CN102775410B - A kind of preparation method of L-084 - Google Patents
A kind of preparation method of L-084 Download PDFInfo
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- CN102775410B CN102775410B CN201110120220.4A CN201110120220A CN102775410B CN 102775410 B CN102775410 B CN 102775410B CN 201110120220 A CN201110120220 A CN 201110120220A CN 102775410 B CN102775410 B CN 102775410B
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Abstract
The invention discloses the preparation method of a kind of L-084 shown in formula I, it comprises the steps of under inert gas shielding, in organic solvent and water, at (R1)3Under the effect of P and organic base, compound III and compound IV is carried out reaction as follows,；Wherein, the volume ratio of organic solvent and water is 1000: 1～20: 1；The temperature of described reaction is 40～50 DEG C；R1For phenyl or the alkyl of 2 to 8 carbon atoms.The preparation method of the present invention is easy and simple to handle, and post processing is simple, and product yield is high, and purity is high, is suitable to industrialized production.
Description
Technical field
The present invention relates to the preparation method of a kind of L-084.
Background technology
L-084 is first oral carbapenems in the world of Meiji Seika Kaisba company of Japan research and development
Antibiotic, on August 26th, 2009 in Japan's Initial Public Offering.
L-084 (Formulas I) is the prodrug of tebipenem.L-084 is broad spectrum antibiotic, to leather orchid
Family name's positive bacteria and gram negative bacteria are all effective, to staphylococcus, streptococcus, streptococcus pneumoniae (including PRSP), catarrhalis (cloth
Blue Han Shi) (including beta lactamase producing strains), hemophilus influenza (including ampicillin-resistant type hemophilus influenza) etc.
There is potent antibacterial action, particularly to causing otitis media in children, nasal sinusitis and the strain of pneumonia.To Penicillin-resistant
Type streptococcus pneumoniae, the pneumococcal antimicrbial power of macrolide drug-resistant type is stronger than the antimicrbial power of conventional oral antimicrobial drug.
Formulas I
Patent WO2004035539 is reported: with compound (III) as initiation material, be directly condensed with side chain (Formula II)
After, obtain L-084.
From above-mentioned patent, side chain (II) is the key intermediate of synthesis L-084.
Document (Chem.Pharm.Bull.2006,54 (10) 1408～1411) reports the synthesis side of side chain (Formula II)
Method (below figure), with benzylamine and epoxychloropropane as initiation material, is melted into Bunte salt 5 through closed loop methylsulfonyl, with 2-first sulfur
Base-4, obtain compound 7 after the reaction of 5-thiazoline quinoline, 7 obtain compound (formula IV), the double sulfur of compound (IV) fracture in oxidation
Key obtains 3-sulfydryl-1-(1,3 thiazoline-2-base) azetidine hydrochloride (II).
Document research finds, compound 7 have 10% oxidation product all the time in product when being directly synthesized side chain (II)
, and cannot remove (IV).Patent JP9278776 also indicates that, directly obtains compound (II) without disulphide (IV)
Time, purity (84.8%) content (86.7%) is the most relatively low.In order to solve this problem, obtain disulphide (IV) by oxidation
Rear fracture cystine linkage obtains compound (II).When synthesizing compound (II), need to be passed through hydrogen chloride gas, equipment is had bigger corruption
Erosion, simultaneously because compound (II) is hydrochlorate, the easy moisture absorption, prepares and preservation is not easy, the needs when reacting with parent nucleus (III)
Add the organic base of more than mole twice, add production cost.
Summary of the invention
The technical problem to be solved is to overcome above-mentioned deficiency present in above-mentioned existing method, and provides
A kind of preparation method of new L-084, wherein, directly use the dimeric compounds (IV) of compound (II) with
The reaction of compound (III) employing " treating different things alike " is to prepare L-084 (compound I), thus avoids use and easily inhale
Tide, prepare and preserve the tebipenem side chain (i.e. compound II) being difficult to.The preparation method of the present invention is easy and simple to handle, post processing letter
Single, product yield is high, and purity is high, is suitable to industrialized production.
