WO2011012965A1 - Improved process for preparation of ceftriaxone disodium hemiheptahydrate - Google Patents
Improved process for preparation of ceftriaxone disodium hemiheptahydrate Download PDFInfo
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- WO2011012965A1 WO2011012965A1 PCT/IB2010/001819 IB2010001819W WO2011012965A1 WO 2011012965 A1 WO2011012965 A1 WO 2011012965A1 IB 2010001819 W IB2010001819 W IB 2010001819W WO 2011012965 A1 WO2011012965 A1 WO 2011012965A1
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- Prior art keywords
- process according
- methyl
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- solvent
- sodium
- Prior art date
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- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- YOBPSXOHCHDCMU-IXIFSOOLSA-M sodium;(6r,7r)-7-[[(2e)-2-(2-amino-1,3-thiazol-4-yl)-2-methoxyiminoacetyl]amino]-3-[(2-methyl-5,6-dioxo-1h-1,2,4-triazin-3-yl)sulfanylmethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound [Na+].S([C@@H]1[C@@H](C(N1C=1C([O-])=O)=O)NC(=O)/C(=N/OC)C=2N=C(N)SC=2)CC=1CSC1=NC(=O)C(O)=NN1C YOBPSXOHCHDCMU-IXIFSOOLSA-M 0.000 title claims abstract description 7
- 238000000034 method Methods 0.000 title claims description 52
- 239000002904 solvent Substances 0.000 claims abstract description 25
- 230000001476 alcoholic effect Effects 0.000 claims abstract description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 45
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 25
- 239000000203 mixture Substances 0.000 claims description 19
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 17
- YXIWHUQXZSMYRE-UHFFFAOYSA-N 1,3-benzothiazole-2-thiol Chemical compound C1=CC=C2SC(S)=NC2=C1 YXIWHUQXZSMYRE-UHFFFAOYSA-N 0.000 claims description 14
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- 239000002253 acid Substances 0.000 claims description 12
- 125000000446 sulfanediyl group Chemical group *S* 0.000 claims description 11
- 239000003960 organic solvent Substances 0.000 claims description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
- 229940054266 2-mercaptobenzothiazole Drugs 0.000 claims description 7
- VYPDUQYOLCLEGS-UHFFFAOYSA-M sodium;2-ethylhexanoate Chemical compound [Na+].CCCCC(CC)C([O-])=O VYPDUQYOLCLEGS-UHFFFAOYSA-M 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- DKPFZGUDAPQIHT-UHFFFAOYSA-N butyl acetate Chemical compound CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 6
- 239000010410 layer Substances 0.000 claims description 6
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 claims description 4
- SYBYTAAJFKOIEJ-UHFFFAOYSA-N 3-Methylbutan-2-one Chemical compound CC(C)C(C)=O SYBYTAAJFKOIEJ-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- FKNQFGJONOIPTF-UHFFFAOYSA-N Sodium cation Chemical compound [Na+] FKNQFGJONOIPTF-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 4
- FDRNWTJTHBSPMW-BBJOQENWSA-L disodium;(6r,7r)-7-[[(2z)-2-(2-amino-1,3-thiazol-4-yl)-2-methoxyimino-1-oxidoethylidene]amino]-3-[(2-methyl-5,6-dioxo-1h-1,2,4-triazin-3-yl)sulfanylmethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound [Na+].[Na+].S([C@@H]1[C@@H](C(N1C=1C([O-])=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1CSC1=NC(=O)C([O-])=NN1C FDRNWTJTHBSPMW-BBJOQENWSA-L 0.000 claims description 4
- 229910001415 sodium ion Inorganic materials 0.000 claims description 4
- -1 cthanol Chemical compound 0.000 claims description 3
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 claims description 2
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims description 2
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 2
- ACTNHJDHMQSOGL-UHFFFAOYSA-N n',n'-dibenzylethane-1,2-diamine Chemical compound C=1C=CC=CC=1CN(CCN)CC1=CC=CC=C1 ACTNHJDHMQSOGL-UHFFFAOYSA-N 0.000 claims description 2
- 150000007530 organic bases Chemical class 0.000 claims description 2
- 239000012044 organic layer Substances 0.000 claims description 2
- PJGSXYOJTGTZAV-UHFFFAOYSA-N pinacolone Chemical compound CC(=O)C(C)(C)C PJGSXYOJTGTZAV-UHFFFAOYSA-N 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 238000010992 reflux Methods 0.000 claims description 2
- 239000001632 sodium acetate Substances 0.000 claims description 2
- 235000017281 sodium acetate Nutrition 0.000 claims description 2
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 claims 3
- DMBHHRLKUKUOEG-UHFFFAOYSA-N diphenylamine Chemical compound C=1C=CC=CC=1NC1=CC=CC=C1 DMBHHRLKUKUOEG-UHFFFAOYSA-N 0.000 claims 2
