CN102127093A - Refining process for Cefotiam hexetil hydrochloride - Google Patents
Refining process for Cefotiam hexetil hydrochloride Download PDFInfo
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- CN102127093A CN102127093A CN2010106004012A CN201010600401A CN102127093A CN 102127093 A CN102127093 A CN 102127093A CN 2010106004012 A CN2010106004012 A CN 2010106004012A CN 201010600401 A CN201010600401 A CN 201010600401A CN 102127093 A CN102127093 A CN 102127093A
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- cefotiam
- salt
- hexetil
- add
- carbonate
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- 229950010227 cefotiam hexetil Drugs 0.000 title claims abstract description 94
- VVFDMWZLBPUKTD-ZKRNHDOASA-N cefotiam hexetil ester Chemical compound O=C([C@@H](NC(=O)CC=1N=C(N)SC=1)[C@H]1SCC=2CSC=3N(N=NN=3)CCN(C)C)N1C=2C(=O)OC(C)OC(=O)OC1CCCCC1 VVFDMWZLBPUKTD-ZKRNHDOASA-N 0.000 title claims abstract description 91
- 238000000034 method Methods 0.000 title claims abstract description 43
- 238000007670 refining Methods 0.000 title claims abstract description 16
- QYQDKDWGWDOFFU-IUODEOHRSA-N Cefotiam Chemical compound CN(C)CCN1N=NN=C1SCC1=C(C(O)=O)N2C(=O)[C@@H](NC(=O)CC=3N=C(N)SC=3)[C@H]2SC1 QYQDKDWGWDOFFU-IUODEOHRSA-N 0.000 claims abstract description 85
- 229960001242 cefotiam Drugs 0.000 claims abstract description 78
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 29
- 239000003960 organic solvent Substances 0.000 claims abstract description 24
- 230000032050 esterification Effects 0.000 claims abstract description 23
- 238000005886 esterification reaction Methods 0.000 claims abstract description 23
- 239000007789 gas Substances 0.000 claims abstract description 23
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims abstract description 23
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims abstract description 23
- 239000002994 raw material Substances 0.000 claims abstract description 11
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 94
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 69
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 36
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 34
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 33
- 238000006243 chemical reaction Methods 0.000 claims description 28
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 27
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 26
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 24
- -1 cefotiam sodium salt Chemical class 0.000 claims description 24
- 239000007787 solid Substances 0.000 claims description 22
- 238000003756 stirring Methods 0.000 claims description 22
- 238000000967 suction filtration Methods 0.000 claims description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 18
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims description 17
- 239000001103 potassium chloride Substances 0.000 claims description 17
- 235000011164 potassium chloride Nutrition 0.000 claims description 17
- 238000002425 crystallisation Methods 0.000 claims description 16
- 230000008025 crystallization Effects 0.000 claims description 16
- 235000015320 potassium carbonate Nutrition 0.000 claims description 16
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 13
- 238000002360 preparation method Methods 0.000 claims description 13
- 238000001035 drying Methods 0.000 claims description 10
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 9
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 8
- 239000000706 filtrate Substances 0.000 claims description 8
- 229910052700 potassium Inorganic materials 0.000 claims description 8
- 239000011591 potassium Substances 0.000 claims description 8
- 235000017550 sodium carbonate Nutrition 0.000 claims description 8
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- 238000005516 engineering process Methods 0.000 claims description 7
- FUKUFMFMCZIRNT-UHFFFAOYSA-N hydron;methanol;chloride Chemical compound Cl.OC FUKUFMFMCZIRNT-UHFFFAOYSA-N 0.000 claims description 7
- 238000009423 ventilation Methods 0.000 claims description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- 230000006837 decompression Effects 0.000 claims description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 5
- 235000011181 potassium carbonates Nutrition 0.000 claims description 5
- 239000007810 chemical reaction solvent Substances 0.000 claims description 4
- 150000004649 carbonic acid derivatives Chemical class 0.000 claims description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- 238000012544 monitoring process Methods 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 238000004090 dissolution Methods 0.000 claims 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-N sodium;hydron;carbonate Chemical compound [Na+].OC(O)=O UIIMBOGNXHQVGW-UHFFFAOYSA-N 0.000 claims 1
- 238000001953 recrystallisation Methods 0.000 abstract description 9
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 abstract 2
- 150000003839 salts Chemical class 0.000 abstract 2
- 159000000000 sodium salts Chemical class 0.000 abstract 2
- 230000002194 synthesizing effect Effects 0.000 abstract 2