Therefore, the present invention relates to the preparation method of a kind of L-084 shown in formula I, it comprises following step
Rapid: under inert gas shielding, in organic solvent and water, at (R1)3Under the effect of P and organic base, by compound III and compound
IV carries out reaction as follows,；
Wherein, the volume ratio of organic solvent and water is 1000: 1～20: 1；The temperature of described reaction is-40～50 DEG C；
R1For phenyl or the alkyl of 2 to 8 carbon atoms.
Wherein, the preferred butyl of alkyl of 2 to 8 described carbon atoms.
Wherein, described organic solvent is this area Conventional solvents, each raw material of solubilized, and to reactionlessness.Can
Selected from acetone, butanone, acetonitrile, oxolane, DMF, N, N-diethylformamide, dioxane, dimethyl
In sulfoxide, ethyl acetate, propyl acetate, butyl acetate, dichloromethane, chloroform, methanol, ethanol, propanol and butanol one
Plant or multiple, preferably one or more in acetonitrile, ethyl acetate and oxolane.Total consumption of organic solvent and water can be normal
The required solvent load of rule reaction, is 5.0～100ml/g with the volume mass of compound III than preferably.
The volume ratio of organic solvent and water is preferably 100: 1～20: 1.
Described organic base is the organic base regulating reaction pH that this area is conventional, is preferably triethylamine, diethylamine, benzene
The substituted aniline of substituted base, diisopropylethylamine, diisopropylamine, N-methylmorpholine, tetramethyl guanidine, pyridine on amine, phenyl ring
With one or more in substituted pyridines on pyridine ring with substituent group etc.；Wherein, the substituent group on phenyl ring or pyridine ring is
One or more in methyl, ethyl, isopropyl, the tert-butyl group, formoxyl, methoxyl group, ethyoxyl, nitro and amino.Described
One or more in the preferred diisopropylethylamine of organic base, triethylamine, lutidines and tetramethyl guanidine.
The consumption of organic base can be popular response consumption, is preferably 0.1～3.0 times of mole of compound III.
Described (R1)3The consumption of P can be popular response consumption, be preferably compound III mole 0.2～1.0
Times.
The temperature of described reaction is preferably-40～50 DEG C.The time of described reaction can be detected reaction and be entirely
Only, generally 1～5 hour.
It is also preferred that the left the preparation method of above-mentioned L-084 I comprises the steps of
Step (1): under inert gas shielding, in organic solvent and water, by compound IV and (R1)3P is at-40～50 DEG C
React 10 minutes to 20 hours；
Step (2): under inert gas shielding, by step (1) gained reactant liquor under the effect of organic base ,-40～50
DEG C reaction 10 minutes to 20 hours,.
Each condition in above-mentioned steps (1) and (2) is if no special instructions, all the same described.
In step (1), described reaction temperature is preferably-20～35 DEG C.The time of reaction is preferably 10 minutes～5
Hour, preferably 0.5～5 hour.
In step (2), described reaction temperature is preferably-20～25 DEG C.The time of reaction is preferably 10 minutes～7
Hour, preferably 2～7 hours.
After above-mentioned reaction completes, can carry out post processing by the post-processing approach that this area is conventional, the present invention is the most following
Post-processing approach:
Step (1 '): by above-mentioned reactant liquor and polar non-solute and the water mixing being newly added, adjust pH be 2.0～
6.0, separatory, it is 7.0～10.0 that water layer is adjusted pH, is extracted by water layer extraction organic solvent, is washed by organic layer, is dried,
Concentrate,；
Step (2 '): temperature controls at-40～40 DEG C (preferably-20～30 DEG C), by step (1 ') gained reactant liquor at knot
Crystallize under the effect of brilliant solvent,.Crystal can be obtained by a conventional method, as filtered and being dried after crystallize.
