CN112094247A - Cephalosporin drug intermediate and synthesis method thereof - Google Patents
Cephalosporin drug intermediate and synthesis method thereof Download PDFInfo
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- CN112094247A CN112094247A CN202010846694.6A CN202010846694A CN112094247A CN 112094247 A CN112094247 A CN 112094247A CN 202010846694 A CN202010846694 A CN 202010846694A CN 112094247 A CN112094247 A CN 112094247A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/587—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with aliphatic hydrocarbon radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms, said aliphatic radicals being substituted in the alpha-position to the ring by a hetero atom, e.g. with m >= 0, Z being a singly or a doubly bound hetero atom
- C07D277/593—Z being doubly bound oxygen or doubly bound nitrogen, which nitrogen is part of a possibly substituted oximino radical
Abstract
The invention provides a cephalosporin drug intermediate and a synthesis method thereof, belonging to the technical field of medicine synthesis. The synthesis method comprises the following steps: d) reacting a compound with a structure shown in a formula (IV) with tin dioxide to obtain a compound with a structure shown in a formula (V-1); e) reacting the compound with the structure of the formula (V-1) with sodium hydroxide to obtain a compound with the structure of the formula (V-2);
Description
Technical Field
The invention belongs to the technical field of medicine synthesis, and particularly relates to a cephalosporin medicine intermediate and a synthesis method thereof.
Background
Cephalosporin drugs hold a great position in the field of Chinese medicine, and cephalosporin antibiotics are the antibiotics with the widest application range and the largest use amount in the world.
The compound of the ainothiazoly loximate is used as a cephalosporin side chain acid, is an important intermediate for synthesizing cephalosporin drugs, and has important economic and practical values in researching the structure and the synthesis method of the compound of the ainothiazoly loximate.
And the methyl aminothiazoline acid compound is oximated to obtain the aminothiazoline oxime acid compound, which is an important intermediate for synthesizing the aminothiazoline oxime acid compound.
In 2008, Kenji Yamawaki et al disclose that [ A novel series of partial cephalosporins exterminating sites against fungi and other gram-reactive strains ] Methylaminothionic acids were reacted to synthesize cephalosporins.
Disclosure of Invention
In one aspect, the invention provides cephalosporin drug intermediates, which can be used for synthesizing an aminothiazoly loximate compound for preparing cephalosporin antibiotics.
On the other hand, the invention provides a synthesis method of a cephalosporin drug intermediate. The method has novel reaction route and mild reaction condition.
The invention provides a cephalosporin drug intermediate which has a structure shown in a formula (V):
wherein R is alkyl or H.
Further, R is C1～C4An alkyl group.
The invention also provides a synthesis method of the cephalosporin drug intermediate, which comprises the following steps:
d) reacting a compound with a structure shown in a formula (IV) with tin dioxide to obtain a compound with a structure shown in a formula (V-1);
e) reacting a compound with a structure of a formula (V-1) with alkali to obtain a compound with a structure of a formula (V-2);
further, the compound with the structure of the formula (IV) is prepared according to the following steps:
c) reacting a compound with a structure shown in a formula (III) with di-tert-butyl dicarbonate and tetramethylethylenediamine to obtain a compound with a structure shown in a formula (IV);
further, the compound with the structure of the formula (III) is prepared according to the following steps:
b) reacting a compound with a structure shown in a formula (II) with thiourea to obtain a compound with a structure shown in a formula (III);
further, the compound with the structure of the formula (II) is prepared according to the following steps:
a) reacting a compound with a structure shown in a formula (I) with bromine to obtain a compound with a structure shown in a formula (II);
further, in the step a): the molar ratio of the compound having the structure of formula (I) to bromine is 1:0.8 to 1.5; mixing a compound having a structure of formula (I) with bromine at 0 ℃; the reaction temperature is 0-40 ℃.
Further, in the step b): the molar ratio of the compound with the structure of the formula (II) to thiourea is 1: 1.5-3; the reaction temperature is 110-120 ℃.
Further, in the step c): the molar ratio of the compound with the structure of formula (III) to di-tert-butyl dicarbonate and tetramethylethylenediamine is (1-5) to (4-7) to (6-8); the reaction temperature is 40-60 ℃.
Further, in the step d): the molar ratio of the compound with the structure of the formula (IV) to the tin dioxide is 1: 1-3; the solvent of the reaction is dioxane; the reaction temperature is 90-130 ℃.
