, and product yield is high, and purity is high, is suitable for suitability for industrialized production.
Therefore, the present invention relates to a kind of preparation method suc as formula the volt ester of the tebipenem shown in the I, it comprises the following step: under the protection of inert gas, in organic solvent and the water, at (R
1)
3Under the effect of P and organic bases, compound III and compound IV are carried out reaction as follows, get final product;
Wherein, the volume ratio of organic solvent and water is 1000: 1~20: 1; The temperature of described reaction is-40~50 ℃; R
1Alkyl for phenyl or 2 to 8 carbon atoms.
Wherein, the preferred butyl of alkyl of described 2 to 8 carbon atoms.
Wherein, described organic solvent is the conventional solvent in this area, each raw material of solubilized, and reactionlessness got final product.Can be selected from acetone, butanone, acetonitrile, THF, N; Dinethylformamide, N; In N-DEF, dioxane, DMSO 99.8MIN., ETHYLE ACETATE, propyl acetate, butylacetate, methylene dichloride, trichloromethane, methyl alcohol, ethanol, propyl alcohol and the butanols one or more, one or more in preferred acetonitrile, ETHYLE ACETATE and the THF.Total consumption of organic solvent and water can be the required solvent load of popular response, with the volume mass of compound III than preferable be 5.0~100ml/g.
What the volume ratio of organic solvent and water was preferable is 100: 1~20: 1.
Described organic bases is the organic bases of the conventional conditioned reaction pH in this area, and preferable have in the substituent substituted pyridines etc. one or more for having on triethylamine, diethylamine, aniline, the phenyl ring on substituent substituted aniline, diisopropylethylamine, diisopropylamine, N-methylmorpholine, tetramethyl guanidine, pyridine and the pyridine ring; Wherein, the substituting group on phenyl ring or the pyridine ring is one or more in methyl, ethyl, sec.-propyl, the tertiary butyl, formyl radical, methoxyl group, oxyethyl group, nitro and the amino.In the preferred diisopropylethylamine of described organic bases, triethylamine, lutidine and the tetramethyl guanidine one or more.
The consumption of organic bases can be the popular response consumption, 0.1~3.0 times of the molar weight of compound III that preferable is.
Described (R
1)
3The consumption of P can be the popular response consumption, 0.2~1.0 times of the molar weight of compound III that preferable is.
What the temperature of described reaction was preferable is-40~50 ℃.The time of described reaction can detection reaction fully till, be generally 1~5 hour.
Preferable, the preparation method of an above-mentioned tebipenem volt ester I comprises the following step:
Step (1): under the protection of inert gas, in organic solvent and water, with compound IV and (R
1)
3P was-40~50 ℃ of reactions 10 minutes to 20 hours;
Step (2): under the protection of inert gas, step (1) gained reaction solution under the effect of organic bases, is reacted 10 minutes by 20 hours at-40~50 ℃, get final product.
Each condition in above-mentioned steps (1) and (2) if no special instructions, and is all ditto said.
In the step (1), what described temperature of reaction was preferable is-20~35 ℃.What the time of reaction was preferable is 10 minutes~5 hours, preferred 0.5~5 hour.
In the step (2), what described temperature of reaction was preferable is-20~25 ℃.What the time of reaction was preferable is 10 minutes~7 hours, preferred 2~7 hours.
After above-mentioned reaction is accomplished, can carry out aftertreatment, the preferred following post-treating method of the present invention by the conventional post-treating method in this area:
Step (1 '): with above-mentioned reaction solution and polar aprotic solvent and the mixing of initiate water, transferring pH is 2.0~6.0, separatory, and it is 7.0~10.0 that water layer is transferred pH, and water layer is used organic solvent extraction with extraction, with the organic layer washing, drying, concentrated, get final product;
Step (2 '): temperature is controlled at-40~40 ℃ (preferred-20~30 ℃), with step (1 ') gained reaction solution crystallization under the effect of recrystallisation solvent, gets final product.Behind crystallization, can obtain crystal, as filtering and drying by the method for routine.