- 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 1
- 229940043279 diisopropylamine Drugs 0.000 claims 1
- 239000011734 sodium Substances 0.000 claims 1
- 229910052708 sodium Inorganic materials 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 150000001875 compounds Chemical class 0.000 description 14
- 238000003756 stirring Methods 0.000 description 12
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical class [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 9
- VAAUVRVFOQPIGI-SPQHTLEESA-N ceftriaxone Chemical compound S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1CSC1=NC(=O)C(=O)NN1C VAAUVRVFOQPIGI-SPQHTLEESA-N 0.000 description 9
- 229960004755 ceftriaxone Drugs 0.000 description 9
- 239000011541 reaction mixture Substances 0.000 description 8
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 8
- 239000004296 sodium metabisulphite Substances 0.000 description 8
- 235000010262 sodium metabisulphite Nutrition 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 7
- 238000009833 condensation Methods 0.000 description 5
- 230000005494 condensation Effects 0.000 description 5
- 231100001261 hazardous Toxicity 0.000 description 5
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 238000001291 vacuum drying Methods 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 230000008929 regeneration Effects 0.000 description 2
- 238000011069 regeneration method Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- RAIPHJJURHTUIC-UHFFFAOYSA-N 1,3-thiazol-2-amine Chemical compound NC1=NC=CS1 RAIPHJJURHTUIC-UHFFFAOYSA-N 0.000 description 1
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 0 CN(C(SCC(CS[C@@]1[C@@]2NC(C(c3c[s]c(N)n3)=*OC)=O)=C(*3=CC3)N1C2=O)=NC1=O)N=C1[N+]([O-])=C Chemical compound CN(C(SCC(CS[C@@]1[C@@]2NC(C(c3c[s]c(N)n3)=*OC)=O)=C(*3=CC3)N1C2=O)=NC1=O)N=C1[N+]([O-])=C 0.000 description 1
- 229930186147 Cephalosporin Natural products 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 229950003476 aminothiazole Drugs 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000000711 cancerogenic effect Effects 0.000 description 1
- 231100000315 carcinogenic Toxicity 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- KTAVBOYXMBQFGR-MAODNAKNSA-J tetrasodium;(6r,7r)-7-[[(2z)-2-(2-amino-1,3-thiazol-4-yl)-2-methoxyimino-1-oxidoethylidene]amino]-3-[(2-methyl-5,6-dioxo-1h-1,2,4-triazin-3-yl)sulfanylmethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate;heptahydrate Chemical compound O.O.O.O.O.O.O.[Na+].[Na+].[Na+].[Na+].S([C@@H]1[C@@H](C(N1C=1C([O-])=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1CSC1=NC(=O)C([O-])=NN1C.S([C@@H]1[C@@H](C(N1C=1C([O-])=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1CSC1=NC(=O)C([O-])=NN1C KTAVBOYXMBQFGR-MAODNAKNSA-J 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 150000007970 thio esters Chemical class 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
Classifications
-
- 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
Definitions
- the present invention is in the field of chemistry and more particularly it relates to the preparation of ceftriaxone disodium hemiheptahydratc of formula (I), reacting 7-amino-3- ⁇ [(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-l ,2,4-triazin-3-yl)thio
- Ceftriaxone disodium hemiheptahydrate of formula (I) is chemically known as disodium salt 7- ⁇ r2-(2-aminothiazol-4-yl)-2-syn-methoxyimino
- Ceftriaxone is a cephalosporin of a great therapeutical interest due to its effective antibacterial activity; and is administered as disodium salt hemiheptahydrate. It finds application in the treatment of several infections.
- Patent '380 describes a preparation which starts from 7-amino-3-(2,5-dihydro- ⁇ -hydroxy ⁇ -methyl-S-oxo-l ⁇ -triazin-S-yOthiomethyl ⁇ -cephem ⁇ -carboxylic acid of formula (II), which suitably protected at the carboxylic group, is made to react with 2-mercaptobenzothiazole 2-(2-aminothiazol-4-yl)-2-synmcthoxyimino acetate, then, after being deprotected, it gives ceftriaxone in the form of free acid. Its corresponding transformation in its soluble form as disodium salt is carried out afterwards according to the known techniques.
- the main object of the present invention is to provide a process for the preparation of a compound of formula (I), which is very safe, simple, economical, iiscr- friendly and commercially viable.
