CN106632399B - A kind of synthetic method of cefroxadine parent nucleus - Google Patents
A kind of synthetic method of cefroxadine parent nucleus Download PDFInfo
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- 0 *C(C*[C@](*1*C(Cc2ccccc2)=O)*2C1=O)=C2O Chemical compound *C(C*[C@](*1*C(Cc2ccccc2)=O)*2C1=O)=C2O 0.000 description 1
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
The invention discloses a kind of synthetic methods of cefroxadine parent nucleus, and using 3- hydroxy-cephams as starting material, cefroxadine parent nucleus is made by the protecting group benzhydryl on the amino protecting group phenylacetyl group and 4 carboxyls in methylation reaction, removing 7 successively.Wherein, methylation reaction is using trimethyl orthoformate as methylating reagent, easy to operate, safety；In removing 4 carboxyl-protecting groups, after the trifluoromethanesulfonic acid scandium catalyst upon activation that the present invention uses, it is recycled and reuses, be conducive to the protection of environment.The cefroxadine parent nucleus that the present invention produces is white solid powder, and purity is 99.0% or more, and the quality of product is preferable, is suitable for industrialized production.
Description
Technical field
The invention belongs to medicine intermediate synthesis technical fields, more particularly to a kind of synthesis side of cefroxadine parent nucleus
Method.
Background technology
Cefroxadine parent nucleus English abbreviation 7-AMOCA, molecular formula：C8H10N2O4S, molecular weight：230.24 appearance is white
Or white solid powder, CAS：51803-38-4, structure are as follows：
Cefroxadine has spectrum antibacterial as a kind of oral cephalosporins to Gram-positive and negative bacterium
Effect, antimicrobial spectrum are similar with Cefaclor.Its antibacterial activity is better than cefalexin.Clinically it is used for respiratory tract, the urinary tract, skin
The infection of skin and soft tissue, genitals official rank position, is also commonly used for tympanitis.This product oral absorption is good, and serum is 1 hour,
Largely from homaluria in 12 hours.Big advantage is embodied in as a kind of children.And to high risk
Diabetic has no adverse effects.
Cefroxadine parent nucleus is the key intermediate for synthesizing cefroxadine, and synthesis difficulty is big, to actual production technique and
Technical merit is required to higher.
Robert R.Chauvette and the Pamela A.Pennington of Lilly Co., Eli. have studied 3- hydroxyls -3
- 3 cephem compounds of spore ene compound and diazomethane reaction synthesis 3- methoxyl groups.(document Chemistry of
Cephalosporin Antibiotics.30.1 3-Methoxy-and 3-Halo-3-cephems,Journal of
Medicinal Chemistry, 1975. and document Chemistry of Cephalosporin Antibiotics.XXIX.1
3-Halo-and 3-Methoxy-3-cephems,Journal of the American Chemical Society,
1974.)
Wherein, the methylating reagent in reaction is excessive diazomethane.Diazomethane is heated, contacts open fire or is rubbed
It can explode when wiping, shake, hitting, not diluted liquid or gas are in contact alkali metal or coarse article surface
It can set off an explosion, therefore the method is not suitable for industrialized production.
Japanese pharmaceutical companies are generally with 3- hydroxyl -3- cephem compounds and dimethyl suflfate reaction synthesis 3- methoxyl groups -3
Cephem compounds, then slough 7 bit amino protecting groups successively and 4 carboxyl-protecting groups obtain cefroxadine parent nucleus.
The technique is disadvantageous in that methylating reagent dimethyl suflfate is deadly poisonous compound, is unfavorable for the safety of production
Management, in addition, 4 carboxyl-protecting groups of removing use alchlor/methyl phenyl ethers anisole method, the method to need to use a large amount of alchlor,
The largely solid waste containing metallic aluminium is will produce, the protection of environment is unfavorable for.
In conclusion since the synthesis difficulty of existing cefroxadine parent nucleus is larger, the methylating reagent used is easy hair
Raw explosion either deadly poisonous compound, is unfavorable for keeping the safety in production.Therefore, a safe operation is developed, is suitble to industrialized production, is right
The production technology of environmental-friendly cefroxadine parent nucleus is meaningful.
