CN103664948A - Crystal of intermediate of tebipenem pivoxil and preparation method thereof - Google Patents
Crystal of intermediate of tebipenem pivoxil and preparation method thereof Download PDFInfo
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- CN103664948A CN103664948A CN201210324345.3A CN201210324345A CN103664948A CN 103664948 A CN103664948 A CN 103664948A CN 201210324345 A CN201210324345 A CN 201210324345A CN 103664948 A CN103664948 A CN 103664948A
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- KCRXSTJZMCTLQR-OHDICMOHSA-N C[C@H]([C@H]([C@@H]([C@H]1C)N2C(C(OCc3ccc(C)cc3)=O)=C1SC(C1)CN1C1=NCCS1)C2=O)O Chemical compound C[C@H]([C@H]([C@@H]([C@H]1C)N2C(C(OCc3ccc(C)cc3)=O)=C1SC(C1)CN1C1=NCCS1)C2=O)O KCRXSTJZMCTLQR-OHDICMOHSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
- C07D477/10—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
- C07D477/12—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6
- C07D477/16—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6 with hetero atoms or carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 3
- C07D477/20—Sulfur atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
- C07D477/02—Preparation
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Abstract
The invention relates to a crystal of an intermediate of carbapenem antibiotic tebipenem pivoxil and a preparation method thereof. The crystal type of the intermediate comprises a type A crystal of the intermediate of tebipenem pivoxil and a type B crystal of the intermediate of tebipenem pivoxil, wherein in a powder X-ray diffraction pattern, the type A crystal has main peaks when the diffraction angle 2(theta) is 5.90, 8.02, 14.93, 19.30, 22.65, 22.10, 24.16, 26.50 and 26.98; the type B crystal has main peaks when the diffraction angle 2(theta) is 6.76, 8.25, 15.13, 16.35, 17.47, 21.02, 22.31, 31.31 and 32.77. The preparation method of the crystal form mainly comprises a preparation method of the type A crystal of the intermediate and a method for preparing the type B crystal through crystal transformation of the type A crystal.
Description
Technical field
The present invention relates to crystallization of a kind of pharmaceutical intermediate and preparation method thereof, be specifically related to a kind of crystallization and preparation method thereof of intermediate of L-084.
Background technology
L-084 (L-084) is first the oral new carbapenem class medicine by the research and development of Japanese Meiji Seika Kaisba company.This compound is reactive precursor tebipenem C
2the prodrug that position carboxylic esterification forms, orally by esterase hydrolyzed, discharged active parent drug tebipenem afterwards, tebipenem has a broad antifungal spectrum, bacterial strain to most of clinical separation, tebipenem all shows than penicillin series and the stronger germ resistance of cephalo series, and compare with the carbapenem antibiotic of other injections, tebipenem also shows in various degree or stronger antibacterial effect.Particularly for PRSP (penicillin resistance pneumococcus), the MRSP (resistance to erythromycin streptococcus pneumoniae) and the Haemophilus influenzae (hemophilus influenzae) that caused in recent years childhood infection major cause, show extremely strong antibacterial effect.
Compound (I) is the important intermediate of preparing L-084,
By it, prepare the visible document of method (J.Antibiot.59 (4): 241-247,2006) of L-084:
Refining, purifying, the preservation of compound (I) and obtain high-purity compound II, L-084 etc. for ensuing reaction and all have many difficulties.As everyone knows, in chemical synthesis process, especially in industrially preparing process, be preferably with the compound that a certain method is produced, have high-purity or can be separated and refiningly become a kind of maneuverable crystallized form.
The manufacture method of having reported compound (I) in document (J.Antibiot.59 (4): 241-247,2006), purity is not high, does not report the crystallized form of compound (I) simultaneously.
Summary of the invention
Technical problem to be solved by this invention is not high in order to overcome existing L-084 midbody compound (I) purity, be unfavorable for industrialized defect, and provide that crystallization of a kind of L-084 intermediate and preparation method thereof, crystallization of the present invention are easily preserved, easy to operate, good stability, purity be high; And its preparation method is simple and reliable, cost-saving, separated simple, suitable industrial enforcement.