Further, in the step e): the molar ratio of the compound with the structure of formula (V-1) to the alkali is 1: 1-2; the base comprises sodium hydroxide or potassium hydroxide; the solvent for reaction is a mixed solvent of tetrahydrofuran and ethanol; wherein the volume ratio of the tetrahydrofuran to the ethanol is 1:1.
The invention has the following advantages:
the synthesis method of the cephalosporin drug intermediate provided by the invention has the advantages of wide raw material source, novel reaction route, mild reaction conditions and high product yield, and is suitable for large-scale production. The obtained cephalosporin drug intermediate can be used as a cephalosporin antibiotic intermediate for preparing cephalosporin antibiotics.
Detailed Description
It should be noted that the embodiments and features of the embodiments may be combined with each other without conflict. The source of the raw material used in the present invention is not particularly limited.
The embodiment of the invention provides a cephalosporin drug intermediate which has a structure shown in a formula (V):
wherein R is alkyl or H.
Further, R is C1～C4An alkyl group. Specifically, R may be methyl, ethyl, propyl, butyl, or the like.
The embodiment of the invention provides a method for synthesizing a cephalosporin drug intermediate, which comprises the following steps:
d) reacting a compound with a structure shown in a formula (IV) with tin dioxide to obtain a compound with a structure shown in a formula (V-1);
e) reacting a compound with a structure of a formula (V-1) with alkali to obtain a compound with a structure of a formula (V-2);
specifically, in step d):
the molar ratio of the compound with the structure of the formula (IV) to the tin dioxide is 1: 1-3; preferably, the molar ratio of the compound with the structure of the formula (IV) to the tin dioxide is 1: 2; the solvent of the reaction is organic solvent; preferably, the solvent of the reaction is dioxane; the concentration of the compound with the structure of formula (IV) in dioxane is 0.5-1.2 mol/L; the concentration of the compound with the structure of the formula (IV) in dioxane is 0.766 mol/L.
The reaction temperature is 90-130 ℃; preferably, the temperature of the reaction is 105 ℃; the reaction time is not limited, and the completion of the reaction can be monitored (TLC).
The post-treatment of the reaction includes: filtering the reaction mixture, concentrating the filtrate under reduced pressure to remove the solvent, and separating the obtained concentrate to obtain the compound with the structure of formula (V-1).
Specifically, in step e):
the molar ratio of the compound with the structure of formula (V-1) to the alkali is 1: 1-2; in some embodiments of the invention, the molar ratio of the compound having the structure of formula (V-1) to the base is 5.09: 7.63; the base comprises sodium hydroxide or potassium hydroxide; preferably, the base is sodium hydroxide; the solvent for reaction is a mixed solvent of tetrahydrofuran and ethanol; wherein the volume ratio of the tetrahydrofuran to the ethanol is 1:1.
Mixing a compound with a structure of formula (V-1) with sodium hydroxide at 0 ℃; the reaction temperature is 0-40 ℃; preferably, the reaction temperature is 10-30 ℃; in some embodiments of the invention, the temperature of the reaction is room temperature; the reaction time is not limited, and the completion of the reaction can be monitored (TLC).
The post-treatment of the reaction includes: concentrating the reaction solution under reduced pressure to remove solvent, cooling to 0 deg.C, adjusting pH to 4 with 1N diluted hydrochloric acid to precipitate, filtering, and drying to obtain white compound with formula (V-2).
In one embodiment of the invention, the compound having the structure of formula (IV) is prepared as follows:
c) reacting a compound with a structure shown in a formula (III) with di-tert-butyl dicarbonate and tetramethylethylenediamine to obtain a compound with a structure shown in a formula (IV);
specifically, in step c):
the molar ratio of the compound with the structure of formula (III) to di-tert-butyl dicarbonate and tetramethylethylenediamine is (1-5) to (4-7) to (6-8); in one embodiment of the invention, the molar ratio of the compound with the structure of formula (III) to di-tert-butyl dicarbonate and tetramethylethylenediamine is 3.45mmol:5.86mmol:6.89 mmol; the solvent of the reaction is organic solvent; preferably, the solvent of the reaction is acetonitrile.
The reaction temperature is 40-60 ℃; preferably, the temperature of the reaction is 50 ℃; the reaction time is not limited, and the completion of the reaction can be monitored (TLC).