Invention content
The invention mainly solves the technical problem of providing a kind of reaction safety, be suitble to industrialized production, it is environmentally friendly,
The synthetic method of the higher cefroxadine parent nucleus of yield.
In order to solve the above technical problems, one aspect of the present invention is：A kind of cefroxadine parent nucleus is provided
Synthetic method in turn includes the following steps：
With trimethyl orthoformate methylation reaction occurs for step (a) 3- hydroxy-cephams, obtains 3-OMe, then removes on 7
Amino protecting group phenylacetyl group obtain BH：
Step (b) BH removes the protecting group benzhydryl system on 4 carboxyls under trifluoromethanesulfonic acid scandium and methyl phenyl ethers anisole effect
Obtain cefroxadine parent nucleus：
A kind of synthetic method of the cefroxadine parent nucleus, in step (a) methylation reaction, 3- hydroxy-cephams and primitive nail
The molar ratio of sour trimethyl is 1:1.0~1.2.
In step (a) methylation reaction, reaction dissolvent is the mixed solvent of methanol and chloroform, and the volume ratio of the two is 1:
1.0~3.0.
In step (a) methylation reaction, anhydrous sulfanilic acid is catalyst, and dosage is 5% (% of 3- hydroxy-cephams
Indicate molar percentage).
In step (a) deamination protecting group, using dichloromethane as reaction dissolvent, pyridine, carbon tetrabromide and triphenyl is added
Phosphine, reaction temperature are 0~5 DEG C, reaction time 2h, add methanol and react 2h at -20~-25 DEG C.
In step (a) deamination protecting group, the molar ratio of 3- hydroxy-cephams and pyridine, carbon tetrabromide and triphenylphosphine is 1:
1.0~2.0:1.0~1.2:1.0~1.2.
In step (b), reaction dissolvent is dichloromethane, and the pH value of reaction is 0.1~0.5.
In step (b), BH is 1 with the molar ratio of trifluoromethanesulfonic acid scandium and methyl phenyl ethers anisole:1.0~1.2:1.0~1.2, reaction
Temperature is 5~8 DEG C, and the reaction time is 3~4h.
Advantageous effect：
The present invention provides a kind of synthetic methods of new cefroxadine parent nucleus, and compared with prior art, the present invention is with original
Trimethyl orthoformate is methylating reagent, and processing safety is high, is suitable for industrialized production.In removing 4 carboxyl-protecting groups, this
After inventing the trifluoromethanesulfonic acid scandium catalyst upon activation used, it is recycled and reuses, be conducive to the protection of environment.The present invention gives birth to
The cefroxadine parent nucleus that output is come is white solid powder, and purity is 99.0% or more, and the quality of product is preferable, is suitable for industry
Metaplasia is produced.
Specific implementation mode
The content of present invention is further explained and described by the following examples, but the examples of implementation provided should not be understood
To be construed as limiting to the scope of the present invention.
Embodiment 1
The synthesis of BH：
500mL four-hole bottles put into 3- hydroxy-cephams (50.06g, 0.10mol), methanol (100mL), CHCl3(200mL)、HC
(OMe)3(11.67g, 0.11mol), stirring and dissolving are added anhydrous sulfanilic acid (TsOH) (0.86g, 0.005mol) and stir
Reflux 8h, sampling are mixed, HPLC detects 3- hydroxy-cephams residual and is less than 1%, and reaction is finished.It is cooled to 0~5 DEG C, 50mL pure water is added,
Stir 10min, layering, water layer CHCl3Extraction 2 times 50mL/ times, merges organic layer, and the stirring of 5g anhydrous magnesium sulfates is added
10min adds 5g activated carbons stirring 10min, filters, collect filtrate.