- TYBWWPALTFYPIQ-UHFFFAOYSA-N 1-bromoethyl cyclohexyl carbonate Chemical compound CC(Br)OC(=O)OC1CCCCC1 TYBWWPALTFYPIQ-UHFFFAOYSA-N 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 230000001376 precipitating effect Effects 0.000 abstract 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 16
- 238000003786 synthesis reaction Methods 0.000 description 11
- 230000015572 biosynthetic process Effects 0.000 description 10
- 239000012065 filter cake Substances 0.000 description 8
- 239000000376 reactant Substances 0.000 description 8
- 238000004519 manufacturing process Methods 0.000 description 7
- 238000010907 mechanical stirring Methods 0.000 description 7
- 239000000047 product Substances 0.000 description 7
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- 230000000845 anti-microbial effect Effects 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 239000012467 final product Substances 0.000 description 3
- 229940127249 oral antibiotic Drugs 0.000 description 3
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- 241000588653 Neisseria Species 0.000 description 2
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- 239000006227 byproduct Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 230000007812 deficiency Effects 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 235000011182 sodium carbonates Nutrition 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- BIIBYWQGRFWQKM-JVVROLKMSA-N (2S)-N-[4-(cyclopropylamino)-3,4-dioxo-1-[(3S)-2-oxopyrrolidin-3-yl]butan-2-yl]-2-[[(E)-3-(2,4-dichlorophenyl)prop-2-enoyl]amino]-4,4-dimethylpentanamide Chemical compound CC(C)(C)C[C@@H](C(NC(C[C@H](CCN1)C1=O)C(C(NC1CC1)=O)=O)=O)NC(/C=C/C(C=CC(Cl)=C1)=C1Cl)=O BIIBYWQGRFWQKM-JVVROLKMSA-N 0.000 description 1
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- Cephalosporin Compounds (AREA)
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a refining process for Cefotiam hexetil hydrochloride prepared by industrial production, which comprises: synthesizing potassium salt or sodium salt of Cefotiam by using Cefotiam hexetil hydrochloride as the raw material; synthesizing Cefotiam hexetil by performing the esterification of the potassium salt or sodium salt of Cefotiam and a brominated material, namely 1-bromo ethyl cyclohexyl carbonate; adding an organic solvent into the Cefotiam hexetil, introducing hydrogen chloride gas to form a salt and precipitating the salt; and finally, obtaining the Cefotiam hexetil hydrochloride by recrystallization. The method is safe, the post treatment is easy, and the product quality is high.
Description
Technical field
The invention belongs to organic synthesis and chemical pharmacy field, the synthesis technique that relates to a kind of compound specifically, is a kind of process for refining of cefotiam hexetil hydrochloride, be a kind of, through the method for esterification, salt-forming reaction, synthetic cefotiam hexetil hydrochloride by the cefotiam compound.
Background technology
Cefotiam hexetil can be made into oral antibiotic, this oral antibiotic self there is no anti-microbial effect, being oral back is hydrolyzed to cefotiam rapidly and is absorbed at intestinal mucosa, cefotiam is identical with oral in the past cynnematin to the anti-microbial activity of gram-positive and negative bacterium, and stable to β-Nei Xiananmei, various bacteria such as clinical isolating streptococcus aureus, coagulase negative staphylococcus, streptococcus pneumoniae, gonococcus, anti-Ampicillin Trihydrate gonococcus all there is stronger anti-microbial activity.The cefotiam hexetil oral antibiotic can be treated infection such as responsive microbial pharyngolaryngitis, acute bronchitis, tonsillitis, pneumonia, pyelonephritis, urocystitis, pouring mattress urethritis, purulence acne, furuncle, erysipelas, perianal abscess, mazoitis, ocular infection or otitis media.
Therefore the cefotiam hexetil poor stability all is to adopt cefotiam hexetil hydrochloride when preparation and use, and the structural formula of cefotiam hexetil hydrochloride is shown in formula I.
In the method for existing preparation cefotiam hexetil hydrochloride, all use cefotiam (II) to be raw material, through over-churning, the salify two-step reaction makes target compound.But there is following some deficiency in existing technology:
(1) yield is lower.The preparation total recovery of bibliographical information makes the production cost of cefotiam hexetil hydrochloride be difficult to reduce about 20%.
(2) byproduct content is higher relatively, greater than Japanese Pharmacopoeia specified standards 2%.
(3) the difficult preparation of raw material, on the high side.Document mostly adopts carbonic acid-1-iodo-ethyl ester cyclohexyl and cefotiam to react, and its preparation is difficulty comparatively, and is on the high side.
(4) post-reaction treatment is numerous and diverse.The post-treating method of bibliographical information mainly comes purified product by the multiple extraction of turning one's coat of column chromatography and soda acid, and its production technique is numerous and diverse, is not suitable for the requirement of industrialized production.
Therefore, press for the synthesis technique of the cefotiam hexetil hydrochloride a kind of suitable suitability for industrialized production, that reaction and aftertreatment thereof are simple, sophisticated, that yield is high and byproduct is low in the industry.
