CN111171050B - Preparation method of cefcapene pivoxil hydrochloride - Google Patents
Preparation method of cefcapene pivoxil hydrochloride Download PDFInfo
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- CN111171050B CN111171050B CN202010198097.7A CN202010198097A CN111171050B CN 111171050 B CN111171050 B CN 111171050B CN 202010198097 A CN202010198097 A CN 202010198097A CN 111171050 B CN111171050 B CN 111171050B
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- cefcapene pivoxil
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- hydrochloric acid
- pivoxil hydrochloride
- trifluoroacetic acid
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/02—Preparation
- C07D501/04—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
- C07D501/26—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group
- C07D501/34—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group with the 7-amino radical acylated by carboxylic acids containing hetero rings
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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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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Cephalosporin Compounds (AREA)
Abstract
The invention discloses a one-step preparation method of antibiotic drug cefcapene pivoxil hydrochloride monohydrate, which comprises the following steps: adding hydrochloric acid and trifluoroacetic acid into an organic solvent, stirring and cooling to 0-10 ℃, adding the cefcapene pivoxil protected by the Boc group, continuing to keep the temperature and stir, after the reaction is finished, crystallizing, filtering and drying to obtain cefcapene pivoxil hydrochloride monohydrate; the molar ratio of hydrochloric acid to trifluoroacetic acid is 10:1 to 5: 1. The preparation method of cefcapene pivoxil hydrochloride provided by the invention has the advantages of high yield, low cost, convenience in treatment, good stability, mild reaction conditions, environmental friendliness and suitability for industrial production.
Description
Technical Field
The invention relates to a preparation method of cefcapene pivoxil hydrochloride, in particular to a preparation method for removing a Boc protective group in the production process of cefcapene pivoxil hydrochloride.
Background
The chemical name of cefcapene pivoxil hydrochloride is 7- [2- (2-amino-1, 3-thiazole-4-yl) pent-3-enamido ] -3- (carbamoyloxymethyl) -8-oxo-5-thio-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid 2, 2-dimethylpropionyloxymethyl ester hydrochloride monohydrate.
The cefcapene pivoxil hydrochloride is a third-generation orally-administrable cephalosporin antibiotic, and pharmacological research shows that the MIC80 of MSSA of aerobic G + bacteria is 3.13 mu G/ml, is the same as cefotiam and cefaclor, and the MIC80 of the cefaclor is not more than 0.1 mu G/ml, is superior to cefaclor, is equivalent to cefditoren, and has strong activity to penicillin-resistant (containing moderate drug resistance) streptococcus pneumoniae, and the MIC80 is 0.78 mu G/ml. The G-bacterium has stronger resistance to Citrobacter freundii, Enterobacter cloacae, providencia rettgeri, Braland Hansenula mucositis and Serratia marcescens than cefditoren and cefotiam. The activity to proteus, haemophilus influenzae, Morganella morganii and gonococcus is stronger than cefaclor and cefotiam, and is equivalent to that of cefoperam. Has strong activity to Haemophilus influenzae resistant to ampicillin, and the MIC80 is 0.05 mu g/ml. The activity against anaerobes was the strongest among the control drugs. Has good clinical effect on adults and children, and is cephalosporin with good curative effect. This product was developed by Nippon salt Yakuyama and was first marketed under the name of FIomox in 1997.
Most of the existing processes use N-Boc protected cefcapene pivoxil as an intermediate, use trifluoroacetic acid to remove a protecting group, and form salt again, so that the existing processes have the problems of difficult treatment and unstable materials, and are not suitable for industrial scale-up production. CN102796117 discloses that the Boc protection is removed from N-Boc protected cefcapene pivoxil by acid, and then salifying is carried out to obtain cefcapene pivoxil hydrochloride monohydrate.
Disclosure of Invention
Aiming at the problems, the invention aims to provide a method for preparing cefcapene pivoxil hydrochloride, which has high yield and convenient treatment and is suitable for industrial production.