In the step (1 '), described polar aprotic solvent can be selected from one or more in ETHYLE ACETATE, propyl acetate, butylacetate and the methylene dichloride etc.Described extraction can be selected from ETHYLE ACETATE, propyl acetate, butylacetate and the methylene dichloride etc. one or more with organic solvent.
In the step (2 '), preferable is stirred crystallization.Crystallization time can be 10min~20h, preferred 1h~5h.
Described recrystallisation solvent can be conventional recrystallisation solvent, and the recrystallisation solvent of described routine is preferable is in acetonitrile, THF, methylene dichloride, methyl alcohol, ethanol, sherwood oil, ETHYLE ACETATE, methyl acetate, n-butyl acetate and the ethyl formate one or more.Preferable is the mixed crystallization solvent, and the mixed solvent (like ETHYLE ACETATE and normal hexane) like polarity and non-polar solvent carries out mixed solvent crystallization.
The volume ratio of described recrystallisation solvent and step (1 ') gained material can confirm that preferable is 1: 1~100: 1 by conventional knowledge, and better is 5: 1~20: 1.If carry out mixed solvent crystallization, what the volume ratio of polarity and non-polar solvent was preferable is 10: 1~1: 10.
On the basis that meets this area general knowledge, above-mentioned each optimum condition, but arbitrary combination promptly get each preferred embodiments of the present invention.
Agents useful for same of the present invention and raw material are all commercially available to be got.
Positive progressive effect of the present invention is: preparation method of the present invention is easy and simple to handle, the tebipenem side chain (being compound I I) of having avoided using the very easily moisture absorption, preparation and preservation to be difficult for; Aftertreatment is simple, and product yield is high, and purity is high, is suitable for suitability for industrialized production.
Embodiment
Mode through embodiment further specifies the present invention below, but does not therefore limit the present invention among the described scope of embodiments.The experimental technique of unreceipted actual conditions in the following example according to ordinary method and condition, or is selected according to catalogue.
Below among each embodiment, described room temperature is 20~35 ℃.Described purity is HPLC purity.
Embodiment 1
Under nitrogen protection, with compound (IV) (20.8g, 0.06mol), tributyl phosphorus (24.6g) and water (2.16g) is added in the 300mL acetonitrile; Stir 40min under the room temperature; Reaction solution is cooled to-10 ℃, add again compound (III) (57.4g, 0.10mol), drip diisopropylethylamine (20.9mL; 0.12mmol), drip-10 ℃ of reactions in back 4h.
Add 500mL ETHYLE ACETATE and 200mL water, it is 4.6 that the aqueous solution is adjusted to acid pH, separatory, and the water intaking layer, it is 7.8 that water layer is transferred alkaline pH, ethyl acetate extraction 2 times (600mL*2), the organic layer washing, the saturated common salt washing, anhydrous magnesium sulfate drying filters, and concentrates.
Add 100mL ETHYLE ACETATE, heating for dissolving drips the 100mL normal hexane, slowly cools to below 0 ℃, stirs 2h under the equality of temperature, filters, and drying obtains target compound (I) 47.1g, yield 94.7%, purity 97.1%.
Embodiment 2
Under argon shield, with compound (IV) (20.8g, 0.06mol), tributyl phosphorus (26.7g) and water (2.16g) is added in the 500mL acetonitrile; Stir 50min under the room temperature; Reaction solution is cooled to-10 ℃, add again compound (III) (57.4g, 0.10mol), drip triethylamine (10.1g; 0.10mmol), drip-10 ℃ of reactions in back 7h.
Add 400mL ETHYLE ACETATE and 200mL water, it is 4.6 that the aqueous solution is adjusted to acid pH, separatory, and the water intaking layer, it is 8.2 that water layer is transferred alkaline pH, ethyl acetate extraction 2 times (500mL*2), the organic layer washing, the saturated common salt washing, anhydrous magnesium sulfate drying filters, and concentrates.
