CN103275104A - Preparation method of ceftobiprole and ceftobiprole medocaril - Google Patents
Preparation method of ceftobiprole and ceftobiprole medocaril Download PDFInfo
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Abstract
The invention discloses a preparation method of ceftobiprole and esters (Ia, Ib) of the ceftobiprole. The preparation method comprises the following steps of: processing (6R,7R)-7-amino-3-chloromethyl-8-oxo-5-thia-1-azabicyclo [4,2,0] octyl-2-alkene-2 formic (part A) and (Z)-2-(5-amino-[1,2,4] thiadiazole-3-yl)-2-hydroxy imino isopropoxyiminoacetate (part B) under the catalyzing of organic base to generate an intermediate (II); and processing the intermediate (II) by catalyzing and Witting reaction to obtain the target product. The preparation method is simple, convenient, economical, environmentally-friendly and beneficial to industrial production of the ceftobiprole and ceftobiprole medocaril.
Description
Technical field
The invention belongs to organic synthesis highway route design and bulk drug thereof and intermediate preparation technical field, particularly the preparation method of a kind of cephalo Toro and cephalo Toro ester.
Background technology
Cephalo Toro ester (Ceftobiprole Medocaril also claims the cephalo pyrrole general ester) is by Switzerland Ba Sai Leah drugmaker (Basilea Pharma-ceutica) and (the Johnso n of Johson ﹠ Johnson; Johnson) the novel cephalosporin analog antibiotic of common research and development, its effective constituent is cephalo Toro (Ceftobiprole).The cephalo Toro is broad-spectrum cephalosporin class microbiotic, its antimicrobial spectrum comprises methicillin-resistant gold Portugal bacterium (MRSA) and vancomycin resistance staphylococcus aureus (VRSA) etc., be at present unique to MRSA and the effective cephalosporins of VRSA, it has a extensive future, and is counted as a member of " the 5th generation " cephalosporins.The cephalo Toro injection of Ba Sai Leah drugmaker application was successively got permission listing in Canada, Switzerland in 2008, and (trade(brand)name is respectively
), can be used for treating complicacy skin and skin soft-tissue infection.Simultaneously, Ba Sai Leah drugmaker has submitted the application for quotation that is used for the treatment of pneumonia to European drug administration (EMEA) in July, 2012.
The chemistry of cephalo Toro (Ia) is by name: (6R, 7R)-7-[(Z)-2-(5-amino-[1,2,4] thiadiazoles-3-yl)-2-oxyimino kharophen]-the 8-oxo-3-[(E)-(3 ' R)-2-oxo-(1,3 '-bihyrrolidinyl)-the 3-ylidenylmethyl]-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-formic acid.
The chemistry of cephalo Toro ester (Ib) is by name: (6R, 7R)-7-[(Z)-2-(5-amino-[1,2,4] thiadiazoles-3-yl)-2-oxyimino kharophen]-the 8-oxo-3-[(E)-(3 ' R)-1 '-(5-methyl-2-oxo-1,3-Dioxol-4-yl methoxycarbonyl)-2-oxo-1,3 '-two tetramethyleneimine-3-ylidenylmethyl]-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-formic acid.
Use for reference the universal method of cephalosporin analog antibiotic preparation, with reference to the molecular structure characteristics as seen, cephalo Toro (Ia) and cephalo Toro ester (Ib) are formed by partA, part B and three structural units of part C, and wherein partA is the mother nucleus structure based on 7-Cephalosporanic acid (7-ACA); Part B is the side chain that contains amino thiadiazoles and hydroxyl imines; Part C is the formed dicyclo side chain of tetramethyleneimine and pyrrolidone or its ester (Ib).
Wherein, part A and part B's is that 7-bit amino by side chain and parent nucleus forms amido linkage and links, particularly, its link can be adopted carboxyl acid method, chloride method or active ester method etc., at present the most ripe, also be that to use the most general method in synthetic be exactly active ester method to cephalosporin analog antibiotic, namely under relatively mild condition, higher yields ground forms amido linkage.PartA and part C are the links of the trans ethylene linkage of carbon carbon, and the most simple and effective formation of this trans ethylene linkage is to be ladder Wei uncommon (Witting) reaction by quaternary alkylphosphonium salt and carbonyl condensation.At functional group's feature of partA and part C, the uncommon reaction of its ladder Wei has two kinds of different selections, and namely the carbonyl (being called for short the M-2 method) of the quaternary alkylphosphonium salt of the quaternary alkylphosphonium salt of the carbonyl of part A and part C (being called for short the M-1 method) and part A and part C carries out condensation.