Summary of the invention
For overcoming deficiency of the prior art, the object of the present invention is to provide a kind of simple and safe, cost is lower, aftertreatment is easy, good product quality, the synthesis technique of the preparation cefotiam hexetil hydrochloride that suitability for industrialized is produced promptly, is fit to the process for refining of the preparation cefotiam hexetil hydrochloride of suitability for industrialized production.
For solving the problems of the technologies described above, realize expected effect, the following technical scheme that the present invention adopts:
The invention provides a kind of process for refining of cefotiam hexetil hydrochloride, this technology comprises the steps:
(1) adopt cefotiam salt as raw material;
(2) with cefotiam salt and carbonic acid-1-bromine ethyl ester cyclohexyl generation esterification, synthetic cefotiam hexetil;
(3) in cefotiam hexetil, add organic solvent, feed hydrogen chloride gas, separate out cefotiam hexetil hydrochloride.
Above-mentioned cefotiam salt is cefotiam sylvite or cefotiam sodium salt.
The present invention is a raw material with cefotiam salt (cefotiam sylvite or cefotiam sodium salt), with more cheap carbonic acid-1-bromine ethyl ester cyclohexyl (III), through the synthetic cefotiam hexetil of esterification, not purifiedly is directly used in that next step is synthetic.It is dissolved in the organic solvent again, feeds dry hydrogen chloride gas, separate out hydrochloride, last recrystallization through the HPLC of " Japanese Pharmacopoeia " regulation check, obtains meeting the product of Japanese Pharmacopoeia definite quality requirement.Described " meeting the Japanese Pharmacopoeia regulation " refers to reference to the correlation detection item (including the amount and the cefotiam ester content of related substance) of the cefotiam hexetil hydrochloride quality standard of " Japanese Pharmacopoeia " record and the specified requirement that the resulting detected result of detection method all meets this " Japanese pharmacy ".By dry product, " Japanese Pharmacopoeia " requires every 1mg product to contain cefotiam hexetil hydrochloride with cefotiam (C
18H
23N
9O
4S
3.2HCl; 525.63) meter should be 615 μ g～690 μ g.Cefotiam hexetil assay of the present invention adopts HPLC, and chromatographic column is C18 post 4.0 * 150mm (5 μ m), and moving phase is 0.2mol/L potassium primary phosphate-acetonitrile-Glacial acetic acid (72: 28: 1); The cefotiam hexetil retention time is about 9min; Detect wavelength: 254nm; About 25 ℃ of column temperatures, the result who obtains all meets above-mentioned requirements through replica test.
Raw material cefotiam salt of the present invention is preferably cefotiam sylvite or cefotiam sodium salt, more preferably cefotiam sylvite.It can adopt cefotiam chloride and carbonate (salt of wormwood or yellow soda ash) reaction to obtain.
Above-mentioned cefotiam sylvite or cefotiam sodium salt can synthesize by the following method: in container (for example 500mL three-necked bottle), add methyl alcohol (100mL), under the mechanical stirring, cool to 0 ℃ and add cefotiam chloride (20g (about 0.035mol)); Dissolving obtains the cefotiam chloride methanol solution, adds salt of wormwood (or yellow soda ash) 9.6g (0.07mol) at 0 ℃ more in batches, stirs (approximately 2h); Suction filtration adds acetone (100ml) and places-5 ℃ to continue to stir (approximately 2h) down in the filtrate, separate out crystallization, suction filtration, and 40 ℃ of drying under reduced pressure obtain cefotiam sylvite or cefotiam sodium salt.
In the above-mentioned synthesis technique of the present invention, the described cefotiam salt of step (2) is under salt of wormwood and/or sodium carbonates' presence, and carbonic acid-1-bromine ethyl ester cyclohexyl generation esterification, synthetic cefotiam hexetil; The described organic solvent that in cefotiam hexetil, adds of step (3), this organic solvent is selected from arbitrary or its arbitrary combination among methylene dichloride, acetone, ether, ethyl acetate, acetonitrile, the THF; Preferred methylene dichloride or ethyl acetate; More preferably ethyl acetate.
In sum, the invention provides a kind of synthesis technique of cefotiam hexetil hydrochloride, this synthesis technique comes down to a kind of process for refining, and wherein, this technology comprises the steps:
(1) cefotiam chloride and carbonate reaction prepare cefotiam salt;
(2) above-mentioned preparation gained cefotiam salt is under salt of wormwood or sodium carbonates' presence, and carbonic acid-1-bromine ethyl ester cyclohexyl generation esterification; Esterification is spin-dried for solvent after finishing, and judges that the method that esterification finishes is to get final product fully through HPLC monitoring raw material reaction;
(3) the reactant adding that step (2) is obtained is selected from the organic solvent of arbitrary or its combination among methylene dichloride, acetone, ether, ethyl acetate, acetonitrile, the THF; Feed hydrogen chloride gas, separate out cefotiam hexetil hydrochloride;
(4) cefotiam hexetil hydrochloride that step (3) is obtained is preferably used 10 times methyl alcohol: after the solution heating for dissolving of sherwood oil=1: 5, crystallization is separated out in cooling, filters and obtains cefotiam hexetil hydrochloride.