The post-treatment of the reaction includes: diluting the reaction mixture with ethyl acetate, washing with brine, drying, concentrating the organic phase, and separating to obtain the compound with the structure of formula (IV).
In one embodiment of the invention, the compound having the structure of formula (iii) is prepared as follows:
b) reacting a compound with a structure shown in a formula (II) with thiourea to obtain a compound with a structure shown in a formula (III);
specifically, in step b):
the molar ratio of the compound with the structure of the formula (II) to thiourea is 1: 1.5-3; preferably, the molar ratio of the compound having the structure of formula (II) to thiourea is 1: 2; the solvent of the reaction is organic solvent; preferably, the solvent of the reaction is toluene.
The reaction temperature is 110-120 ℃; the reaction time is not limited, and the completion of the reaction can be monitored (TLC).
The post-treatment of the reaction includes: after the reaction is finished, adding dichloromethane into the concentrated reaction solution for dilution, adding saturated sodium carbonate and stirring; drying the organic phase, and recrystallizing to obtain the compound with the structure of the formula (III).
In one embodiment of the present invention, the compound having the structure of formula (ii) is prepared as follows:
a) reacting a compound with a structure shown in a formula (I) with bromine to obtain a compound with a structure shown in a formula (II);
specifically, in step a):
the molar ratio of the compound with the structure of formula (I) to bromine is 1: 0.8-1.5; preferably, the molar ratio of the compound with the structure of the formula (I) to bromine is 1: 1.2; the solvent of the reaction is organic solvent; preferably, the solvent of the reaction is dichloromethane.
Mixing a compound having a structure of formula (I) with bromine at 0 ℃; the reaction temperature is 0-40 ℃; preferably, the reaction temperature is 10-30 ℃; in some embodiments of the invention, the temperature of the reaction is room temperature; the reaction time is not limited, and the completion of the reaction can be monitored (TLC).
The post-treatment of the reaction includes: adding saturated sodium carbonate solution into the reaction mixed solution, stirring, extracting with dichloromethane, washing the organic phase with saturated saline, adding anhydrous sodium sulfate, drying, concentrating the organic phase, and separating to obtain the compound with the structure of the formula (II).
The present invention will be described in detail with reference to examples.
Example 1
Step a) preparation of Compound 2 having the Structure of formula (II) (4-bromo-3-oxopentanoic acid ethyl ester)
Compound 1(3g,20.8mmol) having the structure of formula (I) was dissolved in 20mL of dichloromethane, and bromine (1.1mL,20.8mmol) was added dropwise at 0 ℃ and reacted overnight after the temperature of the system was raised to room temperature. After TLC monitoring reaction is completed, adding saturated sodium carbonate solution, stirring for fifteen minutes, extracting a reaction system by using dichloromethane, washing an organic phase by using saturated salt water for three times, adding anhydrous sodium sulfate, drying, concentrating the organic phase, and separating by using column chromatography to obtain an oily compound 2(1.95g, yield 65%) with a structure shown in formula (II), wherein the nuclear magnetic characterization result is as follows:
1H NMR(400MHz,DMSO-d6)H 1.20(t,J＝7.1Hz,3H),1.66(d,J＝6.7Hz,3H),4.11(q,J＝7.1Hz,1H),4.88(q,J＝6.7Hz,2H),5.43(s,1H),11.84(s,1H)。
step b) preparation of Compound 3 having the structure of formula (III) (ethyl 2- (2-amino-5-methylthiazol-4-yl) acetate)
Compound 2(1.2g,5.4mmol) having the structure of formula (II) was dissolved in toluene at room temperature, and addedThiourea(0.82g,10.8mmol) and then heated to 110 ℃ for three hours under reflux. After the completion of the reaction was monitored by TLC, the concentrated reaction solution was diluted with dichloromethane, and then saturated sodium carbonate was added thereto to stir the reaction for fifteen minutes. The organic phase was dried over anhydrous sodium sulfate and recrystallized from dichloromethane and n-hexane to give compound 3(1.1g, yield 87%) as white crystals having the structure of formula (iii) as follows:
1H NMR(400MHz,DMSO-d6)H 1.17(t,J＝7.1Hz,3H),2.12(s,3H),3.83(s,2H),4.05(q,J＝7.1Hz,3H),6.69(s,2H)。