So the preparation of cephalo Toro (Ia) or cephalo Toro ester (Ib) can have following four routes:
The uncommon reaction of ladder Wei (M-1 method) takes place in route article one, part A and part the C quaternary alkylphosphonium salt of the carbonyl by part A and part C earlier, the intermediate of generation again with part B amidate action generation cephalo Toro (Ia) and cephalo Toro ester (Ib).Patent provides a kind of preparation method of similar article one route for EP0849269A1 number and EP2010/136422 number; because this method is when carrying out the uncommon reaction of ladder Wei; need carry out necessary protection to amino and the carboxyl of part A, thereby increase reactions steps, manufacturing cost is increased to some extent.Simultaneously, the carbonyl of part A form to be what the selective oxidation by primary alconol made, needs to use special oxygenant, as Dai Si-Martin (Dess-Martin) oxygenant, Jones (Jones ') oxygenant or radical (TEMPO) oxygenant.
The uncommon reaction of ladder Wei (M-2 method) takes place by the quaternary alkylphosphonium salt of part A and the carbonyl of part C earlier in second route, part A and part C, and the intermediate of generation generates cephalo Toro (Ia) or cephalo Toro ester (Ib) with part B amidate action again.Patent EP1067131A1 number, EP0841339 number and a kind of preparation method who is similar to the second route is provided for WO9529182 number; though this method has been saved special oxidizing reaction, but still the loaded down with trivial details defective of technology that exists protection and deprotection by functional group to cause.
Article three, route, part A and part B generate the intermediate of 7-position functionalization earlier by amidate action, the uncommon reaction of ladder Wei (M-1 method) takes place in the carbonyl functional group that this intermediate oxidation forms and the quaternary alkylphosphonium salt of part C, generates cephalo Toro (Ia) or cephalo Toro ester (Ib).Patent provides a kind of preparation method of similar the 3rd route for WO01/90111 number, studies show that, when part A and part B in advance in conjunction with after, need not to carry out any protection, can carry out the follow-up uncommon reaction of ladder Wei.So this method has been omitted protection and the deprotection of functional group, but because the uncommon reaction of the ladder Wei of the M-1 method of using still needs to use some special oxygenants, increased technology difficulty.
Obviously, article four, route should be part A and part B generate 7-position functionalization earlier by amidate action intermediate, the uncommon reaction of ladder Wei (M-2 method) takes place in the quaternary alkylphosphonium salt that this intermediate forms and the carbonyl functional group of part C, generates cephalo Toro (Ia) or cephalo Toro ester (Ib).This method had both been saved protection and the deprotection of functional group, need not to carry out special oxidizing reaction again.And the halogen (chlorine or bromine) that is used to form part A quaternary alkylphosphonium salt can obtain from the antibiotic bulk raw material GCLE of cephalo or GCLH easily.Article four, at other antibiotic synthetic existing research, but the research that specifically is applied in the preparation process of cephalo Toro (Ia) or cephalo Toro ester (Ib) does not appear in the newspapers the synthetic thinking of route as yet in Chinese patent CN101210021A number.
In addition, patent has been described the medicinal characteristic of cephalo Toro ester for WO99/65920 number and how have been prepared the method for cephalo Toro ester from the cephalo Toro, but does not relate to the preparation of cephalo Toro itself.
Summary of the invention
The objective of the invention is to overcome the defective of prior art, synthetic theory according to Green Chemistry, the preparation method of a kind of improved cephalo Toro and cephalo Toro ester is provided, this preparation method is easy, economy and environmental protection, the suitability for industrialized production that is conducive to this medicine, and can promote the development of the economic technology of this bulk drug.