The methyl alcohol in the above-mentioned steps (4) and the solution of sherwood oil are about methyl alcohol: sherwood oil=1: 2～1: 10 the methyl alcohol and the solution of sherwood oil, consumption is approximately 5 times～50 times of hydrochloride that step (3) obtains, in a preferred embodiment, preferably use about 10 times methyl alcohol: the solution heating for dissolving of sherwood oil=1: 5.
In the above-mentioned synthesis technique, described cefotiam sylvite, cefotiam sodium salt can synthesize by the following method: be selected from the reaction solvent (particular methanol of arbitrary or its combination in methyl alcohol, ethanol, the acetonitrile in adding, methyl alcohol 100mL for example) in the container (generic container is selected the 500mL three-necked bottle), under mechanical stirring, cool to-10～10 ℃ (preferred 0 ℃), add cefotiam chloride, the quality of this cefotiam chloride is 1: 3～1: 10 (for example, adding cefotiam chloride 20g (about 0.035mol)) with the ratio of the volume of this reaction solvent; Dissolving obtains the cefotiam chloride methanol solution, add carbonate at-10～10 ℃ (preferred 0 ℃) more in batches, the reaction mol ratio of cefotiam chloride and carbonate is 1: 1～1: 3, this carbonate is salt of wormwood or yellow soda ash (amount of carbonate is 9.6g (0.07mol) for example), stirring reaction 1.5～3h (about 2h); Suction filtration adds acetone (for example 100ml) and places-10～10 ℃ (preferred 0 ℃～-5 ℃) to continue to stir (approximately 2h) down in the filtrate, separate out crystallization, suction filtration, and 40 ℃ of following drying under reduced pressure obtain cefotiam sylvite or cefotiam sodium salt.
In the above-mentioned synthesis technique, described cefotiam hexetil is the ethyl acetate solution of cefotiam hexetil, it can synthesize by the following method: add THF (200ml) in the 500ml reaction flask, be cooled to 3 ℃, add cefotiam potassium or cefotiam sodium salt 10g (about 0.018mol), be stirred to dissolving fully, add Anhydrous potassium carbonate or anhydrous sodium carbonate, the mol ratio of this cefotiam salt and salt of wormwood or yellow soda ash is 1: 0.5～1: 2, (for example add salt of wormwood 2.42g, about 0.018mol), add carbonic acid-1-bromine ethyl ester cyclohexyl 8.75g (0.035mol), the reaction mol ratio of described cefotiam salt and carbonic acid-1-bromine ethyl ester cyclohexyl is 1: 1～1: 3; Stir, carry out esterification; After reacting completely, the room temperature decompression is evaporate to dryness THF down, adds organic solvent (for example methylene dichloride or ethyl acetate 100ml) dissolving again, filters, and gets the organic solvent solution of cefotiam hexetil, just the ethyl acetate solution of cefotiam hexetil.
In synthesis technique of the present invention, also comprise: the ethyl acetate solution of described cefotiam hexetil is cooled to sub-zero zero, slowly feed dry hydrogen chloride gas, do not stop ventilation when solid is separated out, separate out white solid and be cefotiam hexetil hydrochloride until having again.
The above-mentioned white solid that obtains is the cefotiam hexetil hydrochloride crude product, in order to obtain the higher cefotiam hexetil hydrochloride of purity better, preferred following purification step: with the crude product suction filtration, filter cake methyl alcohol: sherwood oil 1: 2～10 solution weight crystallizations get cefotiam hexetil hydrochloride.
The above-mentioned process that obtains the cefotiam hexetil hydrochloride highly finished product can be summarized as: the ethyl acetate solution of the above-mentioned cefotiam hexetil that obtains (the ethyl acetate solution solution 100ml that for example adds prepared cefotiam hexetil in the 500mL reaction flask) (for example-10～0 ℃ is cooled to sub-zero zero, preferably approximately-5 ℃), slowly feed dry hydrogen chloride gas, the adularescent solid is separated out; When separating out, solid do not stop ventilation until having again.Suction filtration, filter cake methyl alcohol: the petroleum ether solution recrystallization gets cefotiam hexetil hydrochloride.
In the above-mentioned involved re-crystallization step, the recrystallization solvent of employing is a methyl alcohol: sherwood oil 1: 2～1: 10, this is a volume ratio, particular methanol: sherwood oil 1: 5.