In step (1 '), described polar non-solute is selected from ethyl acetate, propyl acetate, butyl acetate and dichloro
One or more in methane etc..Described extraction organic solvent is selected from ethyl acetate, propyl acetate, butyl acetate and two
One or more in chloromethanes etc..
In step (2 '), it it is preferably stirred crystallization.Crystallization time can be 10min～20h, preferably 1h～5h.
Described recrystallisation solvent can be conventional recrystallisation solvent, described conventional recrystallisation solvent be preferably acetonitrile, four
In hydrogen furan, dichloromethane, methanol, ethanol, petroleum ether, ethyl acetate, methyl acetate, n-butyl acetate and Ethyl formate one
Plant or multiple.Be preferably mixed crystallization solvent, as polarity and non-polar solven mixed solvent (as ethyl acetate and just oneself
Alkane), carry out mixed solvent crystallization.
Described recrystallisation solvent can knowledge determine routinely with the volume ratio of step (1 ') gained material, is preferably 1: 1
～100: 1, it is more preferably 5: 1～20: 1.If the volume ratio carrying out mixed solvent crystallization, polarity and non-polar solven is preferably
10: 1～1: 10.
On the basis of meeting common sense in the field, above-mentioned each optimum condition, can combination in any, obtain each preferable reality of the present invention
Example.
Agents useful for same of the present invention and raw material are the most commercially.
The actively progressive effect of the present invention is: the preparation method of the present invention is easy and simple to handle, avoid use easily the moisture absorption,
The tebipenem side chain (i.e. compound II) that preparation and preservation are difficult to；Post processing is simple, and product yield is high, and purity is high, is suitable to work
Industry metaplasia is produced.
Detailed description of the invention
Further illustrate the present invention below by the mode of embodiment, but the most therefore limit the present invention to described reality
Execute among example scope.The experimental technique of unreceipted actual conditions in the following example, conventionally and condition, or according to business
Product description selects.
In following embodiment, described room temperature is 20～35 DEG C.Described purity is HPLC purity.
Embodiment 1
Under nitrogen protection, compound (IV) (20.8g, 0.06mol), tributyl phosphorus (24.6g) and water (2.16g) are added
Enter to 300mL acetonitrile, under room temperature stir 40min, reactant liquor is cooled to-10 DEG C, add compound (III) (57.4g,
0.10mol), drip diisopropylethylamine (20.9mL, 0.12mmol) ,-10 DEG C of reaction 4h after dripping.
Adding 500mL ethyl acetate and 200mL water, it is 4.6 that aqueous solution is adjusted to acid pH, separatory, layer of fetching water, water layer alkali tune
Property pH be 7.8, ethyl acetate extract 2 times (600mL*2), organic layer wash, saturated common salt wash, anhydrous magnesium sulfate is dried, mistake
Filter, concentrates.
Add 100mL ethyl acetate, heating for dissolving, drip 100mL normal hexane, slowly cool to stir under less than 0 DEG C, equality of temperature
Mix 2h, filter, be dried to obtain target compound (I) 47.1g, yield 94.7%, purity 97.1%.
Embodiment 2
Under argon shield, compound (IV) (20.8g, 0.06mol), tributyl phosphorus (26.7g) and water (2.16g) are added
Enter to 500mL acetonitrile, under room temperature stir 50min, reactant liquor is cooled to-10 DEG C, add compound (III) (57.4g,
0.10mol), drip triethylamine (10.1g, 0.10mmol) ,-10 DEG C of reaction 7h after dripping.
Adding 400mL ethyl acetate and 200mL water, it is 4.6 that aqueous solution is adjusted to acid pH, separatory, layer of fetching water, water layer alkali tune
Property pH be 8.2, ethyl acetate extract 2 times (500mL*2), organic layer wash, saturated common salt wash, anhydrous magnesium sulfate is dried, mistake
Filter, concentrates.
Add 200mL ethyl acetate, heating for dissolving, slowly cool to less than 0 DEG C, stir 1h under equality of temperature, filter, be dried
To target compound (I) 45.8g, yield 92.2%, purity 99.2%.