To achieve these goals, main technical schemes provided by the present invention is as follows: the preparation method of a kind of cephalo Toro (Ia) and cephalo Toro ester (Ib),
The method comprising the steps of: (6R, 7R)-7-amino-3-chloromethyl-8-oxo-5-thia-1-azabicyclic [4,2,0] oct-2-ene-2 formic acid (part A) with (Z)-2-(5-amino-[1,2,4] thiadiazoles-3-yl)-2-oxyimino acetic acid sulfydryl benzene isothiazole ester (part B) forms intermediate (6R under the catalysis of organic bases, 7R)-7-[(Z)-2-(5-amino-[1,2,4] thiadiazoles-3-yl)-2-oxyimino kharophen]-8-oxo-3-chloromethyl-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-formic acid (II); Intermediate (II) is prepared into quaternary alkylphosphonium salt (6R with triphenylphosphine under the potassiumiodide katalysis, 7R)-7-[(Z)-2-(5-amino-[1,2,4] thiadiazoles-3-yl)-2-oxyimino kharophen]-8-oxo-3-methyl triphenyl phosphine-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-formic acid iodide (III); And as intermediate (III) and 3 ' R-2, cephalo Toro (Ia) takes place to obtain when ladder is wished reaction Wei in 3-dioxo-1,3 '-two tetramethyleneimine (part C-1); Perhaps, when intermediate (III) and 3 ' R-1 '-(5-methyl-2-oxo-[1,3]-Dioxol-4-yl methoxycarbonyl)-2,3-oxo-1,3 '-two tetramethyleneimine (part C-2) obtains cephalo Toro ester (Ib) when uncommon reaction of ladder Wei taken place.
In addition, the present invention also provides following attached technical scheme:
During preparation cephalo Toro (Ia), raw material (the 6R of ladder Wei uncommon (Witting) reaction, 7R)-7-[(Z)-2-(5-amino-[1,2,4] thiadiazoles-3-yl)-2-oxyimino kharophen]-8-oxo-3-methyl triphenyl phosphine-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-formic acid iodide (III) and 3 ' R-2, the molar ratio of 3-dioxo-1,3 '-two tetramethyleneimine (part C-1) is 1: 1-5, preferred 1: 1.1-1.3.
During preparation cephalo Toro ester (Ib), raw material (the 6R of ladder Wei uncommon (Witting) reaction, 7R)-7-[(Z)-2-(5-amino-[1,2,4] thiadiazoles-3-yl)-2-oxyimino kharophen]-8-oxo-3-methyl triphenyl phosphine-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-formic acid iodide (III) and 3 ' R-1 '-(5-methyl-2-oxo-[1,3]-and the Dioxol-4-yl methoxycarbonyl)-2, the molar ratio of 3-oxo-1,3 '-two tetramethyleneimine (part C-2) is 1: 1.1-1.3.
The solvent of the uncommon reaction of described ladder Wei is methylene dichloride, trichloromethane, toluene, tetrahydrofuran (THF), dioxane, methyl alcohol, ethanol, Virahol, acetonitrile, ethyl acetate, methyl ethyl ketone, methyl iso-butyl ketone (MIBK) or acetone, preferred methylene dichloride or acetone.
The uncommon catalyst for reaction of described ladder Wei is sodium methylate, sodium ethylate, sodium hydroxide, yellow soda ash, potassium hydroxide, salt of wormwood or potassium tert.-butoxide, preferred potassium tert.-butoxide.
The temperature of the uncommon reaction of described ladder Wei is 0-100 ℃, preferred 25-45 ℃.
Than prior art, the preparation method of cephalo Toro involved in the present invention and cephalo Toro ester, its advantage mainly is that the preparation method is simple, the gentle easily control of reaction conditions, raw material is cheap and easy to get, and product yield and product purity height are suitable for large-scale industrial production.
Embodiment
Below in conjunction with several preferred embodiments technical solution of the present invention is done further nonrestrictive explanation.