In the above-mentioned synthesis technique, (3) step wherein is specially and is spin-dried for solvent after esterification finishes, and adds organic solvent, feeds hydrogen chloride gas then, separates out hydrochloride; It is the committed step of purge process of the present invention, determined and product can have been separated out the hydrochloride solid to greatest extent, thereby crystallization obtains the cefotiam hexetil hydrochloride of high purity, high yield, so the organic solvent that the present invention uses this step is optimized:
Select methylene dichloride, ethyl acetate, acetone, acetonitrile, THF and these several those skilled in the art of ether used organic solvent when testing, they are compared test.
1) reactants dissolved that step (2) is obtained cools to-5 ℃ in the 100ml ethyl acetate, slowly feeds dry hydrogen chloride gas, and the adularescent solid is separated out; When separating out, solid do not stop ventilation until having again.Suction filtration is weighed behind the filter cake drying under reduced pressure, crude product yield 72.5%.
2) reactants dissolved that step (2) is obtained cools to-5 ℃ in the 100ml methylene dichloride, slowly feeds dry hydrogen chloride gas, and the adularescent solid is separated out; When separating out, solid do not stop ventilation until having again.Suction filtration is weighed behind the filter cake drying under reduced pressure, crude product yield 60.7%.
3) reactants dissolved that step (2) is obtained cools to-5 ℃ in 100ml acetone, slowly feeds dry hydrogen chloride gas, has a small amount of white solid to separate out.
4) reactants dissolved that step (2) is obtained cools to-5 ℃ in the 100ml acetonitrile, slowly feeds dry hydrogen chloride gas, and the liquid muddiness does not obtain the solid precipitate.
5) reactants dissolved that step (2) is obtained cools to-5 ℃ in 100ml THF, slowly feeds dry hydrogen chloride gas, and the liquid muddiness does not obtain the solid precipitate.
6) reactants dissolved that step (2) is obtained cools to-5 ℃ in the 100ml ether, slowly feeds dry hydrogen chloride gas, only has a small amount of white solid to separate out.
More experimental data since length limit and owe temporarily to give.
By above-mentioned data as can be seen, acetonitrile, THF can not produce crystallization during as solvent; Organic solvents such as methylene dichloride, acetone, ether, ethyl acetate have crystallization to separate out during as solvent; When wherein methylene dichloride, ethyl acetate were as solvent, crystallization output was the highest.
Therefore, the present invention through repetition test, has finally obtained to be fit to preferred organic methylene dichloride of the present invention or ethyl acetate by the conventional organic solvent that adopts in this area has been carried out a large amount of screenings; At particular case of the present invention, in a preferred embodiment, the most preferred organic solvent of the present invention is an ethyl acetate.
The step of building-up reactions of the present invention (2) be cefotiam salt in the presence of carbonate, and carbonic acid-1-bromine ethyl ester cyclohexyl generation esterification.The temperature of esterification is-5～10 ℃, and the reaction times is 15～30min, and the product of esterification is cefotiam hexetil.Wherein, described carbonate is salt of wormwood or yellow soda ash, and this carbonate mainly plays catalyzer, is example with salt of wormwood, and its consumption is a cefotiam salt: salt of wormwood=1: (0.5～2), this is a mol ratio.Carbonic acid-1-bromine ethyl ester cyclohexyl is a reactant, and the reaction mol ratio of cefotiam salt and carbonic acid-1-bromine ethyl ester cyclohexyl is 1: (1～3).Solvent for use is THF, because of its boiling point is low, is easy to remove at low temperatures.The ratio of cefotiam salt and THF is 1: 15～1: 30 (weight: volume).
In the above-mentioned steps (2), the optional ethyl acetate of organic solvent, methylene dichloride, acetone and the ether of last solubilizing reaction thing, ethyl acetate or methylene dichloride; More preferably ethyl acetate.
In another preferred embodiment, raw material cefotiam salt of the present invention is preferably cefotiam sylvite, it can synthesize by the following method: in container (for example 500mL three-necked bottle), add methyl alcohol (100mL), under the mechanical stirring, cool to 0 ℃ and add cefotiam chloride (20g, about 0.035mol); Dissolving obtains the cefotiam chloride methanol solution, and add salt of wormwood at 0 ℃ again (9.6g 0.07mol), stirs about 2h in batches; Suction filtration adds acetone (100ml) and places-5 ℃ to continue down to stir about 2h in the filtrate, separate out crystallization, suction filtration, and 40 ℃ of drying under reduced pressure obtain cefotiam sylvite.
The present invention is raw material with the cefotiam, with carbonic acid-1-bromine ethyl ester cyclohexyl (III), through the synthetic cefotiam hexetil of esterification, again it is dissolved in the organic solvent, feeds dry hydrogen chloride gas, separate out hydrochloride, last recrystallization obtains satisfactory final product.