Embodiment 3
Under nitrogen protection, compound (IV) (20.8g, 0.06mol), tributyl phosphorus (30.3g) and water (2.16g) are added
Enter to 1000mL acetonitrile, under room temperature stir 20min, reactant liquor is cooled to-10 DEG C, add compound (III) (57.4g,
0.10mol), drip tetramethyl guanidine (23.6g, 0.20mmol) ,-10 DEG C of reaction 5h after dripping.
Adding 500mL ethyl acetate and 250mL water, it is 3.9 that aqueous solution is adjusted to acid pH, separatory, layer of fetching water, water layer alkali tune
Property pH be 8.0, ethyl acetate extract 2 times (550mL*2), organic layer wash, saturated common salt wash, anhydrous magnesium sulfate is dried, mistake
Filter, concentrates.
Add 100mL ethyl acetate, heating for dissolving, drip 200mL normal hexane, slowly cool to stir under less than 0 DEG C, equality of temperature
Mix 4h, filter, be dried to obtain target compound (I) 44.8g, yield 90.1%, purity 96.1%.
Embodiment 4
Under argon shield, compound (IV) (20.8g, 0.06mol), triphenyl phosphorus (25.8g) and water (2.16g) are added
Enter to 300mL acetonitrile, under room temperature stir 2h, reactant liquor is cooled to-10 DEG C, add compound (III) (57.4g,
0.10mol), drip diisopropylethylamine (41.8mL, 0.24mmol) ,-20 DEG C of reaction 10h after dripping.
Adding 550mL ethyl acetate and 200mL water, it is 4.2 that aqueous solution is adjusted to acid pH, separatory, layer of fetching water, water layer alkali tune
Property pH be 7.6, ethyl acetate extract 2 times (600mL*2), organic layer wash, saturated common salt wash, anhydrous magnesium sulfate is dried, mistake
Filter, concentrates.
Add 200mL methyl acetate, heating for dissolving, drip 300mL normal heptane, slowly cool to stir under less than 0 DEG C, equality of temperature
Mix 2h, filter, be dried to obtain target compound (I) 46.5g, yield 93.5%, purity 96.7%.
Embodiment 5
Under nitrogen protection, compound (IV) (20.8g, 0.06mol), tributyl phosphorus (24.6g) and water (2.16g) are added
Enter to 300mL acetonitrile, under room temperature stir 50min, reactant liquor is cooled to-10 DEG C, add compound (III) (57.4g,
0.10mol), drip diisopropylethylamine (24.4mL, 0.14mmol), drip rear room temperature reaction 4h.
Adding 500mL ethyl acetate and 200mL water, it is 5.6 that aqueous solution is adjusted to acid pH, separatory, layer of fetching water, water layer alkali tune
Property pH be 7.8, ethyl acetate extract 2 times (600mL*2), organic layer wash, saturated common salt wash, anhydrous magnesium sulfate is dried, mistake
Filter, concentrates.
Add 100mL ethyl acetate, heating for dissolving, drip 250mL normal heptane, slowly cool to stir under less than 0 DEG C, equality of temperature
Mix 2h, filter, be dried to obtain target compound (I) 48.1g, yield 96.8%, purity 98.5%.
Embodiment 6
Under argon shield, compound (IV) (20.8g, 0.06mol), tributyl phosphorus (24.6g) and water (2.16g) are added
Entering to 300mL oxolane, stir 30min under room temperature, reactant liquor is cooled to-10 DEG C, adds compound (III)
(57.4g, 0.10mol), dropping diisopropylethylamine (20.9mL, 0.12mmol), drip rear room temperature reaction 4h.
Adding 500mL ethyl acetate and 200mL water, it is 2.3 that aqueous solution is adjusted to acid pH, separatory, layer of fetching water, water layer alkali tune
Property pH be 8.6, ethyl acetate extract 2 times (600mL*2), organic layer wash, saturated common salt wash, anhydrous magnesium sulfate is dried, mistake
Filter, concentrates.