Embodiment one:
In reaction flask, add (6R, 7R)-7-[(Z)-2-(5-amino-[1,2,4] thiadiazoles-3-yl)-2-oxyimino kharophen]-8-oxo-3-methyl triphenyl phosphine-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-formic acid iodide (III) (7.7g, 10mmol), 3 ' R-2, (2.0g is 12mmol) with methylene dichloride 100mL for 3-dioxo-1,3 '-two tetramethyleneimine (part C-1).Start stirring, (0.15g 1.2mmol), is warming up to 45 ℃, reacts 6 hours, and the TLC detection reaction is finished to add potassium tert.-butoxide.Add water 100mL, and be adjusted to neutrality with sodium bicarbonate.Tell organic phase, drying is evaporated to dried.Resistates Virahol recrystallization gets white solid cephalo Toro (Ia) 4.5g, yield 82.9%.
Embodiment two:
In reaction flask, add (6R, 7R)-7-[(Z)-2-(5-amino-[1,2,4] thiadiazoles-3-yl)-2-oxyimino kharophen]-8-oxo-3-methyl triphenyl phosphine-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-formic acid iodide (III) (7.7g, 10mmol), 3 ' R-1 '-(5-methyl-2-oxo-[1,3]-Dioxol-4-yl methoxycarbonyl)-2,3-oxo-1, (3.9g is 12mmol) with methylene dichloride 100mL for 3 '-two tetramethyleneimine (part C-2).Start stirring, (0.15g 1.2mmol), is warming up to 40 ℃, reacts 5 hours, and the TLC detection reaction is finished to add potassium tert.-butoxide.Add water 100mL, and be adjusted to neutrality with sodium bicarbonate.Tell organic phase, drying is evaporated to dried.Resistates Virahol recrystallization gets white solid cephalo Toro ester (Ib) 5.9g, yield 90.8%.
It is pointed out that above-mentioned preferred embodiment only is explanation technical conceive of the present invention and characteristics, its purpose is to allow the personage who is familiar with this technology can understand content of the present invention and enforcement according to this, can not limit protection scope of the present invention with this.All equivalences that spirit is done according to the present invention change or modify, and all should be encompassed within protection scope of the present invention.
Claims (10)
1. the preparation method of a cephalo Toro (Ia),
Ia cephalo Toro
It is characterized in that described preparation method comprises the steps: (6R, 7R)-7-amino-3-chloromethyl-8-oxo-5-thia-1-azabicyclic [4,2,0] oct-2-ene-2 formic acid (part A) with (Z)-2-(5-amino-[1,2,4] thiadiazoles-3-yl)-2-oxyimino acetic acid sulfydryl benzene isothiazole ester (part B) forms intermediate (6R under the catalysis of organic bases, 7R)-7-[(Z)-2-(5-amino-[1,2,4] thiadiazoles-3-yl)-2-oxyimino kharophen]-8-oxo-3-chloromethyl-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-formic acid (II); Described intermediate (II) is prepared into intermediate quaternary alkylphosphonium salt (6R with triphenylphosphine under the potassiumiodide katalysis, 7R)-7-[(Z)-2-(5-amino-[1,2,4] thiadiazoles-3-yl)-2-oxyimino kharophen]-8-oxo-3-methyl triphenyl phosphine-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-formic acid iodide (III); And described intermediate (III) and 3 ' R-2, the uncommon reaction of ladder Wei takes place and obtains described cephalo Toro (Ia) in 3-dioxo-1,3 '-two tetramethyleneimine (part C-1).
2. according to the preparation method of the described cephalo Toro of claim 1, it is characterized in that: the raw material (6R of the uncommon reaction of described ladder Wei, 7R)-7-[(Z)-2-(5-amino-[1,2,4] thiadiazoles-3-yl)-2-oxyimino kharophen]-8-oxo-3-methyl triphenyl phosphine-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-formic acid iodide (III) and 3 ' R-2, the molar ratio of 3-dioxo-1,3 '-two tetramethyleneimine (part C-1) is 1:1-5.
3. according to the preparation method of the described cephalo Toro of claim 1, it is characterized in that: the solvent of the uncommon reaction of described ladder Wei is methylene dichloride, trichloromethane, toluene, tetrahydrofuran (THF), dioxane, acetonitrile, ethyl acetate, methyl ethyl ketone, methyl iso-butyl ketone (MIBK) or acetone.