The interior temperature of filtrate control is less than 30 DEG C of vacuum distillations to dry, addition CH2Cl2(300mL) is cooled to -10~-5 DEG C, adds
Enter pyridine (11.87g, 0.15mol), CBr4(36.48g, 0.11mol), triphenylphosphine (28.85g, 0.11mol), temperature control 0~5
DEG C, stir 2h.- 60~-80 DEG C are cooled to, methanol (300mL) is added dropwise, heat release makes temperature be slowly raised to -20~-25 DEG C instead
2h, HPLC is answered to detect 3-OMe<2.0%, reaction is finished.20% hydrochloric acid (60g) is added, 0~5 DEG C of temperature control stirs 0.5h.It is added
10% sodium-chloride water solution (400mL) stirs 15min, stands 20min, layering, water layer CH2Cl2(200mL) is extracted, and is merged
Organic layer.Organic layer is evaporated under reduced pressure to dry, addition acetonitrile (300mL), and 0~5 DEG C of temperature control stirs 2h, filters, filter cake 100mL
Acetonitrile elutes, then 4~5h is dried in vacuo at 40~50 DEG C, obtains 41.35g compound BH, molar yield 95.52%,
HPLC purity is 99.11%.
The synthesis of cefroxadine parent nucleus：
500mL four-hole boiling flasks put into CH2Cl2(300mL), BH (43.29g, 0.10mol) is cooled to -5~0 DEG C, is added dropwise three
Fluoroacetic acid adjust pH=0.1~0.5, be added methyl phenyl ethers anisole (11.89g, 0.11mol), trifluoromethanesulfonic acid scandium (54.14g,
0.11mol), 5~8 DEG C of temperature control, are stirred to react 3~4h.HPLC is analyzed：BH is remained<1.0%, reaction is finished.Be added 300g pure water and
200mL methanol, 5~10 DEG C of temperature control stir 15min, stand 20min layerings.Organic layer extracts 2 times (100mL/ times) with pure water,
Ammonium hydroxide is added dropwise in combining water layer, 5~10 DEG C of temperature control, adjusts pH=3.5~4.0, after pH is adjusted in place, 5~10 DEG C of temperature control, and stirring
2h.It filters, filtrate decompression is distilled to dry recycling trifluoromethanesulfonic acid scandium catalyst crude product, place to be activated after catalyst crude product is concentrated
Reason.Filter cake pure water 2 times (50mL/ times), then it is beaten 0.5h with 120mL acetone, it filters, filter cake vacuum at 40~50 DEG C
Dry 4~5h, obtains 21.47g cefroxadine parent nucleus, molar yield 93.25%, and HPLC purity is 99.26%.
Embodiment 2
The synthesis of BH：
500mL four-hole bottles put into 3- hydroxy-cephams (50.06g, 0.10mol), methanol (150mL), CHCl3(150mL)、HC
(OMe)3(10.61g, 0.10mol), stirring and dissolving are added anhydrous sulfanilic acid (TsOH) (0.86g, 0.005mol) and stir
Reflux 8h, sampling are mixed, HPLC detects 3- hydroxy-cephams residual and is less than 1%, and reaction is finished.It is cooled to 0~5 DEG C, 50mL pure water is added,
Stir 10min, layering, water layer CHCl3(50mL/ times) extraction 2 times, merges organic layer, and the stirring of 5g anhydrous magnesium sulfates is added
10min adds 5g activated carbons stirring 10min, filters, collect filtrate.
The interior temperature of filtrate control is less than 30 DEG C of vacuum distillations to dry, addition CH2Cl2(300mL) is cooled to -10~-5 DEG C, adds
Enter pyridine (7.91g, 0.10mol), CBr4(33.16g, 0.10mol), triphenylphosphine (26.23g, 0.10mol), temperature control 0~5
DEG C, stir 2h.- 60~-80 DEG C are cooled to, methanol (300mL) is added dropwise, heat release makes temperature be slowly raised to -20~-25 DEG C instead
2h, HPLC is answered to detect 3-OMe<2.0%, reaction is finished.20% hydrochloric acid (60g) is added, 0~5 DEG C of temperature control stirs 0.5h.It is added
10% sodium-chloride water solution (400mL) stirs 15min, stands 20min, layering, water layer CH2Cl2(200mL) is extracted, and is merged
Organic layer.Organic layer is evaporated under reduced pressure to dry, addition acetonitrile (300mL), and 0~5 DEG C of temperature control stirs 2h, filters, filter cake 100mL
Acetonitrile elutes, then 4~5h is dried in vacuo at 40~50 DEG C, obtains 38.85g compound BH, molar yield 89.74%,
HPLC purity is 98.59%.