- Another objective of the present invention is to provide a process for the preparation of a compound of formula (I), which would be easy to implement on commercial scale, and to avoid excessive use of reagent(s) and organic solvcnt(s) and to avoid hazardous and risky solvents, which makes the present invention more safe and eco-friendly as well.
- Yet another objective of the present invention is to provide a process for the preparation of a compound of formula (I) in a greater yield with higher chemical purity.
- Still another objective of the present invention is to provide a process for the preparation of a compound of formula (I), wherein the alcoholic solvent used during the reaction can be reusable and thereby recyclable, which makes the process industrially more suitable.
- the present invention provides a process for the preparation of ceftriaxone disodium hemiheptahydrate of formula (I), which comprises the steps of:
- step (iv) adjusting the pH of aqueous layer as obtained from step (iii) with an acid
- step (v) adding sodium ion source and an organic solvent to the aqueous layer as obtained from step (iv);
- the said alcoholic solvent in step (i) may be selected from the group consisting of methanol, ethanol. isopropanol, tertiary butyl alcohol and the like or mixture thereof, more preferably methanol.
- the said base in step (i) is an organic base which may be selected from the group consisting of tricthylaminc. pyridine, N-methylpiperidine, 1,8-diazabicycloundecene, 4,4-dimcthylaminopyridinc, dicyclo hexylamine, diphenylaminc, diisopropylaminc, N-tcrt-butylcyclohcxylaminc and N,N-dibenzylethylenediamine and the like or mixtures thereof, more preferably triethylamine.
- step (i) is performed at a low temperature, preferably in the range of -10 0 C to 10 0 C.
- step (i) is accomplished relatively in a shorter time, which makes the process more useful against the prior art processes.
- the said condensation of step (i) is proceeding to completion in 1 to 4 hrs.
- the said organic solvent in step (ii) is n -butyl acetate or ethyl acetate.
- the said acid in step (iv) is hydrochloric acid or sulfuric acid and the like, more preferably hydrochloric acid.
- the pH disclosed in step (iv) is in the range of 5 to 7, more preferably 6.0 to 6.3.
- the said sodium ion source in step (v) may be selected from the group consisting of sodium hydroxide, sodium acetate or sodium 2-ethylhexanoate and the like, - more preferably sodium 2- ethylhexanoate.
- the said organic solvent in step (v) is a ketonic solvent which may be selected from the group consisting of acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl isopropyl ketone, methyl tertiary butyl ketone and mixture thereof or alcoholic solvent which may be selected from the group consisting of methanol, ethanol, isopropyl alcohol, tertiary butyl alcohol and mixture thereof.
- all the steps except step (i) arc preferably performed at a temperature in the range of -10 0 C to reflux temperature of the solvent used.
- the mixture was kept at (-) 2 0 C to 2 0 C and 0.55 kg of triethylamine was dropwise added under stirring over 30 mins.
- the solution was stirred at O 0 C to 3 0 C until the reaction was completed.
- 0.02 kg sodium metabisulphite, 6 L water and 10 L r ⁇ -butyl acetate were added at 3 0 C to 7 0 C.
- the reaction mixture was stirred for 15 to20 mins and settled at 2O 0 C to 25 0 C.
- the aqueous phase was separated and pH was adjusted to 6.0 to 6.3 with dilute hydrochloric acid solution.
- the process of the present invention is very safe, simple and yields higher purity and greater yield of a compound of formula (1).
- the process of the present invention avoids excess usages of rcagent(s) and organic solvent(s), thereby promoting green chemistry and ensuring a cleaner surrounding by putting less load on environment.
- the process of the present invention uses a solvent which can be recycled and reused. This makes the process more economical and industrially & commercially viable.
- the process of the present invention is a simple process, which avoids more number of operations, thus resulting in shortening of reaction time and lowering of labor.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Cephalosporin Compounds (AREA)
Abstract
The preparation of ceftriaxone disodium hemiheptahydrate of formula (I) using alcoholic solvent in a very safe, simple, economical, user-friendly and in an industrially viable manner is provided.
Description
IMPROVED PROCESS FOR PREPARATION OF CEFTRIAXONE DISODIUM
HEMIHEPTAHYDRATE
The following specification particularly describes the invention and the manner in which it is to be performed.
Field of the invention
The present invention is in the field of chemistry and more particularly it relates to the preparation of ceftriaxone disodium hemiheptahydratc of formula (I), reacting 7-amino-3-{[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-l ,2,4-triazin-3-yl)thio|mcthyl}- 3-cephem-4-carboxylic acid of formula (II) with 2-mercaptobcn/.othia/.olc 2-(2- aminothiazol-4-yl)-2-syn-methoxyiminoacetate of formula (III) in presence of a base and using alcohol as a solvent in a very safe, simple, economical, uscr-fricndly and in an industrially viable manner.