The present invention relates to a kind of Type B crystallization of midbody compound (I) of L-084:
In its x-ray diffractogram of powder case, in diffraction angle 2 θ=6.76, there is main peak at 8.25,15.13,16.35,17.47,21.02,22.31,31.31 and 32.77 places, 2 θ value limit of error are ± 0.20.
Another object of the present invention is to provide the method for the Type B crystallization of tebipenem intermediate of the present invention, the method comprises the steps: compound (I) heated and stirred in organic solvent, cooling crystallization, isolation of crystalline, the dry Type B crystallization that obtains compound (I).
Described organic solvent is: the mixed solvent of wherein a kind of of C1-C5 alcohols and/or acetone and/or C5-C10 ester class or optional two kinds,
Described C1-C5 alcohol is: methyl alcohol, ethanol or Virahol, be more preferably ethanol.
Described C5-C10 ester class is: ethyl formate, ethyl acetate or butylacetate, be more preferably ethyl acetate.
Wherein two kinds of optional mixed solvents are above-mentioned alcohols, acetone or ester class, and preferably ethanol, acetone, ethyl acetate, be more preferably ethanol and ethyl acetate.
The ratio of above-mentioned mixed solvent is 1: 10～10: 1, is preferably 1: 5～5: 1, is more preferably 1: 2～2: 1.
During described stirring, temperature is 0 ℃～solvent refluxing temperature, and preferred temperature is room temperature～solvent refluxing temperature.
Described be coolingly preferably cooled to-20～20 ℃, better being cooled to-10～10 ℃, better being cooled to-5～5 ℃.
Another object of the present invention is to provide the A type crystallization of the midbody compound (I) of another kind of L-084:
The characteristic peak 2 θ angle numbers of its x-ray diffractogram of powder are: 5.90, there is main peak at 8.02,13.15,14.93,19.30,22.65,22.10,24.16,26.50,26.98 places.
The raw material the present invention relates to and reagent equal commercially available obtaining except specified otherwise.
Positive progressive effect of the present invention is: the crystallization of compound of the present invention easily preserves, easy to operate, good stability, purity are high, is particularly suitable for preparing medicine tebipenem; And its preparation method is simple and reliable, suitable industrial enforcement.
Accompanying drawing explanation
The powder x-ray diffraction collection of illustrative plates of the compound that Fig. 1: embodiment 1 makes (I) A type crystallization.
The powder x-ray diffraction collection of illustrative plates of the compound that Fig. 2: embodiment 2～8 makes (I) Type B crystallization.
Embodiment
The following examples can make the present invention of those skilled in the art comprehend, but do not limit the present invention in any way.
Embodiment 1
By 1-(4,5-dihydro-2-thiazolyl) azetidine-3-thiolate hydrochlorate 105g, [4R-[4a, 5b, 6b (R*)]]-3-diphenylphosphine acyloxy-6-(1-hydroxyethyl)-4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy (MAP) 297g is mixed in 1700ml acetonitrile, cooling and stirring ,-10 ℃ drip DIEA, drip and finish, insulation reaction 2h.HPLC monitors reaction end.Add 1000ml water to stir 0.5h.Suction filtration, the washing of 500ml acetonitrile-water, 50 ℃ of vacuum-drying 2h, obtain faint yellow solid crystallization 258g, yield 99.1%.Be A crystal formation.
Gained crystallization is through X-ray diffraction test analysis, and test condition is as follows: adopt Bruker D8 ADVANCE instrument to measure, take CuKa40Kv40mA as light source, and 0.02 ° of step-length, sweep velocity: 8 °/min, sweep limit: 3 °～80 °, room temperature.Powder x-ray diffraction analytical results is in Table 1 and accompanying drawing 1.
