CN106083896A - A kind of preparation method of Method of cefcapene pivoxil hydrochloride - Google Patents
A kind of preparation method of Method of cefcapene pivoxil hydrochloride Download PDFInfo
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- CN106083896A CN106083896A CN201610706164.5A CN201610706164A CN106083896A CN 106083896 A CN106083896 A CN 106083896A CN 201610706164 A CN201610706164 A CN 201610706164A CN 106083896 A CN106083896 A CN 106083896A
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- CN
- China
- Prior art keywords
- preparation
- compound
- hydrochloride
- layer
- cefcapene pivoxil
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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
-
- 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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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Cephalosporin Compounds (AREA)
Abstract
The invention discloses the preparation method of a kind of important third generation orally available cephalosporins Method of cefcapene pivoxil hydrochloride, BCN is dissolved in dichloroethanes, dock with 4 side chain iodometyl pivalates, then slough the BOC of 7 bit aminos with the ethyl acetate solution of hydrogen chloride protect and directly generate semicarbazide hydrochloride, last in methanol with diluted hydrochloric acid aqueous solution recrystallization, obtain 7 [2 (2 amino 1 of band a part water, 3 thiazole 4 bases) penta 3 acrylamide bases] pungent 2 alkene 2 formic acid 2 of 3 (carbamoyloxymethyl) 8 oxo 5 sulfur 1 azabicyclo [4.2.0], the white crystal of 2 dimethyl propylene acyloxymethyl ester hydrochlorides.The synthesis step of the present invention is few, low cost, and each material used is cheap and easy to get, beneficially industrialized production, pollute little.
Description
Technical field
The invention belongs to pharmaceutical chemistry technical field, be specifically related to the preparation method of a kind of Method of cefcapene pivoxil hydrochloride.
Background technology
Method of cefcapene pivoxil is the orally available cephalosporins of the third generation, and it is the novel cephalo of Yan Yeyi company of Japan exploitation
Bacteriums antibiotic, it all has the strongest antibacterial activity to Gram-positive, negative bacterium.
Method of cefcapene pivoxil hydrochloride, chemistry is entitled: (6R, 7R)-3-(((carbamyl) oxygen) methyl)-7-(((2Z)-2-(2-
Amino-4-thiazolyl)-1-oxo-2-amylene) amino)-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-
Formic acid (2,2-dimethyl-1-oxopropoxy) methyl ester hydrochloride monohydrate, at present about its synthetic method report relatively
Many, but all there is various problem.
Ishikura K et al. (The Joural of Antibiotics.1994,466-476) discloses a kind of cephalo
The synthetic method of card product ester, the method, with 7 aminocephalosporanic acid as raw material, is first modified to amine methanoyl methyl, 4-through 3-position
Position becomes ester to obtain compound, and this compound is anti-with (Z)-2-(thiazolamine-4-the base)-2-penetenoic acid (1) of Boc base protection again
Should, it being then passed through hydrolysis and obtain key intermediate cefcapene, cefcapene is at K2CO3Act on lower and iodometyl pivalate
(POMI) become ester, finally protect to obtain Method of cefcapene pivoxil with the de-Boc base of trifluoroacetic acid (TFA).In the method, carboxylic acid is condensed with amino
Reaction and becomes the reaction of ester with iodometyl pivalate (POMI), reaction reagent selects the best, all exist main ring parent nucleus product
Raw destruction, causes yield low, and by-product is many.
WO2008155615 discloses a kind of method synthesizing Method of cefcapene pivoxil, uses the double (trimethyl of N, 0-in the method
Silylation) acetamide protects 4-carboxyl and the hydroxyl of 3-methylol, then the aminothiazole penetenoic acid protected with Boc base carries out amide
Change reaction, directly react with CSI without isolation, then obtain target product through steps such as esterification, deprotections.The method operation is multiple
Miscellaneous, relatively costly, be not suitable for large-scale production.
CN102775425A discloses treating different things alike of a kind of Method of cefcapene pivoxil key intermediate cefcapene diisopropyl amine salt
Preparation method, although easy and simple to handle, but the method yield is the highest, two-step reaction product is in the case of purity the unknown,
Only have 67%.
Therefore, this area needs that a kind of yield is high and the preparation method of the Method of cefcapene pivoxil hydrochloride of applicable large-scale production badly.
Summary of the invention
The invention provides the preparation method of a kind of Method of cefcapene pivoxil hydrochloride, solve prior art and prepare hydrochloric acid cephalo card
Product ester purity is low, the low problem of yield, and quality and cost for subsequent product provide guarantee.The crude product of the present invention, product yield
And purity is high, can directly carry out lower step synthesis without high vacuum distillation.