Add 200mL ETHYLE ACETATE, heating for dissolving slowly cools to below 0 ℃, stirs 1h under the equality of temperature, filters, and drying obtains target compound (I) 45.8g, yield 92.2%, purity 99.2%.
Embodiment 3
Under nitrogen protection, with compound (IV) (20.8g, 0.06mol), tributyl phosphorus (30.3g) and water (2.16g) is added in the 1000mL acetonitrile; Stir 20min under the room temperature; Reaction solution is cooled to-10 ℃, add again compound (III) (57.4g, 0.10mol), drip tetramethyl guanidine (23.6g; 0.20mmol), drip-10 ℃ of reactions in back 5h.
Add 500mL ETHYLE ACETATE and 250mL water, it is 3.9 that the aqueous solution is adjusted to acid pH, separatory, and the water intaking layer, it is 8.0 that water layer is transferred alkaline pH, ethyl acetate extraction 2 times (550mL*2), the organic layer washing, the saturated common salt washing, anhydrous magnesium sulfate drying filters, and concentrates.
Add 100mL ETHYLE ACETATE, heating for dissolving drips the 200mL normal hexane, slowly cools to below 0 ℃, stirs 4h under the equality of temperature, filters, and drying obtains target compound (I) 44.8g, yield 90.1%, purity 96.1%.
Embodiment 4
Under argon shield, with compound (IV) (20.8g, 0.06mol), triphenyl phosphorus (25.8g) and water (2.16g) is added in the 300mL acetonitrile; Stir 2h under the room temperature; Reaction solution is cooled to-10 ℃, add again compound (III) (57.4g, 0.10mol), drip diisopropylethylamine (41.8mL; 0.24mmol), drip-20 ℃ of reactions in back 10h.
Add 550mL ETHYLE ACETATE and 200mL water, it is 4.2 that the aqueous solution is adjusted to acid pH, separatory, and the water intaking layer, it is 7.6 that water layer is transferred alkaline pH, ethyl acetate extraction 2 times (600mL*2), the organic layer washing, the saturated common salt washing, anhydrous magnesium sulfate drying filters, and concentrates.
Add the 200mL methyl acetate, heating for dissolving drips the 300mL normal heptane, slowly cools to below 0 ℃, stirs 2h under the equality of temperature, filters, and drying obtains target compound (I) 46.5g, yield 93.5%, purity 96.7%.
Embodiment 5
Under nitrogen protection, with compound (IV) (20.8g, 0.06mol), tributyl phosphorus (24.6g) and water (2.16g) is added in the 300mL acetonitrile; Stir 50min under the room temperature; Reaction solution is cooled to-10 ℃, add again compound (III) (57.4g, 0.10mol), drip diisopropylethylamine (24.4mL; 0.14mmol), drip back room temperature reaction 4h.
Add 500mL ETHYLE ACETATE and 200mL water, it is 5.6 that the aqueous solution is adjusted to acid pH, separatory, and the water intaking layer, it is 7.8 that water layer is transferred alkaline pH, ethyl acetate extraction 2 times (600mL*2), the organic layer washing, the saturated common salt washing, anhydrous magnesium sulfate drying filters, and concentrates.
Add 100mL ETHYLE ACETATE, heating for dissolving drips the 250mL normal heptane, slowly cools to below 0 ℃, stirs 2h under the equality of temperature, filters, and drying obtains target compound (I) 48.1g, yield 96.8%, purity 98.5%.
Embodiment 6
Under argon shield, with compound (IV) (20.8g, 0.06mol), tributyl phosphorus (24.6g) and water (2.16g) is added in the 300mL THF; Stir 30min under the room temperature; Reaction solution is cooled to-10 ℃, add again compound (III) (57.4g, 0.10mol), drip diisopropylethylamine (20.9mL; 0.12mmol), drip back room temperature reaction 4h.
Add 500mL ETHYLE ACETATE and 200mL water, it is 2.3 that the aqueous solution is adjusted to acid pH, separatory, and the water intaking layer, it is 8.6 that water layer is transferred alkaline pH, ethyl acetate extraction 2 times (600mL*2), the organic layer washing, the saturated common salt washing, anhydrous magnesium sulfate drying filters, and concentrates.