(II) (III)
Background of the invention .
Ceftriaxone disodium hemiheptahydrate of formula (I), is chemically known as disodium salt 7-{r2-(2-aminothiazol-4-yl)-2-syn-methoxyimino| acctamido}-3-{|(2,5- dih ydro-6-hydroxy-2-methyl-5-oxo-l ,2,4-triazin-3-yl)thio|mcthyl}-3-ccphcm-4- carboxylic acid. Ceftriaxone is a cephalosporin of a great therapeutical interest due to
its effective antibacterial activity; and is administered as disodium salt hemiheptahydrate. It finds application in the treatment of several infections.
(D
All relevant processes described in literature starts with 7-amino-3-{|(2.5- dihydro-ό-hydroxy^-methyl-S-oxo-l ^^-triazin^-y^thioJmethyll^-ccphcm^- carboxylic acid of formula (II) whereby the side chain in N-protectcd or unprotected form is introduced into the amino group in position 7 using various acylation techniques.
The most elegant method of introducing the side chain uses a reactive thiocstcr. e.g. 2-mercaptobenzothiazole 2-(2-aminothiazol-4-yl)-2-syn-mcthoxyiminoacctatc of formula (III), as here it is not necessary to protect the amino function of the 2- aminothiazolyl group. This process was first described in EP-Λ-0037380 (Biochcmic GmbH) henceforth '380, and since then has been used in a few slightly modified processes such as EP-A-0399094 (Synthetic Biolog Dev.), henceforth "094.
Patent '380 describes a preparation which starts from 7-amino-3-(2,5-dihydro- ό-hydroxy^-methyl-S-oxo-l ^^-triazin-S-yOthiomethyl^-cephem^-carboxylic acid of formula (II), which suitably protected at the carboxylic group, is made to react with 2-mercaptobenzothiazole 2-(2-aminothiazol-4-yl)-2-synmcthoxyimino acetate, then, after being deprotected, it gives ceftriaxone in the form of free acid. Its corresponding transformation in its soluble form as disodium salt is carried out afterwards according to the known techniques.
Another process, which operates without a protecting group at the amino function of the aminothiazole, is described in EP-A-0175814 (Hanmi Pharma Ind Co Ltd). In this process, active esters with 1-hydroxybenzotriazole arc employed.
Processes using an amino protecting group arc described in Gli-Λ-2022090 (Hoffmann La Roche) and in '094. Of all the processes described, the one using activated thioester, as described in the patent '380, appears to be the best.
According to the patent '380, 7-amino-3-{[(2,5-dihydro-6-hydroxy-2-mcthyl-5- oxo-l,2,4-triazin-3-yl)thio]methyl}-3-cephem-4-carboxylic acid of formula (II) is silylated in dichloromethane with N,O-bis-(trimethylsilyl)acctamidc and reacted with 2-mercaptobenzothiazole 2-(2-aminothiazol-4-yl)-2-syn-mcthoxyirninoacctatc of formula (III),. By adding methanol-containing acetonitrile, the ceftriaxone formed is precipitated as a free acid. This then has to be converted in a further reaction step into the desired form of the disodium salt.
In the process described in patent '380, not only an ecologically hazardous chlorinated hydrocarbon (dichloromethane) is used as the reaction solvent which is difficult to recycle or dispose of in an environmentally acceptable manner, but also the toxic acetonitrile is employed to isolate the active substance. In this process, mother liquor is obtained, which consists of a mixture of dichloromethane, methanol, acetonitrile, acetamide and siloxanes. Apart from the ecologically hazardous dichloromethane, this mixture also contains the solvents methanol and acetonitrile. and in addition the suspected carcinogenic acetamide. Regeneration of the individual components from this mixture may only be carried out at very great expense, if at all. A further disadvantage of the process described in the patent '380 is that first of all ceftriaxone has to be isolated, and in an additional step of the process, the disodium sail form thereof which is necessary for parenteral application must be produced.