The chemical formula of Method of cefcapene pivoxil hydrochloride of the present invention (I) is: 7-[2-(2-amino-1,3-thiazole-4-yl)
Amyl-3-acrylamide base]-3-(carbamoyloxymethyl)-8-oxo-5-sulfur-1-azabicyclo [4.2.0] oct-2-ene-2-formic acid
2,2-dimethyl propylene acyloxymethyl ester hydrochlorides,
Its chemical general formula is (I):
(I)
The preparation method of Method of cefcapene pivoxil hydrochloride of the present invention, it is characterised in that comprise the following steps:
A) with compound BCN as raw material, react with iodometyl pivalate, obtain formula for the compound of (II):
(BCN) (II)
B) compound that formula is (II) of described step (A) gained and the ethyl acetate solution of hydrogen chloride carry out de-BOC and react,
Obtain formula for the compound of (I):
(II) (I)
In above-mentioned synthetic method, the dichloroethanes in described step (A) should be anhydrous, and reaction temperature is at-20 DEG C；In step (B)
The ethyl acetate solution of the hydrogen chloride described in reaction need to now be made, and reaction temperature is-5 DEG C.
7-[2-(2-amino-1,3-thiazole-4-yl) amyl-3-acrylamide base]-3-(the carbamyl oxygen first that the present invention provides
Base)-8-oxo-5-sulfur-1-azabicyclo [4.2.0] oct-2-ene-2-formic acid 2,2-dimethyl propylene acyloxymethyl ester hydrochloride
Synthetic method, compared with other synthetic methods, has route short, and synthetic operation is simple, it is easy to industrialization, it addition, the product of the present invention
Product purity (LC) can reach 99%, and the product that therefore the method provides has great advantage in terms of purity.
Detailed description of the invention
Describe the present invention below in conjunction with embodiment, but the scope of protection of present invention is not limited to reality
Execute the scope that example is stated.
Embodiment 1: the synthesis of Method of cefcapene pivoxil hydrochloride
There-necked flask adds 200g dichloroethanes, adds 20gBCN under stirring, stirs, then start to be cooled to-25 at room temperature 25 DEG C
DEG C ~-20 DEG C, T=-20 DEG C starts to drip 25.7g iodine ester, drips off holding-25 DEG C ~-20 DEG C stirring reaction 3h.
Post processing: add 200gEA and 300g water, room temperature 25 DEG C stirring extraction in system；Layering, water layer extracts with 100EA again
Take once.Merging EA layer, EA layer saturated sodium bicarbonate 300g washed once, and EA layer washs one with 350g saturated aqueous common salt again
Secondary, EA layer is concentrated into solid after being dried decolouring, adds to instill after 2 times of EA dissolve and stir analysis of material, mistake in 400g petroleum ether after weighing
Filter obtains faint yellow solid powder.
Obtain (II) compound, yield: 85% ~ 90%, LC:99%；
Under nitrogen protection, there-necked flask adds the ethyl acetate solution 200ml of hydrogen chloride, cool to 0 ~ 5 DEG C and add compound
(II) 10g, then reacts 6h at 0 ~ 5 DEG C.Obtain the white crystal of compound that formula is (I), yield: 80% ~ 85%, LC:
99%。
This overall yield of reaction is 80%, LC:99%.
The qualification of product in embodiment 2 embodiment of the present invention 1
Authentication method: Brooker Avance III 400MHz superconduction nuclear magnetic resonance spectrometer
Analysis method: LC(liquid chromatograph purity), Shimadzu LC-10AT VP, Shimadzu C-18 chromatographic column,
Flowing phase: acetonitrile: water=65:35, flow velocity 2ml/min.
1H NMR (500 MHz, (CD3) 2 SO) δ: 0. 97～1. 01 (m, 3H), 1. 15 (s,
9H), 2. 12～2. 21 (m, 2H), 3. 50 (d, J=18. 5 Hz, 1H), 3. 60 (d, J=18. 5
Hz, 1H), 4. 55 (d, J=13. 0Hz, 1H), 4. 79 (d, J=13. 0 Hz, 1H), 17 (d, J=5.
0 Hz, 1H), 5. 79～5. 82 (m, 2H), 5. 87 (d, J=5. 0 Hz, 1H), 6. 23 (t, J=7. 5
Hz, 1H), 6. 51～73 (m, 2H), 7. 14 (s, 1H), 9. 27 (d, J=8. 0Hz, 1H).