step c) preparation of Compound 4 having the structure of formula (IV) (Ethyl 2- (2- (((tert-butoxycarbonyl) amino) -5-methylthiazol-4-yl) -2-oxoacetate)
Compound 3(0.69g, 3.45mmol) having the structure of formula (III) was dissolved in 15mL of acetonitrile (MeCN), and di-tert-butyl dicarbonate (Boc) was added at room temperature2O) (1.28g, 5.86mmol) and Tetramethylethylenediamine (TMEAD) (0.8g, 6.89 mmol). The reaction mixture was heated to 50 ℃ and reacted for 8 hours, and completion of the reaction was confirmed by TLC. The reaction mixture was diluted with ethyl acetate, washed successively with water, brine three times, and dried over anhydrous sodium sulfate. The organic phase was concentrated and separated by column chromatography to give the target compound 4(0.46g, 66% yield) having the structure of formula (iv) as a yellow solid, and characterized by the following nuclear magnetic properties:
1H NMR(400MHz,DMSO-d6)H 1.17(t,J＝7.1Hz,3H),1.46(s,9H),2.23(s,3H),3.56(s,2H),4.05(q,J＝7.1Hz,2H),11.24(s,1H)。
step d) preparation of Compound 5 having the structure of formula (V-1) (Ethyl 2- (2- (((tert-butoxycarbonylcarbonyl) amino) -5-methylthiazol-4-yl) acetate)
Compound 4(4.6g,15.32mmol) having the structure of formula (IV) was dissolved in 20ml of Dioxane (Dioxane), and tin dioxide (SeO2) (3.4g, 30.63mmol) was added at room temperature. The reaction mixture was then refluxed at 105 ℃ for 24 hours. After TLC monitoring completion of the reaction, the reaction mixture was filtered on a silica gel pad and the filtrate was concentrated under reduced pressure to remove the solvent. The obtained concentrate was subjected to column chromatography to obtain a yellow amorphous target compound 5 having a structure of formula (V-1) (1.5g, yield 33%), and nuclear magnetic characterization as follows:
1H NMR(400MHz,DMSO-d6)H1.29(t,J＝7.1Hz,3H),1.47(s,9H),2.66(s,3H),4.32(q,J＝7.1Hz,2H),11.74(s,1H).
step e) preparation of Compound 6 having the structure of formula (V-2) 2- (2- ((tert-butoxycarbonyl) amino) -5-methylthiazol-4-yl) -2-oxoacetic acid)
Compound 5(1.6g,5.09mmol) having the structure of formula (V-1) was dissolved in a mixed solvent of tetrahydrofuran (8mL) and ethanol (8mL), cooled to 0 ℃ and added dropwise with an aqueous solution of sodium hydroxide (1N, 7.63mL), warmed to room temperature and reacted for 6 hours. After TLC monitoring reaction, the reaction solution was concentrated under reduced pressure to remove the solvent, cooled to 0 deg.C, and the precipitate was precipitated by adjusting pH to 4 with 1N diluted hydrochloric acid, and the precipitate was filtered and dried to obtain white compound 6(1.3g, yield 85%) having the structure of formula (V-2), and the nuclear magnetic characterization results were as follows:
1H NMR(400MHz,DMSO-d6):1.46(s,9H),2.61(s,3H),11.7(s,1H).
the present invention is not limited to the above preferred embodiments, and any modifications, equivalent substitutions, improvements, etc. within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. The cephalosporin drug intermediate has a structure shown in a formula (V):
wherein R is alkyl or H.
2. The compound of claim 1, wherein R is C1～C4An alkyl group.
3. A synthetic method of a cephalosporin drug intermediate comprises the following steps:
d) reacting a compound with a structure shown in a formula (IV) with tin dioxide to obtain a compound with a structure shown in a formula (V-1);
e) reacting a compound with a structure of a formula (V-1) with alkali to obtain a compound with a structure of a formula (V-2);
4. the method of claim 3, wherein the compound having the structure of formula (IV) is prepared by the following steps:
c) reacting a compound with a structure shown in a formula (III) with di-tert-butyl dicarbonate and tetramethylethylenediamine to obtain a compound with a structure shown in a formula (IV);
5. the method of claim 3, wherein the compound having the structure of formula (III) is prepared by the steps of:
b) reacting a compound with a structure shown in a formula (II) with thiourea to obtain a compound with a structure shown in a formula (III);
6. the method of claim 3, wherein the compound having the structure of formula (II) is prepared by the following steps:
a) reacting a compound with a structure shown in a formula (I) with bromine to obtain a compound with a structure shown in a formula (II);
7. the method of claim 6,
in the step a): the molar ratio of the compound having the structure of formula (I) to bromine is 1:0.8 to 1.5; mixing a compound having a structure of formula (I) with bromine at 0 ℃; the reaction temperature is 0-40 ℃.