In the process described in patent '094, the reaction of 7-amino-3-{|(2.5- dihydro-6-hydroxy-2-methyl-5-oxo-l ,2,4-triazin-3-yl)thio]methyl}-3-cephcm-4- carboxylic acid of formula (II) with 2-mercaptobenzothiazole 2-(2-aminothiazol-4vyl)- 2-syn-methoxyiminoacetate of formula (III) is effected in a mixture of dimethylacetamide, tetrahydrofuran and water. In order to be able to isolate . a product of high purity, in this process first of all the N,N-dibenzylethylcnediaminc salt of ceftriaxone must be produced. For this, two further solvents arc employed, namely ethyl acetate and dichloromethane, so that the mother liquor to be regenerated is finally a mixture of 5 different solvents, containing again the ecologically hazardous
dichloromethane. Finally, in order to produce the desired ceftriaxone disodium salt hemiheptahydrate, acetone is required. In this process, the result is thus a mixture of solvents, the regeneration of which into pure individual components in an economical manner is not possible. In addition, two isolation steps are necessary to obtain the desired product.
Accordingly therefore, there is an urgent need to develop an alternative industrially viable process for the preparation of a compound of formula (I), which is readily amenable to scale-up. Hence we focused our research to simplify the process for the preparation of a compound of formula (I) by using alcoholic solvent and substantially low amounts of reagent(s) and solvent(s), in a substantially lesser reaction time, while getting a greater yield with higher purity and avoiding unwanted by products and impurities by using substantially different method of making thereof to obviate the aforesaid problems associated with the prior art proccss(s).
As discussed above none of the prior art references disclosed or claimed the use of alcoholic solvent for the preparation of compound of formula (I), for the condensation of 7-amino-3-{[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo- l ,2.4-lria/in-3- yl)thio]methyl}-3-cephem-4-carboxylic acid of formula (II) with 2- mercaptobenzothiazole 2-(2-aminothiazol-4-yl)-2-syn-methoxyiminoacctatc of formula (III), hence we focused our research to develop an improved and efficient process for the preparation of a compound of formula (I) along with substantially fair operational safety, satisfactory yield and high chemical purity, which makes the process more economical, distinct and successful at industrial & commercial level.
It should be pointed out that the said condensation, which is extremely aggressive, in alcoholic solvents and mixtures thereof, has never before been reported in literature. The present invention provides remarkable advantages in the industrial processes for the production of ceftriaxone disodium hemiheptahydrate. In fact, the method of the invention provides good quality ceftriaxone disodium hemiheptahydrate of formula (I) in yields quite comparable to those expected with the prior art methods.
Objective of the invention
The main object of the present invention is to provide a process for the preparation of a compound of formula (I), which is very safe, simple, economical, iiscr- friendly and commercially viable.
Another objective of the present invention is to provide a process for the preparation of a compound of formula (I), which would be easy to implement on commercial scale, and to avoid excessive use of reagent(s) and organic solvcnt(s) and to avoid hazardous and risky solvents, which makes the present invention more safe and eco-friendly as well.
Yet another objective of the present invention is to provide a process for the preparation of a compound of formula (I) in a greater yield with higher chemical purity.
Still another objective of the present invention is to provide a process for the preparation of a compound of formula (I), wherein the alcoholic solvent used during the reaction can be reusable and thereby recyclable, which makes the process industrially more suitable.
Summary of the invention
Accordingly, the present invention provides a process for the preparation of ceftriaxone disodium hemiheptahydrate of formula (I), which comprises the steps of:
(I)
(i) condensing 7-amino-3-{[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo- l ,2.4-tria/in- 3-yl)thio]methyl}-3-cephem-4-carboxylic acid of formula (II) with 2-mercaptobenzothiazole 2-(2-aminothiazol-4-yl)-2-syn-mcthoxyiminoacctatc of formula (III) in presence of a base in an alcoholic solvent;
(ii) adding water and an organic solvent;
(iii) separating the organic layer and aqueous layer;
(iv) adjusting the pH of aqueous layer as obtained from step (iii) with an acid;
(v) adding sodium ion source and an organic solvent to the aqueous layer as obtained from step (iv); and
(vi) isolating the ceftriaxone disodium hemihcptahydratc of formula (I) in pure form.
The above process is illustrated in the following synthetic scheme:
(II) (IW
Base
Alcoholic solvent
(I)
Detailed description of the invention
Accordingly in an embodiment of the present invention, the said alcoholic solvent in step (i) may be selected from the group consisting of methanol, ethanol. isopropanol, tertiary butyl alcohol and the like or mixture thereof, more preferably methanol.
In another embodiment of the present invention, the said base in step (i) is an organic base which may be selected from the group consisting of tricthylaminc. pyridine, N-methylpiperidine, 1,8-diazabicycloundecene, 4,4-dimcthylaminopyridinc,
dicyclo hexylamine, diphenylaminc, diisopropylaminc, N-tcrt-butylcyclohcxylaminc and N,N-dibenzylethylenediamine and the like or mixtures thereof, more preferably triethylamine.
In another embodiment of the present invention, the condensation of step (i) is performed at a low temperature, preferably in the range of -100C to 100C.