The synthesis of cefroxadine parent nucleus：
500mL four-hole boiling flasks put into CH2Cl2(300mL), BH (43.29g, 0.10mol) is cooled to -5~0 DEG C, is added dropwise three
Fluoroacetic acid adjust pH=0.1~0.5, be added methyl phenyl ethers anisole (10.81g, 0.10mol), trifluoromethanesulfonic acid scandium (49.22g,
0.10mol), 5~8 DEG C of temperature control, are stirred to react 3~4h.HPLC is analyzed：BH is remained<1.0%, reaction is finished.Be added 300g pure water and
200mL methanol, 5~10 DEG C of temperature control stir 15min, stand 20min layerings.Organic layer extracts 2 times (100mL/ times) with pure water,
Ammonium hydroxide is added dropwise in combining water layer, 5~10 DEG C of temperature control, adjusts pH=3.5~4.0, after pH is adjusted in place, 5~10 DEG C of temperature control, and stirring
2h.It filters, filtrate decompression is distilled to dry recycling trifluoromethanesulfonic acid scandium catalyst crude product, place to be activated after catalyst crude product is concentrated
Reason.Filter cake pure water 2 times (50mL/ times), then it is beaten 0.5h with 120mL acetone, it filters, filter cake vacuum at 40~50 DEG C
Dry 4~5h, obtains 20.89g cefroxadine parent nucleus, molar yield 90.73%, and HPLC purity is 99.08%.
Embodiment 3
The synthesis of BH：
500mL four-hole bottles put into 3- hydroxy-cephams (50.06g, 0.10mol), methanol (75mL), CHCl3(225mL)、HC
(OMe)3(12.73g, 0.12mol), stirring and dissolving are added anhydrous sulfanilic acid (TsOH) (0.86g, 0.005mol) and stir
Reflux 8h, sampling are mixed, HPLC detects 3- hydroxy-cephams residual and is less than 1%, and reaction is finished.It is cooled to 0~5 DEG C, 50mL pure water is added,
Stir 10min, layering, water layer CHCl3(50mL/ times) extraction 2 times, merges organic layer, and the stirring of 5g anhydrous magnesium sulfates is added
10min adds 5g activated carbons stirring 10min, filters, collect filtrate.
The interior temperature of filtrate control is less than 30 DEG C of vacuum distillations to dry, addition CH2Cl2(300mL) is cooled to -10~-5 DEG C, adds
Enter pyridine (15.83g, 0.20mol), CBr4(39.80g, 0.12mol), triphenylphosphine (31.47g, 0.12mol), temperature control 0~5
DEG C, stir 2h.- 60~-80 DEG C are cooled to, methanol (300mL) is added dropwise, heat release makes temperature be slowly raised to -20~-25 DEG C instead
2h, HPLC is answered to detect 3-OMe<2.0%, reaction is finished.20% hydrochloric acid (60g) is added, 0~5 DEG C of temperature control stirs 0.5h.It is added
10% sodium-chloride water solution (400mL) stirs 15min, stands 20min, layering, water layer CH2Cl2(200mL) is extracted, and is merged
Organic layer.Organic layer is evaporated under reduced pressure to dry, addition acetonitrile (300mL), and 0~5 DEG C of temperature control stirs 2h, filters, filter cake 100mL
Acetonitrile elutes, then 4~5h is dried in vacuo at 40~50 DEG C, obtains 40.54g compound BH, molar yield 93.65%,
HPLC purity is 98.91%.
The synthesis of cefroxadine parent nucleus：
500mL four-hole boiling flasks put into CH2Cl2(300mL), BH (43.29g, 0.10mol) is cooled to -5~0 DEG C, is added dropwise three
Fluoroacetic acid adjust pH=0.1~0.5, be added methyl phenyl ethers anisole (12.97g, 0.12mol), trifluoromethanesulfonic acid scandium (59.06g,
0.12mol), 5~8 DEG C of temperature control, are stirred to react 3~4h.HPLC is analyzed：BH is remained<1.0%, reaction is finished.Be added 300g pure water and
200mL methanol, 5~10 DEG C of temperature control stir 15min, stand 20min layerings.Organic layer extracts 2 times (100mL/ times) with pure water,
Ammonium hydroxide is added dropwise in combining water layer, 5~10 DEG C of temperature control, adjusts pH=3.5~4.0, after pH is adjusted in place, 5~10 DEG C of temperature control, and stirring
2h.It filters, filtrate decompression is distilled to dry recycling trifluoromethanesulfonic acid scandium catalyst crude product, place to be activated after catalyst crude product is concentrated
Reason.Filter cake pure water 2 times (50mL/ times), then it is beaten 0.5h with 120mL acetone, it filters, filter cake vacuum at 40~50 DEG C
Dry 4~5h, obtains 21.43g cefroxadine parent nucleus, molar yield 93.08%, and HPLC purity is 99.15%.