The powder x-ray diffraction data of table 1 A type crystallization
Embodiment 2
Embodiment 1 gained solid (50g) adds in 500ml ethanol, and reflux 30min, is cooled to after room temperature, and-5～5 ℃ are stirred 2h, suction filtration, with the cold washing with alcohol filter cake of 50ml, 45 ℃ of reduced vacuum are dried to obtain off-white color solid 46g, productive rate 92%, HPLC purity 99.98%, is B crystal formation.
Gained crystallization is through X-ray diffraction test analysis, and test condition is as follows: adopt Bruker D8 ADVANCE instrument to measure, take CuKa 40Kv40mA as light source, and 0.02 ° of step-length, sweep velocity: 8 °/min, sweep limit: 3 °～80 °, room temperature.Powder x-ray diffraction analytical results is in Table 2 and accompanying drawing 2.
The powder x-ray diffraction data of table 2 Type B crystallization
Embodiment 3
Embodiment 1 gained solid (20g) adds in 200ml methyl alcohol, reflux 30min, be cooled to after room temperature,-10～0 ℃ is stirred 2h, and suction filtration, with the cold methanol wash filter cake of 10ml, 45 ℃ of reduced vacuum are dried to obtain off-white color solid 15.2g, productive rate 76%, HPLC purity 99.94%, is B crystal formation.
Embodiment 4
Embodiment 1 gained solid (10g) adds in 100ml Virahol, reflux 30min, be cooled to after room temperature,-5～5 ℃ are stirred 2h, and suction filtration, with the cold washed with isopropyl alcohol filter cake of 10ml, 45 ℃ of reduced vacuum are dried to obtain off-white color solid 8.8g, productive rate 88%, HPLC purity 99.95%, is B crystal formation.
Embodiment 5
Embodiment 1 gained solid (10g) adds in 80ml acetone, and reflux 30min, is cooled to after room temperature, and-5～5 ℃ are stirred 2h, suction filtration, with the cold washing with acetone filter cake of 10ml, 45 ℃ of reduced vacuum are dried to obtain off-white color solid 8.2g, productive rate 82%, HPLC purity 99.92%, is B crystal formation.
Embodiment 6
Embodiment 1 gained solid (20g) adds in 80ml acetone, and reflux 30min, is cooled to after room temperature, and-5～5 ℃ are stirred 2h, suction filtration, with the cold washing with acetone filter cake of 10ml, 45 ℃ of reduced vacuum are dried to obtain off-white color solid 8.2g, productive rate 82%, HPLC purity 99.89%, is B crystal formation.
Embodiment 7
Embodiment 1 gained solid (50g) adds in 300ml ethyl acetate, reflux 30min, be cooled to after room temperature,-5～5 ℃ are stirred 2h, and suction filtration, with the cold ethyl acetate washing leaching cake of 30ml, 45 ℃ of reduced vacuum are dried to obtain off-white color solid 48.2g, productive rate 96.4%, HPLC purity 99.86%, is B crystal formation.
Embodiment 8
Embodiment 1 gained solid (20g) adds 100ml ethanol, 100ml ethyl acetate, reflux 30min, is cooled to after room temperature, and-5～5 ℃ are stirred 2h, suction filtration, with cold ethanol: ethyl acetate (1: 1) washing leaching cake, 45 ℃ of dry off-white color solid 18.8g, productive rates 94% of obtaining of reduced vacuum, HPLC purity 99.93%, is B crystal formation.
The preparation of embodiment 9 tebipenems
By (the 4R of above-described embodiment 2～8 preparations, 5S, 6S)-3-[[1-(4,5-dihydro-2-thiazolyl)-3-azetidinyl] sulfo-]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy's (formula (I) compound) Type B crystallization 250g, 3.0L ethyl acetate, 900ml0.5mol/L potassium bicarbonate aqueous solution, 50g (in butt) palladium carbon 10% palladium carbon (moisture 50%～60%) add in 10L hydriding reactor successively, logical hydrogen 1.0MPa, reacts 10 hours; Suction filtration, separatory, concentrated hydrochloric acid regulates pH value 5.6 left and right, and 0～5 ℃ adds 2.5L acetone to stir 30min, is added dropwise to 2.5L acetone, stirs 3h, suction filtration, 100ml washing with acetone filter cake, 35 ℃ of vacuum-dryings obtain 98.6g tebipenem, yield: 59%.