In another embodiment of the present invention, the condensation of step (i) is accomplished relatively in a shorter time, which makes the process more useful against the prior art processes. The said condensation of step (i) is proceeding to completion in 1 to 4 hrs.
In another embodiment of the present invention, the said organic solvent in step (ii) is n -butyl acetate or ethyl acetate.
In another embodiment of the present invention, the said acid in step (iv) is hydrochloric acid or sulfuric acid and the like, more preferably hydrochloric acid.
In another embodiment of the present invention, the pH disclosed in step (iv) is in the range of 5 to 7, more preferably 6.0 to 6.3.
In another embodiment of the present invention, the said sodium ion source in step (v) may be selected from the group consisting of sodium hydroxide, sodium acetate or sodium 2-ethylhexanoate and the like, - more preferably sodium 2- ethylhexanoate.
In another embodiment of the present invention, the said organic solvent in step (v) is a ketonic solvent which may be selected from the group consisting of acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl isopropyl ketone, methyl tertiary butyl ketone and mixture thereof or alcoholic solvent which may be selected from the group consisting of methanol, ethanol, isopropyl alcohol, tertiary butyl alcohol and mixture thereof.
In another embodiment of the present invention, all the steps except step (i) arc preferably performed at a temperature in the range of -100C to reflux temperature of the solvent used.
In the present invention starting material(s) for the preparation of a compound of formula (I), were prepared according to the known processes in the prior art.
The invention is further illustrated by the following examples, which should not be construed to limit the scope of the invention in anyway.
EXAMPLE 1
Preparation of disodium salt of ceftriaxone hemiheptahydrate
1.0 kg of 7-amino-3-{[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-l ,2,4-tria/in-3- yl)thio]methyl}-3-cephem-4-carboxy!ic acid and 1.04 kg of 2-mercaptobenzothia/olc 2-(2-aminothiazol-4-yl)-2-syn-methoxyiminoacetate were added in 4.5 L of methanol at O0C to 50C and 0.5 L of methanol was flushed into the reactor. The mixture was kept at (-) 20C to 20C and 0.55 kg of triethylamine was dropwise added under stirring over 30 mins. The solution was stirred at O0C to 30C until the reaction was completed. Subsequently, 0.02 kg sodium metabisulphite, 6 L water and 10 L /?-butyl acetate were added at 30C to 70C. The reaction mixture was stirred for 15 to20 mins and settled at 2O0C to 250C. The aqueous phase was separated and pH was adjusted to 6.0 to 6.3 with dilute hydrochloric acid solution. 0.02 kg ethylenediaminetetraacctic acid and 0.01 kg sodium metabisulphite were added thereto under stirring at 250C to 3O0C. Λ solution consisting of 1.1 kg sodium 2-ethylhexanoate in 5 L acetone was added to the reaction mixture within 1 hr at 260C to 3O0C under stirring. Afterwards 25.0 L of acetone was added dropwise and the resulting crystal suspension was stirred further for 1 hr at the same temperature .The material was filtered, washed with 2 L of acetone and dried in a vacuum drying chamber at 4O0C for 3 hrs to get 1.65 kg (92.7 %) of the title compound with 99.79 % chromatographic purity.
EXAMPLE 2
Preparation of disodium salt of ceftriaxone hemihcptahydratc
1.0 kg of 7-amino-3-{[(2,5-dihydro-6-hydroxy-2-mcthyl-5-oxo- 1.2,4-tria/in-3- yl)thio]methyl}-3-cephem-4-carboxylic acid and 1.04 kg of 2-mercaptobcnzolhia/.olc 2-(2-aminothiazol-4-yl)-2-syn-methoxyiminoacetate were added in 4.5 I. of ethanol at O0C to 50C and 0.5 L of ethanol was flushed into the reactor. The mixture was kept at (-) 20C to 20C and 0.55 kg of triethylamine was dropwise added under stirring over 30 mins. The solution was stirred at O0C to 30C until the reaction was completed. Subsequently, 0.02 kg sodium metabisulphite, 6 L water and 10 L /7-butyl acetate were added at 30C to 70C. The reaction mixture was stirred for 15 to20 mins and settled at 2O0C to 25°C. The aqueous phase was separated and pH was adjusted to 6.0 to 6.3 with dilute hydrochloric acid solution. 0.02 kg ethylenediaminctetraacctic acid and 0.01 kg sodium metabisulphite were added thereto under stirring at 250C to 3O0C. Λ solution consisting of 1.1 kg sodium 2-ethylhexanoate in 5 L ethanol was added to the reaction mixture within 1 hr at 260C to 3O0C under stirring. Afterwards 30.0 L of ethanol was added dropwise and the resulting crystal suspension was stirred further for 1 hr at the same temperature .The material was filtered, washed with 2 L of ethanol and dried in a vacuum drying chamber at 4O0C for 3 hrs to get 1.65 kg (92.7 %) of the title compound with 99.75 % chromatographic purity.