8. The method of claim 5,
in the step b): the molar ratio of the compound with the structure of the formula (II) to thiourea is 1: 1.5-3; the reaction temperature is 110-120 ℃.
9. The method of claim 4,
in the step c): the molar ratio of the compound with the structure of formula (III) to di-tert-butyl dicarbonate and tetramethylethylenediamine is (1-5) to (4-7) to (6-8); the reaction temperature is 40-60 ℃.
10. The method of claim 3,
in the step d): the molar ratio of the compound with the structure of the formula (IV) to the tin dioxide is 1: 1-3; the solvent of the reaction is dioxane; the reaction temperature is 90-130 ℃;
in step e): the molar ratio of the compound with the structure of formula (V-1) to the alkali is 1: 1-2; the base comprises sodium hydroxide or potassium hydroxide; the solvent for reaction is a mixed solvent of tetrahydrofuran and ethanol; wherein the volume ratio of the tetrahydrofuran to the ethanol is 1:1.
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4191762A (en) * | 1974-03-14 | 1980-03-04 | Fujisawa Pharmaceutical Co., Ltd. | 2-Lower alkyl-7-substituted amino-2 or 3-cephem-4-carboxylic acid compounds |
| US4288436A (en) * | 1977-04-13 | 1981-09-08 | Fujisawa Pharmaceutical Co., Ltd. | 3,7-Disubstituted-3-cephem-4-carboxylic acid compounds |
| US4386089A (en) * | 1978-04-26 | 1983-05-31 | Bayer Aktiengesellschaft | β-Lactam antibiotics and their medicinal use |
| US4440766A (en) * | 1976-03-09 | 1984-04-03 | Fujisawa Pharmaceutical Co., Ltd. | 3,7-Disubstituted-3-cephem-4-carboxylic acid compounds |
| US20180153860A1 (en) * | 2016-12-02 | 2018-06-07 | T3D Therapeutics, Inc. | Methods of dose administration for treating or preventing cognitive impairment using indane acetic acid derivatives |
| CN114728953A (en) * | 2020-08-06 | 2022-07-08 | 宁夏农林科学院 | Beta-lactam compounds, process for their preparation and their use as antibiotics |
-
2020
- 2020-08-21 CN CN202010846694.6A patent/CN112094247A/en not_active Withdrawn
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4191762A (en) * | 1974-03-14 | 1980-03-04 | Fujisawa Pharmaceutical Co., Ltd. | 2-Lower alkyl-7-substituted amino-2 or 3-cephem-4-carboxylic acid compounds |
| US4440766A (en) * | 1976-03-09 | 1984-04-03 | Fujisawa Pharmaceutical Co., Ltd. | 3,7-Disubstituted-3-cephem-4-carboxylic acid compounds |
| US4288436A (en) * | 1977-04-13 | 1981-09-08 | Fujisawa Pharmaceutical Co., Ltd. | 3,7-Disubstituted-3-cephem-4-carboxylic acid compounds |
| US4386089A (en) * | 1978-04-26 | 1983-05-31 | Bayer Aktiengesellschaft | β-Lactam antibiotics and their medicinal use |
| US20180153860A1 (en) * | 2016-12-02 | 2018-06-07 | T3D Therapeutics, Inc. | Methods of dose administration for treating or preventing cognitive impairment using indane acetic acid derivatives |
| CN114728953A (en) * | 2020-08-06 | 2022-07-08 | 宁夏农林科学院 | Beta-lactam compounds, process for their preparation and their use as antibiotics |
Non-Patent Citations (1)
| Title |
|---|
| KENJI YAMAWAKI 等: "A novel series of parenteral cephalosporins exhibiting potent activities against Pseudomonas aeruginosa and other Gram-negative pathogens: Synthesis and structure–activity relationships" * |
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