Add 100mL methyl acetate, heating for dissolving, drip 100mL normal hexane, slowly cool to stir under less than 0 DEG C, equality of temperature
Mix 3h, filter, be dried to obtain target compound (I) 45.6g, yield 92.0%, purity 98.9%.
Embodiment 7
Under nitrogen protection, compound (IV) (20.8g, 0.06mol), tributyl phosphorus (24.6g) and water (4.32g) are added
Entering to 200mL ethyl acetate, stir 50min under room temperature, reactant liquor is cooled to-10 DEG C, adds compound (III)
(57.4g, 0.10mol), dropping triethylamine (20.2g, 0.20mmol) ,-30 DEG C of reaction 15h after dripping.
Adding 200mL ethyl acetate and 200mL water, it is 3.6 that aqueous solution is adjusted to acid pH, separatory, layer of fetching water, water layer alkali tune
Property pH be 7.8, ethyl acetate extract 2 times (600mL*2), organic layer wash, saturated common salt wash, anhydrous magnesium sulfate is dried, mistake
Filter, concentrates.
Add 100mL ethyl acetate, heating for dissolving, drip 150mL normal heptane, slowly cool to stir under less than 0 DEG C, equality of temperature
Mix 2h, filter, be dried to obtain target compound (I) 45.3g, yield 91.6%, purity 95.8%.
Embodiment 8
Under argon shield, compound (IV) (20.8g, 0.06mol), tributyl phosphorus (0.3mol) and water (1ml) are added
Entering to 1000mL oxolane, stir 40min under room temperature, reactant liquor is cooled to-40 DEG C, adds compound (III)
(0.10mol), drip N-methylmorpholine (0.12mol), drip rear 30 DEG C of reaction 2h.
Adding 500mL dichloromethane and 200mL water, aqueous solution adjusts pH to be 3.0, separatory, layer of fetching water, and water layer adjusts pH to be 7.0,
Dichloromethane extraction 2 times (600mL*2), organic layer washing, saturated common salt washing, anhydrous magnesium sulfate is dried, and filters, and concentrates.
Add 100mL ethyl acetate, heating for dissolving, drip 100mL normal hexane, slowly cool to-40 DEG C, stir under equality of temperature
2h, filters, is dried to obtain target compound (I) 46.8g, yield 94.7%, purity 97%.
Embodiment 9
Under nitrogen protection, compound (IV) (20.8g, 0.06mol), tributyl phosphorus (0.3mol) and water (10ml) are added
Entering to 600mLN, in dinethylformamide, stir 20 hours under room temperature, reactant liquor is cooled to-40 DEG C, adds compound
(III) (0.10mol), dropping N-methylmorpholine (0.12mol), drips latter 30 DEG C and reacts 10 minutes.
Adding 500mL ethyl acetate and 200mL water, aqueous solution adjusts pH to be 4.0, separatory, layer of fetching water, and water layer tune pH is
10.0, ethyl acetate extracts 2 times (600mL*2), and organic layer is washed, and saturated common salt is washed, and anhydrous magnesium sulfate is dried, and filters, dense
Contracting.
Add 100mL ethyl acetate, heating for dissolving, drip 100mL methyl tertiary butyl ether(MTBE), 50 DEG C of stirring 2h, filter, be dried
Obtain target compound (I) 44.8g, yield 90.7%, purity 97%.
Embodiment 10
Under argon shield, by compound (IV) (20.8g, 0.06mol), tributyl phosphorus (0.02mol) and water (15ml)
Adding to 300mL dimethyl sulfoxide ,-20 DEG C are stirred 20 hours, and reactant liquor is cooled to-40 DEG C, adds compound (III)
(0.10mol), drip lutidines (0.12mol), drip 4h under rear room temperature.
Adding 500mL ethyl acetate and 200mL water, aqueous solution adjusts pH to be 4.0, separatory, layer of fetching water, and water layer adjusts pH to be 9.0,
Ethyl acetate extracts 2 times (600mL*2), and organic layer is washed, and saturated common salt is washed, and anhydrous magnesium sulfate is dried, and filters, and concentrates.