Add the 100mL methyl acetate, heating for dissolving drips the 100mL normal hexane, slowly cools to below 0 ℃, stirs 3h under the equality of temperature, filters, and drying obtains target compound (I) 45.6g, yield 92.0%, purity 98.9%.
Embodiment 7
Under nitrogen protection, with compound (IV) (20.8g, 0.06mol), tributyl phosphorus (24.6g) and water (4.32g) is added in the 200mL ETHYLE ACETATE; Stir 50min under the room temperature; Reaction solution is cooled to-10 ℃, add again compound (III) (57.4g, 0.10mol), drip triethylamine (20.2g; 0.20mmol), drip-30 ℃ of reactions in back 15h.
Add 200mL ETHYLE ACETATE and 200mL water, it is 3.6 that the aqueous solution is adjusted to acid pH, separatory, and the water intaking layer, it is 7.8 that water layer is transferred alkaline pH, ethyl acetate extraction 2 times (600mL*2), the organic layer washing, the saturated common salt washing, anhydrous magnesium sulfate drying filters, and concentrates.
Add 100mL ETHYLE ACETATE, heating for dissolving drips the 150mL normal heptane, slowly cools to below 0 ℃, stirs 2h under the equality of temperature, filters, and drying obtains target compound (I) 45.3g, yield 91.6%, purity 95.8%.
Embodiment 8
Under argon shield; With compound (IV) (20.8g; 0.06mol), tributyl phosphorus (0.3mol) and water (1ml) is added in the 1000mL THF, stirs 40min under the room temperature, reaction solution is cooled to-40 ℃; Add again compound (III) (0.10mol), drip N-methylmorpholine (0.12mol), drip back 30 ℃ of reaction 2h.
Add 500mL methylene dichloride and 200mL water, it is 3.0 that the aqueous solution is transferred pH, separatory, and the water intaking layer, it is 7.0 that water layer is transferred pH, dichloromethane extraction 2 times (600mL*2), the organic layer washing, the saturated common salt washing, anhydrous magnesium sulfate drying filters, and concentrates.
Add 100mL ETHYLE ACETATE, heating for dissolving drips the 100mL normal hexane, slowly cools to-40 ℃, stirs 2h under the equality of temperature, filters, and drying obtains target compound (I) 46.8g, yield 94.7%, purity 97%.
Embodiment 9
Under nitrogen protection; With compound (IV) (20.8g, 0.06mol), tributyl phosphorus (0.3mol) and water (10ml) is added to 600mLN, in the dinethylformamide; Stirred 20 hours under the room temperature; Reaction solution is cooled to-40 ℃, add again compound (III) (0.10mol), drip N-methylmorpholine (0.12mol), drip back 30 ℃ of reactions 10 minutes.
Add 500mL ETHYLE ACETATE and 200mL water, it is 4.0 that the aqueous solution is transferred pH, separatory, and the water intaking layer, it is 10.0 that water layer is transferred pH, ethyl acetate extraction 2 times (600mL*2), the organic layer washing, the saturated common salt washing, anhydrous magnesium sulfate drying filters, and concentrates.
Add 100mL ETHYLE ACETATE, heating for dissolving drips the 100mL MTBE, and 50 ℃ are stirred 2h, filter, and drying obtains target compound (I) 44.8g, yield 90.7%, purity 97%.
Embodiment 10
Under argon shield; With compound (IV) (20.8g; 0.06mol), tributyl phosphorus (0.02mol) and water (15ml) is added in the 300mL DMSO 99.8MIN. ,-20 ℃ were stirred 20 hours, reaction solution is cooled to-40 ℃; Add again compound (III) (0.10mol), drip lutidine (0.12mol), drip 4h under the room temperature of back.
Add 500mL ETHYLE ACETATE and 200mL water, it is 4.0 that the aqueous solution is transferred pH, separatory, and the water intaking layer, it is 9.0 that water layer is transferred pH, ethyl acetate extraction 2 times (600mL*2), the organic layer washing, the saturated common salt washing, anhydrous magnesium sulfate drying filters, and concentrates.