The above-mentioned final product that obtains is analyzed through HPLC according to the correlation detection condition of Japanese Pharmacopoeia record, checks such as titration, and the result meets the requirement of Japanese Pharmacopoeia definite quality.
THF described in the present invention is the abbreviation of tetrahydrofuran (THF).
One of compared with prior art, the present invention has following advantage:, be in esterification, change habitual carbonic acid-1-iodo-ethyl ester cyclohexyl into carbonic acid-1-bromine ethyl ester cyclohexyl more with low cost, that conveniently be easy to get; Two, the cefotiam hexetil that obtains of reaction is not purified to be directly used in next step reaction, has simplified production process, reduces the loss, and has improved yield; Three in salt-forming reaction, change direct feeding hydrogen chloride gas into, separate out hydrochloride, simplified post-treating method, the requirement of more suitable industrialized production.
Embodiment
For more clear explanation goal of the invention and technical scheme, be described in further detail by following embodiment.
The preparation method of embodiment 1 cefotiam hexetil hydrochloride
1) cefotiam salt is synthetic
In the 500ml three-necked bottle, add 100ml methyl alcohol, cool to 0 ℃ under the mechanical stirring and add cefotiam chloride 20.00g (0.035mol); Dissolving obtains the cefotiam chloride methanol solution, adds salt of wormwood 9.66g (0.07mol) at 0 ℃ more in batches, stirs 2h.Suction filtration adds acetone 100ml and places-5 ℃ to continue to stir 2h down in the filtrate, separate out crystallization, suction filtration, and 40 ℃ of drying under reduced pressure obtain cefotiam sylvite 27.07g.
2) cefotiam hexetil is synthetic
In the 500ml reaction flask, add THF200ml, be cooled to 3 ℃, add cefotiam potassium 13.50g (0.018mol), be stirred to dissolving fully, add Anhydrous potassium carbonate 2.42g (0.018mol), add carbonic acid-1-bromine ethyl ester cyclohexyl 8.80g (0.035mol), stir, carry out esterification; After reacting completely, the room temperature decompression is evaporate to dryness THF down, adds ethyl acetate 100ml again, filters, and gets the ethyl acetate solution of cefotiam hexetil.
3) cefotiam hexetil hydrochloride is synthetic
The ethyl acetate solution of prepared cefotiam hexetil of step cools to-5 ℃ on adding in the 500ml reaction flask, slowly feeds dry hydrogen chloride gas, and the adularescent solid is separated out, and does not stop ventilation when solid is separated out until having again.Suction filtration, filter cake methyl alcohol: the solution 100ml of sherwood oil=1: 5 is heated to 50 ℃ of dissolvings, is cooled to 0 ℃ of crystallization, cefotiam hexetil hydrochloride 8.58g.
In the present embodiment, the yield of white cefotiam hexetil hydrochloride is 62.0%, detects through HPLC, and its isomery ratio is A
a/ (A
a+ A
b)=0.49, purity are 98.5%.
The preparation method of embodiment 2 cefotiam hexetil hydrochlorides
1) cefotiam salt is synthetic
In the 500ml three-necked bottle, add 100ml methyl alcohol, cool to 0 ℃ under the mechanical stirring and add cefotiam chloride 20.00g (0.035mol); Dissolving obtains the cefotiam chloride methanol solution, adds salt of wormwood 9.66g (0.07mol) at 0 ℃ more in batches, stirs 2h.Suction filtration adds acetone 100ml and places-5 ℃ to continue to stir 2h down in the filtrate, separate out crystallization, suction filtration, and 40 ℃ of drying under reduced pressure obtain cefotiam sylvite 27.07g.
2) cefotiam hexetil is synthetic
In the 500ml reaction flask, add THF200ml, be cooled to 3 ℃, add cefotiam potassium 13.50g (0.018mol), be stirred to dissolving fully, add Anhydrous potassium carbonate 2.42g (0.018mol), add carbonic acid-1-bromine ethyl ester cyclohexyl 8.80g (0.035mol), stir, carry out esterification; After reacting completely, the room temperature decompression is evaporate to dryness THF down, adds methylene dichloride 100ml again, filters, and gets the dichloromethane solution of cefotiam hexetil.
3) cefotiam hexetil hydrochloride is synthetic
Spore is cooled to-5 ℃ for the dichloromethane solution of peace ester, slowly feed dry hydrogen chloride gas and feed dry hydrogen chloride gas, separate out the white hydrochloride salt solid, filter, filter cake methyl alcohol: the solution 100ml recrystallization of sherwood oil=1: 5 gets cefotiam hexetil hydrochloride 7.81g.
In the present embodiment, the yield of white cefotiam hexetil hydrochloride is 56.4%, detects through HPLC, and its isomery ratio is A
a/ (A
a+ A
b)=0.49, purity are 98.6%.