Add 100mL ethyl acetate, heating for dissolving, drip 100mL methyl tertiary butyl ether(MTBE), 50 DEG C of stirring 2h, filter, be dried
Obtain target compound (I) 44.7g, yield 90.2%, purity 97%.
Embodiment 11
Under nitrogen protection, by compound (IV) (20.8g, 0.06mol), tributyl phosphorus (0.02mol) and water (10ml)
Adding to 1000mL dimethyl sulfoxide, stir 2 hours under room temperature, reactant liquor is cooled to-40 DEG C, adds compound (III)
(0.10mol), drip lutidines (0.12mol), drip latter 40 DEG C and react 2 hours.
Adding 500mL ethyl acetate and 200mL water, aqueous solution adjusts pH to be 6.0, separatory, layer of fetching water, and water layer adjusts pH to be 9.3,
Ethyl acetate extracts 2 times (600mL*2), and organic layer is washed, and saturated common salt is washed, and anhydrous magnesium sulfate is dried, and filters, and concentrates.
Add 100mL ethyl acetate, heating for dissolving, drip 100mL normal heptane, 50 DEG C of stirring 2h, filter, be dried to obtain mesh
Mark compound (I) 45.7g, yield 92.1%, purity 97%.
Comparative example (is carried out according to the method for contrast patent CN101891756)
Under nitrogen protection, by compound (IV) (20.8g, 0.06mol), tributyl phosphorus (24.6g), compound (III),
Diisopropylethylamine (20.9mL, 0.12mmol) is sequentially added into 300mL acetonitrile, reacts 6h.
Adding 500mL ethyl acetate and 200mL water, aqueous solution is adjusted to acidity, separatory, layer of fetching water, water layer alkali tune, acetic acid
Ethyl ester extracts 2 times (600mL*2), and organic layer is washed, and saturated common salt is washed, and anhydrous magnesium sulfate is dried, and filters, and concentrates.
Add 100mL ethyl acetate, heating for dissolving, drip 100mL normal hexane, slowly cool to stir under less than 0 DEG C, equality of temperature
Mix 2h, filter, be dried to obtain target compound (I) 31.1g, yield 62.7%, purity 80.1%.
The physical detection result of the compound (I) that each embodiment prepares is as follows:
Fusing point: 136～140 DEG C；
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, CDCl3): δ 1.176～1.199 (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): C22H31N3O6S2, m/z 497.31 (M+H)+。
Claims (1)
1. the preparation method of a L-084 shown in formula I, it is characterised in that comprise the steps of and protect at nitrogen
Protect down, 20.8g compounds Ⅳ, 24.6g tributyl phosphorus and 2.16g water are added to 300mL acetonitrile, stirs at 20～35 DEG C
50min, reactant liquor is cooled to-10 DEG C, adds 57.4g compound III, drips 24.4mL diisopropylethylamine, drips rear 20
～35 DEG C of reaction 4h；Adding 500mL ethyl acetate and 200mL water, aqueous solution is adjusted to acidity, and pH is 5.6, separatory, layer of fetching water, water
Layer alkali tune, pH is 7.8, and ethyl acetate is extracted 2 times, each 600mL, and organic layer is washed, and saturated common salt is washed, anhydrous magnesium sulfate
It is dried, filters, concentrate；Add 100mL ethyl acetate, heating for dissolving, drip 250mL normal heptane, slowly cool to less than 0 DEG C,
Stir 2h under equality of temperature, filter, be dried to obtain compound I 48.1g, yield 96.8%, HPLC purity 98.5%；
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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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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| Publication number | Priority date | Publication date | Assignee | Title |
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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 |
Non-Patent Citations (1)
| Title |
|---|
| A Practical and Facile Synthesis of Azetidine Derivatives for Oral Carbapenem, L-084;Takeshi Isoda et al.;《Chem. Pharm. Bull.》;20060807;第54卷(第10期);第1408-1411页 * |
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