Add 100mL ETHYLE ACETATE, heating for dissolving drips the 100mL MTBE, and 50 ℃ are stirred 2h, filter, and drying obtains target compound (I) 44.7g, yield 90.2%, purity 97%.
Embodiment 11
Under nitrogen protection; With compound (IV) (20.8g; 0.06mol), tributyl phosphorus (0.02mol) and water (10ml) is added in the 1000mL DMSO 99.8MIN., stirs 2 hours under the room temperature, reaction solution is cooled to-40 ℃; Add again compound (III) (0.10mol), drip lutidine (0.12mol), drip back 40 ℃ of reactions 2 hours.
Add 500mL ETHYLE ACETATE and 200mL water, it is 6.0 that the aqueous solution is transferred pH, separatory, and the water intaking layer, it is 9.3 that water layer is transferred pH, ethyl acetate extraction 2 times (600mL*2), the organic layer washing, the saturated common salt washing, anhydrous magnesium sulfate drying filters, and concentrates.
Add 100mL ETHYLE ACETATE, heating for dissolving drips the 100mL normal heptane, and 50 ℃ are stirred 2h, filter, and drying obtains target compound (I) 45.7g, yield 92.1%, purity 97%.
Comparative example (method according to contrast patent CN101891756 is carried out)
Under nitrogen protection, with compound (IV) (20.8g, 0.06mol), (20.9mL 0.12mmol) is added in the 300mL acetonitrile successively, reaction 6h for tributyl phosphorus (24.6g), compound (III), diisopropylethylamine.
Add 500mL ETHYLE ACETATE and 200mL water, the aqueous solution is adjusted to acidity, separatory, and the water intaking layer, water layer is transferred alkalescence, ethyl acetate extraction 2 times (600mL*2), the organic layer washing, the saturated common salt washing, anhydrous magnesium sulfate drying filters, and concentrates.
Add 100mL ETHYLE ACETATE, heating for dissolving drips the 100mL normal hexane, slowly cools to below 0 ℃, stirs 2h under the equality of temperature, filters, and drying obtains target compound (I) 31.1g, yield 62.7%, purity 80.1%.
The physical detection result of the compound that each embodiment makes (I) is all following:
Fusing point: 136~140 ℃;
Outward appearance: white powder crystal;
IR(KBr):3162.7,2961.1,2863.5,1778.6,1752.7,1609.6,1541.2,1376.8,1345.9,1278.3,1117.5;
1H-NMR(400MHz,CDCl
3):δ1.176~1.199(3H,d,J=9.2Hz),1.214(9H,s),1.275~1.290(3H,d,J=6.0Hz),3.171~3.208(1H,dq,J=8.8,3.6Hz),3.219~3.225(1H,dd,J=4.4,2.4Hz),3.333~3.370(2H,t,J=14.8Hz),3.904~3.996(4H,m),4.140~4.218(3H,m),4.367~4.551(2H,m),5.811~5.942(2H,m);
HRMS(FAB):C
22H
31N
3O
6S
2,m/z?497.31(M+H)
+。
Claims (13)
1. the preparation method suc as formula the volt ester of the tebipenem shown in the I is characterized in that comprising the following step: under the protection of inert gas, in organic solvent and the water, at (R
1)
3Under the effect of P and organic bases, compound III and compound IV are carried out reaction as follows, get final product;
Wherein, the volume ratio of organic solvent and water is 1000: 1~20: 1; The temperature of described reaction is-40~50 ℃; R
1Alkyl for phenyl or 2 to 8 carbon atoms.
2. preparation method as claimed in claim 1 is characterized in that: the alkyl of described 2 to 8 carbon atoms is a butyl.
3. preparation method as claimed in claim 1; It is characterized in that: described organic solvent is selected from acetone, butanone, acetonitrile, THF, N; Dinethylformamide, N, one or more in N-DEF, dioxane, DMSO 99.8MIN., ETHYLE ACETATE, propyl acetate, butylacetate, methylene dichloride, trichloromethane, methyl alcohol, ethanol, propyl alcohol and the butanols.