EXAMPLE 3
Preparation of disodium salt of ceftriaxone hemihcptahydratc
1.0 kg of 7-amino-3-{[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-1.2,4-tria/in-3- yl)thio]methyl}-3-cephem-4-carboxylic acid and 1 .04 kg of 2-mcrcaptoben/othia/olc 2-(2-aminothiazol-4-yl)-2-syn-methoxyiminoacetatc were added in 4.5 L oC methanol at O0C to 5°C and 0.5 L of methanol was flushed into the reactor. The mixture was kept at (-) 20C to 20C and 0.55 kg of triethylamine was dropwise added under stirring over 30 mins. The solution was stirred at O0C to 30C until the reaction was completed. Subsequently, 0.02 kg sodium metabisulphite, 6 L water and 10 L rø-butyl acetate were added at 30C to 70C. The reaction mixture was stirred for 15 to20 mins and settled at
2O0C to 250C. The aqueous phase was separated and pH was adjusted to 6.0 to 6.3 with dilute hydrochloric acid solution. 0.02 kg ethylenediaminetctraacetic acid and 0.01 kg sodium metabisulphite were added thereto under stirring at 250C to 3O0C. Λ solution consisting of 1.1 kg sodium 2-ethylhexanoate in 5 L isopropanol was added to the •reaction mixture within 1 hr at 260C to 3O0C under stirring. Afterwards 35.0 L of isopropanol was added dropwise and the resulting crystal suspension was stirred further for 1 hr at the same temperature .The material was filtered, washed with 2 \ , of isopropanol and dried in a vacuum drying chamber at 4O0C for 3 hrs to get 1 .66 kg to 1.70 kg (93.2 % to 95.5 %) of the title compound with 99.60 % chromatographic purity.
EXAMPLE 4
Preparation of disodium salt of ceftriaxone hemihcptahydratc
1.0 kg of 7-amino-3-{[(2,5-dihydro-6-hydroxy-2-mcthyl-5-oxo- 1.2,4-triazin-3- yl)thio]methyl}-3-cephem-4-carboxylic acid and 1.04 kg of 2-mcrcaptobcnzothia/o!c 2-(2-aminothiazol-4-yl)-2-syn-methoxyiminoacetate were added in 4.5 L of methanol at O0C to 50C and 0.5 L of methanol was flushed into the reactor. The mixture was kept at (-) 20C to 20C and 0.55 kg of triethylamine was dropwise added under stirring over 30 mins. The solution was stirred at O0C to 30C until the reaction was completed. Subsequently, 0.02 kg sodium metabisulphite, 6 L water and 10 L n-butyl acetate were added at 30C to 70C. The reaction mixture was stirred for 15 to20 mins and settled at 2O0C to 250C. The aqueous phase was separated and pH was adjusted to 6.0 to 6.3 with dilute hydrochloric acid solution. 0.02 kg ethylenediaminetctraacetic acid and 0.01 kg sodium metabisulphite were added thereto under stirring at 250C to 3O0C. Λ solution consisting of 1.1 kg sodium 2-ethylhexanoate in 5 L ethanol was added to the reaction mixture within 1 hr at 260C to 3O0C under stirring. Afterwards 25.0 L of ethanol was added dropwise and the resulting crystal suspension was stirred further for 1 hr at the same temperature .The material was filtered, washed with 2 L of ethanol and dried in a vacuum drying chamber at 4O0C for 3 hrs to get 1.65 kg (92.7 %) of the title compound with 99.89 % chromatographic purity.
Substantial Advantages and Industrial applicability
(1) The process of the present invention is very safe, simple and yields higher purity and greater yield of a compound of formula (1).
(2) The process of the present invention avoids excess usages of rcagent(s) and organic solvent(s), thereby promoting green chemistry and ensuring a cleaner surrounding by putting less load on environment.
(3) The process of the present invention avoids the use of solvents like tctrahydrofuran. dichloromethane, N,N-dimethylformamide, acetonitrile which arc harmful for the environment and are very hazardous in nature.
(4) The process of the present invention uses a solvent which can be recycled and reused. This makes the process more economical and industrially & commercially viable.
(5) The process of the present invention is a simple process, which avoids more number of operations, thus resulting in shortening of reaction time and lowering of labor.