The invention has the following advantages: the intermediate is subjected to protecting group removal, treatment and purification to directly obtain a target product, the reaction is carried out in one step, the conversion rate is high, the treatment is simple and convenient, and high-purity cefcapene pivoxil hydrochloride is directly obtained.
The technical points of the invention are as follows:
a method for preparing cefcapene pivoxil hydrochloride is characterized by comprising the following steps: adding hydrochloric acid and trifluoroacetic acid into an organic solvent, stirring and cooling to 0-10 ℃, adding the cefcapene pivoxil protected by the Boc group, continuing to keep the temperature and stir, after the reaction is finished, crystallizing, filtering and drying to obtain cefcapene pivoxil hydrochloride monohydrate; the molar ratio of hydrochloric acid to trifluoroacetic acid is 10:1 to 5: 1.
Further, solvents used for removing the Boc group protection are acetonitrile, alkane and methanol. Organic solvents typically include the following: dichloromethane, trichloromethane, methanol, ethyl acetate and acetonitrile, wherein acetonitrile is preferred.
Further, the temperature is reduced to-5 ℃ by stirring. Since hydrochloric acid is volatile, a low temperature reaction is controlled using a ice salt bath to remove the Boc group.
Further, the crystallization method may be recrystallization, or crystallization by continuing addition of a polar solvent.
Further, the molar ratio of hydrochloric acid to trifluoroacetic acid was 8: 1. The concentration of hydrochloric acid required for removing the protecting group and salifying is 1N-8N, and 4N is preferred. The use of trifluoroacetic acid to increase the acidity of the hydrochloric acid may further promote the conversion and rate of the reaction.
Further, in the reaction for removing the Boc protecting group, the feeding ratio of raw materials, hydrochloric acid and an organic solvent is 1:2:5.
Further, the reaction time for removing the Boc protecting group was 120 min.
In the reaction step, the feeding amount ratio of the raw material, the concentrated hydrochloric acid and the organic solvent is 1: 1-5: 5-20, and preferably 1: 1-2: 5-15.
Compared with the prior art, the invention has the following advantages:
1) the mixed solution of hydrochloric acid and trifluoroacetic acid is used for removing the Boc protecting group, so that a large amount of trifluoroacetic acid is avoided, and the method has the advantages of high conversion rate, quick reaction, no side reaction, simple and convenient treatment, easy amplification, low cost and the like.
2) The method carries out deprotection and salification in one step, is simple and convenient to operate, consumes less time, generates less waste liquid and gas, and is green and environment-friendly.
Detailed Description
The technical solution of the present invention will be further described with reference to the following specific examples, but the scope of the present invention is not limited thereto.
Example one
Adding acetonitrile (375 mL), 4N hydrochloric acid (56.3mL) and 3.2g of trifluoroacetic acid into a reaction vessel, cooling to-10-0 ℃ while stirring, adding N-Boc protected cefcapene pivoxil (75g), stirring for 120min, recrystallizing, centrifuging, washing crude products with water (500 mL x 3), and drying to obtain a fine cefcapene pivoxil hydrochloride monohydrate product (65 g).
Example two
Acetonitrile (375 mL), 4N hydrochloric acid (56.3mL), 2.56g trifluoroacetic acid were added to the reaction vessel, the temperature was reduced to-10-0 ℃ while stirring, N-Boc protected cefcapene pivoxil (75g) was added, after stirring for 120min, recrystallization and centrifugation were carried out, the crude product was washed with water (500 mL x 3), and the 20 hour crude cefcapene pivoxil hydrochloride monohydrate (58 g) was dried.
EXAMPLE III
Acetonitrile (375 mL), 4N hydrochloric acid (56.3mL), 5.13g trifluoroacetic acid were added to the reaction vessel, incubated-10-0 ℃ with stirring, N-Boc protected cefcapene pivoxil (75g) was added, after stirring for 120min, recrystallization, centrifugation, washing of the crude product with water (500 mL x 3), and drying of the 20 hour fine cefcapene pivoxil hydrochloride monohydrate (60 g).