The preparation method of embodiment 3 cefotiam hexetil hydrochlorides
1) cefotiam salt is synthetic
In the 500ml three-necked bottle, add 100ml ethanol, cool to 0 ℃ under the mechanical stirring and add cefotiam chloride 20.00g (0.035mol); Dissolving obtains the cefotiam chloride ethanolic soln, adds salt of wormwood 9.66g (0.07mol) at 0 ℃ more in batches, stirs 2h.Suction filtration adds acetone 100ml and places-5 ℃ to continue to stir 2h down in the filtrate, separate out crystallization, suction filtration, and 40 ℃ of drying under reduced pressure obtain cefotiam sylvite 26.63g.
2) cefotiam hexetil is synthetic
In the 500ml reaction flask, add THF200ml, be cooled to 3 ℃, add cefotiam potassium 13.50g (0.018mol), be stirred to dissolving fully, add Anhydrous potassium carbonate 2.42g (0.018mol), add carbonic acid-1-bromine ethyl ester cyclohexyl 8.75g (0.035mol), stir, carry out esterification; After reacting completely, the room temperature decompression is evaporate to dryness THF down, adds ethyl acetate 100ml again, filters, and gets the ethyl acetate solution of cefotiam hexetil.
3) cefotiam hexetil hydrochloride is synthetic
The ethyl acetate solution of prepared cefotiam hexetil of step cools to-5 ℃ on adding in the 500ml reaction flask, slowly feeds dry hydrogen chloride gas, and the adularescent solid is separated out, and does not stop ventilation when solid is separated out until having again.Suction filtration, filter cake methyl alcohol: the solution 100ml recrystallization of sherwood oil=1: 5 gets cefotiam hexetil hydrochloride 7.50g.
In the present embodiment, the yield of white cefotiam hexetil hydrochloride is 54.2%, detects through HPLC, and its isomery ratio is A
a/ (A
a+ A
b)=0.48, purity are 98.3%.
The preparation method of embodiment 4 cefotiam hexetil hydrochlorides
1) cefotiam salt is synthetic
In the 500ml three-necked bottle, add 100ml methyl alcohol, cool to 0 ℃ under the mechanical stirring and add cefotiam chloride 20.00g (0.035mol); Dissolving obtains the cefotiam chloride methanol solution, adds yellow soda ash 7.42g (0.07mol) at 0 ℃ more in batches, stirs 2h.Suction filtration adds acetone 100ml and places-5 ℃ to continue to stir 2h down in the filtrate, separate out crystallization, suction filtration, and 40 ℃ of drying under reduced pressure obtain cefotiam sodium salt 24.73g.
2) cefotiam hexetil is synthetic
In the 500ml reaction flask, add THF200ml, be cooled to 3 ℃, add cefotiam sodium 12.83g (0.018mol), be stirred to dissolving fully, add anhydrous sodium carbonate 1.91g (0.018mol), add carbonic acid-1-bromine ethyl ester cyclohexyl 8.75g (0.035mol), stir, carry out esterification; After reacting completely, the room temperature decompression is evaporate to dryness THF down, adds ethyl acetate 100ml again, filters, and gets the ethyl acetate solution of cefotiam hexetil.
3) cefotiam hexetil hydrochloride is synthetic
Spore feeds dry hydrogen chloride gas for the ethyl acetate solution of peace ester, separates out the white hydrochloride salt solid, filters filter cake methyl alcohol: the solution 100ml recrystallization of sherwood oil=1: 5 gets cefotiam hexetil hydrochloride 8.06g.
In the present embodiment, the yield of white cefotiam hexetil hydrochloride is 58.3%, detects through HPLC, and its isomery ratio is A
a/ (A
a+ A
b)=0.49, purity are 98.1%.
A in the foregoing description
a, A
bTwo isomery composition peak areas for cefotiam hexetil hydrochloride.
More than described the preferred embodiment for the present invention, so it is not in order to limit the present invention.Those skilled in the art are not to can departing from the improvement and the variation of category of the present invention and spirit in a little disclosed embodiments.
Claims (10)
1. the exquisite technology of a cefotiam hexetil hydrochloride, this method comprises the steps:
(1) adopt cefotiam salt as raw material;
(2) with cefotiam salt and carbonic acid-1-bromine ethyl ester cyclohexyl generation esterification, synthetic cefotiam hexetil;
(3) in cefotiam hexetil, add organic solvent, feed hydrogen chloride gas, separate out cefotiam hexetil hydrochloride.
2. process for refining as claimed in claim 1, wherein, cefotiam sylvite or the cefotiam sodium salt of the described cefotiam salt of step (1) for adopting cefotiam chloride and carbonate reaction to obtain.