Example the above is only the implementation of the present invention is not intended to limit the scope of the invention, every to utilize this hair
The equivalent structure or equivalent flow shift that bright description is done is applied directly or indirectly in other relevant technology necks
Domain is included within the scope of the present invention.
Claims (8)
1. a kind of synthetic method of cefroxadine parent nucleus, which is characterized in that in turn include the following steps：
With trimethyl orthoformate by catalyst of anhydrous sulfanilic acid methylation reaction occurs for step (a) 3- hydroxy-cephams,
3-OMe is obtained, the amino protecting group phenylacetyl group then removed on 7 obtains BH：
For step (b) BH under trifluoromethanesulfonic acid scandium and methyl phenyl ethers anisole effect, head is made in the protecting group benzhydryl removed on 4 carboxyls
Spore sand determines parent nucleus：
2. a kind of synthetic method of cefroxadine parent nucleus according to claim 1, which is characterized in that step (a) methylates
In reaction, the molar ratio of 3- hydroxy-cephams and trimethyl orthoformate is 1:1.0~1.2.
3. a kind of synthetic method of cefroxadine parent nucleus according to claim 1, which is characterized in that step (a) methylates
In reaction, reaction dissolvent is the mixed solvent of methanol and chloroform, and the volume ratio of the two is 1:1.0~3.0.
4. a kind of synthetic method of cefroxadine parent nucleus according to claim 1, which is characterized in that step (a) methylates
In reaction, anhydrous sulfanilic acid adds mole as the 5% of 3- hydroxy-cepham moles.
5. a kind of synthetic method of cefroxadine parent nucleus according to claim 1, which is characterized in that step (a) deamination
In protecting group, using dichloromethane as reaction dissolvent, pyridine, carbon tetrabromide and triphenylphosphine is added, reaction temperature is 0~5 DEG C, instead
It is 2h between seasonable, adds methanol and react 2h at -20~-25 DEG C.
6. a kind of synthetic method of cefroxadine parent nucleus according to claim 1 or 5, which is characterized in that step (a) deamination
In base protecting group, the molar ratio of 3- hydroxy-cephams and pyridine, carbon tetrabromide and triphenylphosphine is 1:1.0~2.0:1.0~1.2:
1.0~1.2.
7. a kind of synthetic method of cefroxadine parent nucleus according to claim 1, which is characterized in that in step (b), reaction
Solvent is dichloromethane, and the pH value of reaction is 0.1~0.5.
8. a kind of synthetic method of cefroxadine parent nucleus according to claim 1, which is characterized in that in step (b), BH with
The molar ratio of trifluoromethanesulfonic acid scandium and methyl phenyl ethers anisole is 1:1.0~1.2:1.0~1.2, reaction temperature is 5~8 DEG C, and the reaction time is
3~4h.
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| CN110878101A (en) * | 2019-12-11 | 2020-03-13 | 华中药业股份有限公司 | Novel method for preparing cefixime mother nucleus 7-AMOCA |
| CN112321611B (en) * | 2020-10-29 | 2022-05-06 | 湖北凌晟药业有限公司 | Preparation method of cefixadine mother nucleus |
| CN113563365B (en) * | 2021-08-17 | 2024-05-28 | 华中药业股份有限公司 | Preparation method of 7-amino-3-methoxy-4-cephalosporanic acid |
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| CN102268022B (en) * | 2011-08-15 | 2014-04-09 | 南京丰融化学技术有限公司 | Reference standard product for representing Cefroxadine and preparation method and application thereof |
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