Stability test
(4R prepared by the present invention, 5S, 6S)-3-[[1-(4,5-dihydro-2-thiazolyl)-3-azetidinyl] sulfo-]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy's (formula (I) compound) Type B crystallization, further investigated stability.
Under the condition of 40 ℃ and relative humidity 75%, place 6 months, investigate related substance and the content situation of sample, the results are shown in Table 4 and 5.Related substance and content adopt high performance liquid phase (HPLC) method to measure.
HPLC Liquid Detection condition:
Chromatographic column: waters XBridge
tMc18 5 μ m 4.6mm * 250mm; Column temperature: 35 ℃; Flow velocity: 1.0ml/min; Detect wavelength: 215nm; Sample size: 10ul.
Moving phase: NaH A.0.01mol/L
2pO
4(1mol/L NaOH adjusts pH 7.0)
B. acetonitrile
Gradient table: in Table 3.
Table 3 gradient table
Table 4 determination of related substances result (%)
Table 5 assay result (%)
Aforementioned stable test-results shows, (4R, 5S, 6S)-3-[[1-(4,5-dihydro-2-thiazolyl)-3-azetidinyl] sulfo-]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy's (formula (I) compound) Type B crystallization investigates 6 months under accelerated stability test condition, and related substance and content have no significant change.
Claims (9)
1. the Type B crystallization of L-084 intermediate (I)
In its x-ray diffractogram of powder case, in diffraction angle 2 θ=6.76, there is main peak at 8.25,15.13,16.35,17.47,21.02,22.31,31.31 and 32.77 places.
2. the preparation method of the crystallization of compound (I) described in claim 1, is characterized in that compound (I) to stir in solvent, obtains the Type B crystallization of compound (I).
3. preparation method claimed in claim 2, is characterized in that solvent is the mixed solvent of wherein a kind of of C1-C5 alcohols, acetone or C5-C10 ester class or optional two kinds.
4. C1-C5 alcohol claimed in claim 3 is methyl alcohol, ethanol or Virahol.
5. C5-C10 ester class claimed in claim 3 is ethyl formate, ethyl acetate or butylacetate.
6. preparation method claimed in claim 3, the ratio that it is characterized in that the mixed solvent of optional two kinds is 1: 10～10: 1.
7. preparation method claimed in claim 2, while it is characterized in that stirring, temperature is 0 ℃～reflux temperature.
8. preparation method claimed in claim 2, is characterized in that when cooling that temperature is-20～20 ℃.
9. the A type crystallization of L-084 intermediate (I)
The characteristic peak 2 θ angle numbers of its x-ray diffractogram of powder are: 5.90, there is main peak at 8.02,14.93,19.30,22.65,22.10,24.16,26.50,26.98 places.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10889587B2 (en) | 2017-02-06 | 2021-01-12 | Spero Therapeutics, Inc. | Tebipenem pivoxil crystalline forms, compositions including the same, methods of manufacture, and methods of use |
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Non-Patent Citations (1)
| Title |
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| 史颖等: "泰比培南酯的合成工艺研究", 《中国药物化学杂志》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10889587B2 (en) | 2017-02-06 | 2021-01-12 | Spero Therapeutics, Inc. | Tebipenem pivoxil crystalline forms, compositions including the same, methods of manufacture, and methods of use |
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Effective date of registration: 20160406 Address after: Hi tech District Ji'nan city Shandong province 250104 Road No. 3333 Patentee after: Shandong Mingren Furuida Pharmaceutical Co., Ltd. Patentee after: Pharmaceutical Sciences, Shandong Province Address before: Xinluo Avenue high tech Zone of Ji'nan City, Shandong Province, No. 989 250101 Patentee before: Ling Peixue |