3. process for refining as claimed in claim 1, wherein, the described cefotiam salt of step (2) is in the presence of carbonate, and carbonic acid-1-bromine ethyl ester cyclohexyl generation esterification, the synthetic cefotiam hexetil that obtains.
4. process for refining as claimed in claim 1, wherein, the described organic solvent that in cefotiam hexetil, adds of step (3), this organic solvent is selected from arbitrary or its combination among methylene dichloride, acetone, ether, ethyl acetate, acetonitrile, the THF.
5. process for refining as claimed in claim 1, wherein, this method comprises the steps:
(1) cefotiam chloride and carbonate reaction prepare cefotiam salt;
(2) above-mentioned preparation gained cefotiam salt is in the presence of carbonate, and carbonic acid-1-bromine ethyl ester cyclohexyl generation esterification, synthetic cefotiam hexetil;
(3) complete through HPLC monitoring raw material reaction, be spin-dried for solvent, add organic solvent, this organic solvent is selected from arbitrary or its combination among methylene dichloride, acetone, ether, ethyl acetate, acetonitrile, the THF; Feed hydrogen chloride gas then, separate out cefotiam chloride;
(4) the cefotiam chloride methyl alcohol that above-mentioned steps (3) is obtained: sherwood oil is solution weight crystallization in 1: 2.5～1: 10, filters to obtain cefotiam hexetil hydrochloride.
6. as each described process for refining of claim 1-5, wherein, described cefotiam salt is cefotiam sylvite or cefotiam sodium salt.
7. process for refining as claimed in claim 6, wherein, described cefotiam sylvite or cefotiam sodium salt are synthetic by the following method: be selected from the container of the reaction solvent of arbitrary or its combination in methyl alcohol, ethanol, the acetonitrile in adding, cool to-10～10 ℃ under stirring, add cefotiam chloride, the quality of this cefotiam chloride is 1: 3～1: 10 with the ratio of the volume of this reaction solvent; Dissolving obtains the cefotiam chloride methanol solution, adds carbonate at-10～10 ℃ more in batches, and the reaction mol ratio of cefotiam chloride and carbonate is 1: 1～1: 3, and this carbonate is salt of wormwood or yellow soda ash; Suction filtration adds acetone and places-5 ℃ to continue to stir down in the filtrate, separate out crystallization, and 40 ℃ of drying under reduced pressure obtain cefotiam sylvite or cefotiam sodium salt.
8. process for refining as claimed in claim 5, wherein, described cefotiam hexetil is the ethyl acetate solution of cefotiam hexetil.
9. process for refining as claimed in claim 8, wherein, the ethyl acetate solution of described cefotiam hexetil is synthetic by the following method: add THF in reaction flask, be cooled to 3 ℃, add cefotiam potassium or cefotiam sodium salt, be stirred to dissolving fully, add Anhydrous potassium carbonate or anhydrous sodium carbonate, the mol ratio of this cefotiam potassium or cefotiam sodium and salt of wormwood or yellow soda ash is 1: 0.5～1: 2, add carbonic acid-1-bromine ethyl ester cyclohexyl, the reaction mol ratio of described cefotiam potassium or cefotiam sodium salt and carbonic acid-1-bromine ethyl ester cyclohexyl is 1: 1～1: 3; Stir, carry out esterification; After reacting completely, the room temperature decompression is evaporate to dryness THF down, adds organic solvent dissolution again, filters, and gets the organic solvent solution of cefotiam hexetil, and the organic solvent solution of this cefotiam hexetil is the ethyl acetate solution of cefotiam hexetil.
10. process for refining as claimed in claim 8, wherein, this technology also comprises: the ethyl acetate solution of described cefotiam hexetil is cooled to sub-zero zero, slowly feeds dry hydrogen chloride gas, do not stop ventilation when solid is separated out until having again, separate out white solid and be cefotiam hexetil hydrochloride.
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| CN104031068A (en) * | 2014-06-11 | 2014-09-10 | 济南诚汇双达化工有限公司 | Method of preparing cefotiam hexetil hydrochloride by one-pot method |
| CN106749334A (en) * | 2016-11-23 | 2017-05-31 | 扬子江药业集团北京海燕药业有限公司 | A kind of preparation method of high-purity cefotiam hexetil dihydrochloride |
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| CN101619069A (en) * | 2009-07-28 | 2010-01-06 | 余小强 | Preparation method of cefotiam hexetil hydrochloride |
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| CN104031068A (en) * | 2014-06-11 | 2014-09-10 | 济南诚汇双达化工有限公司 | Method of preparing cefotiam hexetil hydrochloride by one-pot method |
| CN106749334A (en) * | 2016-11-23 | 2017-05-31 | 扬子江药业集团北京海燕药业有限公司 | A kind of preparation method of high-purity cefotiam hexetil dihydrochloride |
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