7-[2-(2-amino-1,3-thiazole-4-yl) amyl-3-acrylamide base]-3-(the carbamyl oxygen first that the present invention provides
Base)-8-oxo-5-sulfur-1-azabicyclo [4.2.0] oct-2-ene-2-formic acid 2,2-dimethyl propylene acyloxymethyl ester hydrochloride
Synthetic method, compared with other synthetic methods, has route short, and synthetic operation is simple, it is easy to industrialization, it addition, the product of the present invention
Product purity (LC) can reach 99%, and the product that therefore the method provides has great advantage in terms of purity.
The foregoing is only the preferred embodiments of the present invention, be not limited to the present invention, although with reference to previous embodiment
Being described in detail the present invention, for a person skilled in the art, it still can be to foregoing embodiments institute
The technical scheme recorded is modified, or wherein portion of techniques feature is carried out equivalent.All spirit in the present invention and
Within principle, any modification, equivalent substitution and improvement etc. made, should be included within the scope of the present invention.
Claims (5)
1. the preparation method of a Method of cefcapene pivoxil hydrochloride, it is characterised in that comprise the following steps:
A) with compound BCN as raw material, react with iodometyl pivalate and obtain the compound that formula is (II)；
(BCN) (II)
B) compound that formula is (II) of step (A) gained carries out de-BOC reaction in the ethyl acetate solution of hydrogen chloride, and
Directly become semicarbazide hydrochloride, obtain formula for the compound of (I):
(II) (I)
C) last in methanol with diluted hydrochloric acid aqueous solution recrystallization, obtain band a part water 7-[2-(2-amino-1,3-thiazoles-
4-yl) amyl-3-acrylamide base]-3-(carbamoyloxymethyl)-8-oxo-5-sulfur-1-azabicyclo [4.2.0] oct-2-ene-
The white crystal of 2-formic acid 2,2-dimethyl propylene acyloxymethyl ester hydrochloride.
Preparation method the most according to claim 1, it is characterised in that: described iodometyl pivalate is 4 side chain pivalic acids
Iodine methyl ester.
Preparation method the most according to claim 1, it is characterised in that: described step (A) reaction temperature is-25 DEG C ~-20
DEG C, response time 3h.
Preparation method the most according to claim 1, it is characterised in that: the post processing that described step (A) is reacted: add in system
Enter EA and water that mass ratio is 2:3, room temperature 25 DEG C stirring extraction；Layering, water layer extracts once with EA again；Merge EA layer, EA layer
Washed once with saturated sodium bicarbonate, then washed once with saturated aqueous common salt, EA layer is concentrated into solid after being dried decolouring, after weighing
Add to instill after 2 times of EA dissolve and petroleum ether stirs analysis of material, be filtrated to get faint yellow solid powder, i.e. (II) compound.
Preparation method the most according to claim 1, it is characterised in that: in described step (B), reaction temperature controls at 0 ~ 5 DEG C
Under, react 6h.
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| CN201610706164.5A CN106083896A (en) | 2016-08-23 | 2016-08-23 | A kind of preparation method of Method of cefcapene pivoxil hydrochloride |
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH04295485A (en) * | 1991-03-25 | 1992-10-20 | Shionogi & Co Ltd | Cephalosporin hydrate crystal for oral administration |
| JP2006022042A (en) * | 2004-07-08 | 2006-01-26 | Shionogi & Co Ltd | Crystal of cephem compound |
| CN105131017A (en) * | 2015-09-09 | 2015-12-09 | 山东罗欣药业集团股份有限公司 | Preparation method for cefcapene pivoxil hydrochloride |
| CN105198906A (en) * | 2015-11-02 | 2015-12-30 | 青岛辰达生物科技有限公司 | Preparation method of cefcapene pivoxil hydrochloride |
| CN105254649A (en) * | 2015-11-02 | 2016-01-20 | 青岛辰达生物科技有限公司 | Preparation method for cefcapene pivoxil hydrochloride |
-
2016
- 2016-08-23 CN CN201610706164.5A patent/CN106083896A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH04295485A (en) * | 1991-03-25 | 1992-10-20 | Shionogi & Co Ltd | Cephalosporin hydrate crystal for oral administration |
| JP2006022042A (en) * | 2004-07-08 | 2006-01-26 | Shionogi & Co Ltd | Crystal of cephem compound |
| CN105131017A (en) * | 2015-09-09 | 2015-12-09 | 山东罗欣药业集团股份有限公司 | Preparation method for cefcapene pivoxil hydrochloride |
| CN105198906A (en) * | 2015-11-02 | 2015-12-30 | 青岛辰达生物科技有限公司 | Preparation method of cefcapene pivoxil hydrochloride |
| CN105254649A (en) * | 2015-11-02 | 2016-01-20 | 青岛辰达生物科技有限公司 | Preparation method for cefcapene pivoxil hydrochloride |
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Application publication date: 20161109 |