4. preparation method as claimed in claim 1 is characterized in that: the volume ratio of described organic solvent and water is 100: 1~20: 1.
5. preparation method as claimed in claim 1 is characterized in that: described organic bases is to have on triethylamine, diethylamine, aniline, the phenyl ring to have in substituent substituted pyridines etc. one or more on substituent substituted aniline, diisopropylethylamine, diisopropylamine, N-methylmorpholine, tetramethyl guanidine, pyridine and the pyridine ring; Wherein, the substituting group on phenyl ring or the pyridine ring is one or more in methyl, ethyl, sec.-propyl, the tertiary butyl, formyl radical, methoxyl group, oxyethyl group, nitro and the amino.
6. preparation method as claimed in claim 1 is characterized in that: the consumption of described organic bases is 0.1~3.0 times of molar weight of compound III.
7. preparation method as claimed in claim 1 is characterized in that: described (R
1)
3The consumption of P is 0.2~1.0 times of molar weight of compound III.
8. preparation method as claimed in claim 1 is characterized in that: the temperature of described reaction is-40~50 ℃; The time of described reaction with detection reaction fully till.
9. like each described preparation method of claim 1~8, it is characterized in that: the preparation method of a described tebipenem volt ester I comprises the following step:
Step (1): under the protection of inert gas, in organic solvent and water, with compound IV and (R
1)
3P was-40~50 ℃ of reactions 10 minutes to 20 hours;
Step (2): under the protection of inert gas, step (1) gained reaction solution under the effect of organic bases, is reacted 10 minutes by 20 hours at-40~50 ℃, get final product.
10. preparation method as claimed in claim 9 is characterized in that:
In the step (1), described temperature of reaction is-20~35 ℃; The time of reaction is 10 minutes~5 hours;
And/or in the step (2), described temperature of reaction is-20~25 ℃; The time of reaction is 10 minutes~7 hours.
11. preparation method as claimed in claim 10 is characterized in that: in the step (1), the time of described reaction is 0.5~5 hour;
And/or in the step (2), the time of described reaction is 2~7 hours.
12. preparation method as claimed in claim 1 is characterized in that: after reaction is accomplished, carry out aftertreatment by following post-treating method:
Step (1 '): with above-mentioned reaction solution and polar aprotic solvent and the mixing of initiate water, transferring pH is 2.0~6.0, separatory, and it is 7.0~10.0 that water layer is transferred pH, and water layer is used organic solvent extraction with extraction, with the organic layer washing, drying, concentrated, get final product;
Step (2 '): temperature is controlled at-40~50 ℃, with step (1 ') gained reaction solution crystallization under the effect of recrystallisation solvent, gets final product.
13. preparation method as claimed in claim 1 is characterized in that:
In the step (1 '), described polar aprotic solvent is selected from one or more in ETHYLE ACETATE, propyl acetate, butylacetate and the methylene dichloride etc.; Described extraction is selected from ETHYLE ACETATE, propyl acetate, butylacetate and the methylene dichloride etc. one or more with organic solvent;
And/or in the step (2 '), described recrystallisation solvent is one or more in acetonitrile, THF, methylene dichloride, methyl alcohol, ethanol, sherwood oil, ETHYLE ACETATE, methyl acetate, n-butyl acetate and the ethyl formate;
The volume ratio of described recrystallisation solvent and step (1 ') gained material is 1: 1~100: 1.
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CN1708504A (en) * | 2002-11-13 | 2005-12-14 | 株式会社钟化 | Novel intermediate for carbapenem compound for oral administration and process for producing the same |
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Non-Patent Citations (1)
Title |
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TAKESHI ISODA ET AL.: "A Practical and Facile Synthesis of Azetidine Derivatives for Oral Carbapenem, L-084", 《CHEM. PHARM. BULL.》, vol. 54, no. 10, 7 August 2006 (2006-08-07), pages 1408 - 1411 * |
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