Example four
Methanol (400 mL), 4N hydrochloric acid (56.3mL), 3.2g trifluoroacetic acid were added to the reaction vessel, incubated at-10-0 ℃ with stirring, N-Boc protected cefcapene pivoxil (75g) was added, after stirring for 120min, recrystallization, centrifugation, washing of the crude product with water (500 mL x 3), and drying of the 20 hour fine cefcapene pivoxil hydrochloride monohydrate (52 g).
Comparative example 1
Prepared according to the method of cn102796117B as follows:
adding ethyl acetate (1500mL) and aluminum trichloride (75g) into a reaction vessel, cooling to-5-5 ℃ while stirring, adding N-Boc protected cefcapene pivoxil (75g), and stirring for 45min at the temperature of-5-5 ℃. Then, water (1500ml) was added to the reactor, stirred for 30min, allowed to stand for 30min, and the water layer was drained. Washing with 10% sodium chloride solution (750mL), draining off the aqueous layer, controlling the temperature at 15-25 deg.C, adding 4N hydrochloric acid (56.3mL) into the reactor, stirring for 30min, adding acetonitrile (300 mL), and stirring for 3 h. Centrifuging, crude product
Washed with water (500 mL x 3) and dried for 20 hours of cefcapene pivoxil hydrochloride monohydrate (55 g).
Comparative example No. two
Acetonitrile (375 mL), 4N hydrochloric acid (56.3mL), 3.2g trifluoroacetic acid were added to the reaction vessel, cooled to-20 ℃ with stirring, N-Boc protected cefcapene pivoxil (75g) was added, recrystallized after stirring for 120min, centrifuged, the crude product was washed with water (500 mL x 3), and the 20 hour fine cefcapene pivoxil hydrochloride monohydrate (60 g) was dried.
Comparative example No. three
Acetonitrile (375 mL), 4N hydrochloric acid (56.3mL), 3.2g trifluoroacetic acid were added to the reaction vessel, the temperature was controlled while stirring at 30 ℃, N-Boc protected cefcapene pivoxil (75g) was added, the temperature was controlled while stirring at 30 ℃ for 120min before recrystallization, centrifugation, washing of the crude product with water (500 mL x 3), and drying of the 20 hour fine cefcapene pivoxil hydrochloride monohydrate (40 g).
Comparative example No. four
Acetonitrile (375 mL), 4N hydrochloric acid (56.3mL), 1.28g trifluoroacetic acid were added to the reaction vessel, the temperature was controlled at-10-0 ℃ while stirring, N-Boc protected cefcapene pivoxil (75g) was added, recrystallization after stirring for 120min, centrifugation, washing of the crude product with water (500 mL x 3), and drying of the 20 hour fine cefcapene pivoxil hydrochloride monohydrate (50 g).
Comparative example five
Acetonitrile (375 mL), 4N hydrochloric acid (56.3mL), 12.8g trifluoroacetic acid were added to the reaction vessel, the temperature was controlled at-10-0 ℃ while stirring, N-Boc protected cefcapene pivoxil (75g) was added, recrystallization after stirring for 120min, centrifugation, washing of the crude product with water (500 mL x 3), and drying of the 20 hour fine cefcapene pivoxil hydrochloride monohydrate (44 g).
Comparative example six
Acetonitrile (375 mL), 4N hydrochloric acid (56.3mL), 3.2g trifluoroacetic acid were added to the reaction vessel, the temperature was controlled at-10-0 ℃ while stirring, N-Boc protected cefcapene pivoxil (75g) was added, recrystallization after stirring for 60min, centrifugation, washing of the crude product with water (500 mL x 3), and drying of the 20 hour fine cefcapene pivoxil hydrochloride monohydrate (44 g).