Claims
(1) An improved process for the preparation of ceftriaxone disodium hcmihcptahydratc of formula (I); comprising the steps of:
(I)
(i) condensing 7-amino-3-{[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo- 1 ,2,4-tria/in- 3- yl)thio] methyl }-3-cephem-4-carboxy lie acid of formula (II) with 2- mercaptobenzothiazole 2-(2-aminothiazol-4-yl)-2-syn-mcthoxyiminoacctatc of formula (III) in presence of a base in an alcoholic solvent;
(II) (HI)
(ii) adding water and an organic solvent;
(iii) separating the organic layer and aqueous layer;
(iv) adjusting the pH of the aqueous layer as obtained from step (iii) with an acid:
(v) adding sodium ion source and an organic solvent to the aqueous layer as obtained from step (iv); and
(vi) isolating the ceftriaxone disodium hemiheptahydrate of formula (I) in pure form.
(2) A process according to claim 1 , wherein the said alcoholic solvent in step (i) is selected from the group consisting of methanol, ethanol, isopropyl alcohol, tertiary butyl alcohol or mixtures thereof, preferably methanol.
(3) A process according to claim 1 , wherein the said base in step (i) is an organic base. and is selected from the group consisting of triethylaminc, pyridine, N- methylpiperidine, 1 ,8-diazabicycloundecene, 4,4-dimcthylaminopyridinc. dicyclo hexylamine, diphenylamine, diisopropylamine, N-tert-butylcyclohcxylaminc and N,N- dibenzylethylenediamine or mixtures thereof, preferably triethylaminc.
(4) A process according to claim 1, wherein the said organic solvent in step (ii) is
n -butyl acetate or ethyl acetate.
(5) A process according to claim 1 , wherein the said pl f in step (iv) is in the range of 5 to 7, preferably 6.0 to 6.3.
(6) A process according to claim 1, wherein the said acid in step (iv) is hydrochloric acid or sulfuric acid, preferably hydrochloric acid.
(7) A process according to claim 1 , wherein the said sodium ion source in step (v) is selected from the group consisting of sodium hydroxide, sodium acetate or sodium 2-ethylhexanoate, preferably sodium 2-ethylhexanoatc.
(8) A process according to claim 1 , wherein the said organic solvent in step (v) is a ketonic solvent, which is selected from the group consisting of acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl isopropyl ketone, methyl tertiary butyl ketone or mixtures thereof.
(9) A process according to claim 1, wherein the said organic solvent in step (v) is an alcoholic solvent, which is selected from the group consisting of methanol, cthanol, isopropyl alcohol and tertiary butyl alcohol or mixtures thereof.
(10) A process according to claim 1 , wherein all the steps are preferably performed at a temperature in the range of -100C to reflux temperature of the solvent used.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106366099A (en) * | 2016-08-22 | 2017-02-01 | 山东罗欣药业集团恒欣药业有限公司 | Anti-infection medicine ceftriaxone sodium crystal compound and preparation method thereof |
| CN110452255A (en) * | 2019-09-05 | 2019-11-15 | 上海龙翔生物医药开发有限公司 | Crystal form of Ceftriaxone Sodium and preparation method thereof |
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| WO2004037833A1 (en) * | 2002-10-24 | 2004-05-06 | Orchid Chemicals & Pharmaceuticals Ltd | Process for the preparation of cephalosporin antibiotics |
| CN1634933A (en) * | 2004-10-27 | 2005-07-06 | 山东瑞阳制药有限公司 | Process for preparing ceftriaxone sodium |
| CN1765902A (en) * | 2004-10-27 | 2006-05-03 | 山东瑞阳制药有限公司 | One-step preparation process of aseptic ceftriaxone sodium for injection |
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| WO2004037833A1 (en) * | 2002-10-24 | 2004-05-06 | Orchid Chemicals & Pharmaceuticals Ltd | Process for the preparation of cephalosporin antibiotics |
| CN1634933A (en) * | 2004-10-27 | 2005-07-06 | 山东瑞阳制药有限公司 | Process for preparing ceftriaxone sodium |
| CN1765902A (en) * | 2004-10-27 | 2006-05-03 | 山东瑞阳制药有限公司 | One-step preparation process of aseptic ceftriaxone sodium for injection |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106366099A (en) * | 2016-08-22 | 2017-02-01 | 山东罗欣药业集团恒欣药业有限公司 | Anti-infection medicine ceftriaxone sodium crystal compound and preparation method thereof |
| CN110452255A (en) * | 2019-09-05 | 2019-11-15 | 上海龙翔生物医药开发有限公司 | Crystal form of Ceftriaxone Sodium and preparation method thereof |
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