4. according to the preparation method of the described cephalo Toro of claim 1, it is characterized in that: the uncommon reaction of described ladder Wei catalyst system therefor is sodium methylate, sodium ethylate, sodium hydroxide, yellow soda ash, potassium hydroxide, salt of wormwood or potassium tert.-butoxide.
5. according to the preparation method of the described cephalo Toro of claim 1, it is characterized in that: the temperature of the uncommon reaction of described ladder Wei is 0-100 ℃.
6. the preparation method of a cephalo Toro ester (Ib),
Ib cephalo Toro ester
It is characterized in that described preparation method comprises the steps: (6R, 7R)-7-amino-3-chloromethyl-8-oxo-5-thia-1-azabicyclic [4,2,0] oct-2-ene-2 formic acid (part A) with (Z)-2-(5-amino-[1,2,4] thiadiazoles-3-yl)-2-oxyimino acetic acid sulfydryl benzene isothiazole ester (part B) forms intermediate (6R under the catalysis of organic bases, 7R)-7-[(Z)-2-(5-amino-[1,2,4] thiadiazoles-3-yl)-2-oxyimino kharophen]-8-oxo-3-chloromethyl-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-formic acid (II); Described intermediate (II) is prepared into intermediate quaternary alkylphosphonium salt (6R with triphenylphosphine under the potassiumiodide katalysis, 7R)-7-[(Z)-2-(5-amino-[1,2,4] thiadiazoles-3-yl)-2-oxyimino kharophen]-8-oxo-3-methyl triphenyl phosphine-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-formic acid iodide (III); And described intermediate (III) and 3 ' R-1 '-(5-methyl-2-oxo-[1,3]-Dioxol-4-yl methoxycarbonyl)-2, the uncommon reaction of ladder Wei takes place and obtains described cephalo Toro ester (Ib) in 3-oxo-1,3 '-two tetramethyleneimine (part C-2).
7. according to the preparation method of the described cephalo Toro of claim 6 ester, it is characterized in that: the raw material (6R of the uncommon reaction of described ladder Wei, 7R)-7-[(Z)-2-(5-amino-[1,2,4] thiadiazoles-3-yl)-2-oxyimino kharophen]-8-oxo-3-methyl triphenyl phosphine-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-formic acid iodide (III) and 3 ' R-1 '-(5-methyl-2-oxo-[1,3]-and the Dioxol-4-yl methoxycarbonyl)-2, the molar ratio of 3-oxo-1,3 '-two tetramethyleneimine (part C-2) is 1:1-5.
8. according to the preparation method of the described cephalo Toro of claim 6 ester, it is characterized in that: the solvent of the uncommon reaction of described ladder Wei is methylene dichloride, trichloromethane, toluene, tetrahydrofuran (THF), dioxane, acetonitrile, ethyl acetate, methyl ethyl ketone, methyl iso-butyl ketone (MIBK) or acetone.
9. according to the preparation method of the described cephalo Toro of claim 6 ester, it is characterized in that: the uncommon reaction of described ladder Wei catalyst system therefor is sodium methylate, sodium ethylate, sodium hydroxide, yellow soda ash, potassium hydroxide, salt of wormwood or potassium tert.-butoxide.
10. according to the preparation method of the described cephalo Toro of claim 6 ester, it is characterized in that: the temperature of the uncommon reaction of described ladder Wei is 0-100 ℃.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105601648A (en) * | 2016-03-09 | 2016-05-25 | 上海宁瑞生化技术有限公司 | Method for preparing ceftobiprole through one-pot reaction |
| CN111471058A (en) * | 2019-01-23 | 2020-07-31 | 中国医学科学院药物研究所 | Process for preparing cephapirin analogues |
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| EP0382268A1 (en) * | 1989-01-06 | 1990-08-16 | Gist-Brocades N.V. | New amino carboxylic acid derivatives |
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| CN105601648A (en) * | 2016-03-09 | 2016-05-25 | 上海宁瑞生化技术有限公司 | Method for preparing ceftobiprole through one-pot reaction |
| CN111471058A (en) * | 2019-01-23 | 2020-07-31 | 中国医学科学院药物研究所 | Process for preparing cephapirin analogues |
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