Comparative example seven
Acetonitrile (375 mL), 4N hydrochloric acid (56.3mL), 3.2g trifluoroacetic acid were added to the reaction vessel, the temperature was controlled at-10-0 ℃ while stirring, N-Boc protected cefcapene pivoxil (75g) was added, recrystallization after stirring for 180min, centrifugation, washing of the crude product with water (500 mL x 3), and drying of the 20 h fine cefcapene pivoxil hydrochloride monohydrate (65 g).
| Example one | Example two | EXAMPLE III | Example four | Comparative example 1 | Comparative example No. two | Comparative example No. three | Comparative example No. four | Comparative example five | Comparative example six | Comparative example seven | |
| Solvent(s) | Acetonitrile | Acetonitrile | Acetonitrile | Methanol | Ethyl acetate | Acetonitrile | Acetonitrile | Acetonitrile | Acetonitrile | Acetonitrile | Acetonitrile |
| The dropping temperature is lower | -10-0 | -10-0 | -10-0 | -10-0 | -5-5 | -20 | 30 | -10-0 | -10-0 | -10-0 | -10-0 |
| Reaction time min | 120 | 120 | 120 | 120 | 315 | 120 | 120 | 120 | 120 | 60 | 180 |
| Hydrochloric acid and trifluoroacetic acid mol Ratio of | 8:1 | 10:1 | 5:1 | 8:1 | - | 8:1 | 8:1 | 20:1 | 2:1 | 8:1 | 8:1 |
| Yield% | 93 | 83 | 85 | 74 | 78 | 86 | 56 | 71 | 92 | 62 | 93 |
Comparing example 1 with example 4, it was found that the preferred solvent was acetonitrile. Comparing examples 1, 2,3 with comparative examples 4,5, it was found that when the molar ratio of hydrochloric acid to trifluoroacetic acid was within the range defined by the present invention, the yield was high and the amount of trifluoroacetic acid used was small. Comparative example 1 and comparative examples 2 and 3, it was found that the yield was high and stable when the temperature was within the range defined in the present invention. Comparative example 1 and comparative examples 6 and 7, it was found that the reaction time is preferably within the range defined in the present invention, the time is short and the yield can be secured. The method carries out deprotection and salification in one step, is simple and convenient to operate, consumes less time, is simple in post-treatment, is easy to control the temperature, generates less waste liquid and gas, is green and environment-friendly, and has high yield.
Claims (1)
1. A method for preparing cefcapene pivoxil hydrochloride is characterized by comprising the following steps: adding 375mL of acetonitrile, 56.3mL of 4N hydrochloric acid and 3.2g of trifluoroacetic acid into a reaction vessel, cooling to-10-0 ℃ while stirring, adding 75g of N-Boc protected cefcapene pivoxil, stirring for 120min, recrystallizing, centrifuging, washing a crude product with 500mL of 3 water, and drying to obtain 65g of a fine cefcapene pivoxil hydrochloride monohydrate product.
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| CN202010198097.7A CN111171050B (en) | 2020-03-20 | 2020-03-20 | Preparation method of cefcapene pivoxil hydrochloride |
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| CN111171050B true CN111171050B (en) | 2021-08-20 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102796117B (en) * | 2011-05-27 | 2016-08-10 | 江苏豪森药业集团有限公司 | A kind of preparation method of Method of cefcapene pivoxil hydrochloride |
| CN105254649B (en) * | 2015-11-02 | 2018-06-26 | 湖北凌晟药业有限公司 | A kind of preparation method of Method of cefcapene pivoxil hydrochloride |
| CN108033971B (en) * | 2017-12-29 | 2020-02-14 | 湖北凌晟药业有限公司 | Method for synthesizing cefcapene pivoxil hydrochloride |
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Effective date of registration: 20211011 Address after: 518028 room 1612, 16th floor, Zhonghao building, baguasi Road, Yuanling street, Futian District, Shenzhen, Guangdong Patentee after: Shenzhen botail Biotechnology Co.,Ltd. Address before: Kunming Medical University, No. 1168, Chunrong West Road, Yuhua street, Gongqu District, Kunming 650500, Yunnan Province Patentee before: Mao Tao |