WO2014140699A1 - A novel process of liberation of erythromycin and preparation of its salts - Google Patents
A novel process of liberation of erythromycin and preparation of its salts Download PDFInfo
- Publication number
- WO2014140699A1 WO2014140699A1 PCT/IB2013/053860 IB2013053860W WO2014140699A1 WO 2014140699 A1 WO2014140699 A1 WO 2014140699A1 IB 2013053860 W IB2013053860 W IB 2013053860W WO 2014140699 A1 WO2014140699 A1 WO 2014140699A1
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- WO
- WIPO (PCT)
- Prior art keywords
- erythromycin
- base
- water
- thiocyanate
- liberation
- Prior art date
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- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 title claims abstract description 226
- 229960003276 erythromycin Drugs 0.000 title claims abstract description 101
- 238000000034 method Methods 0.000 title claims abstract description 76
- 238000002360 preparation method Methods 0.000 title claims abstract description 36
- 150000003839 salts Chemical class 0.000 title abstract description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 56
- PGNYNCTUBKSHHL-UHFFFAOYSA-N 2,3-diaminobutanedioic acid Chemical compound OC(=O)C(N)C(N)C(O)=O PGNYNCTUBKSHHL-UHFFFAOYSA-N 0.000 claims abstract description 41
- YAVZHCFFUATPRK-YZPBMOCRSA-N Erythromycin stearate Chemical compound CCCCCCCCCCCCCCCCCC(O)=O.O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 YAVZHCFFUATPRK-YZPBMOCRSA-N 0.000 claims abstract description 31
- 229960004142 erythromycin stearate Drugs 0.000 claims abstract description 31
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims abstract description 29
- 239000002904 solvent Substances 0.000 claims abstract description 29
- 235000021355 Stearic acid Nutrition 0.000 claims abstract description 27
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims abstract description 27
- 239000008117 stearic acid Substances 0.000 claims abstract description 27
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical group N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 37
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 24
- 229910021529 ammonia Inorganic materials 0.000 claims description 15
- 238000006243 chemical reaction Methods 0.000 claims description 13
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 10
- 150000007529 inorganic bases Chemical class 0.000 claims description 9
- 150000007530 organic bases Chemical class 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 8
- 238000001914 filtration Methods 0.000 claims description 6
- ROSDSFDQCJNGOL-UHFFFAOYSA-N protonated dimethyl amine Natural products CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 claims description 6
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 5
- 235000017550 sodium carbonate Nutrition 0.000 claims description 5
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 4
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 4
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 4
- 238000002955 isolation Methods 0.000 claims description 4
- 239000011736 potassium bicarbonate Substances 0.000 claims description 4
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 4
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- 235000011181 potassium carbonates Nutrition 0.000 claims description 4
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 4
- 235000011118 potassium hydroxide Nutrition 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 3
- 238000005406 washing Methods 0.000 claims description 3
- 239000000047 product Substances 0.000 description 18
- 238000004128 high performance liquid chromatography Methods 0.000 description 17
- 229930006677 Erythromycin A Natural products 0.000 description 16
- 239000002585 base Substances 0.000 description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- MWFRKHPRXPSWNT-UHFFFAOYSA-N Erythromycin-C Natural products CC1C(OC2C(C(CC(C)O2)N(C)C)O)C(C)(O)CC(C)C(=O)C(C)C(O)C(O)(C)C(CC)OC(=O)C(C)C1OC1CC(C)(O)C(O)C(C)O1 MWFRKHPRXPSWNT-UHFFFAOYSA-N 0.000 description 10
- 239000003960 organic solvent Substances 0.000 description 10
- IDRYSCOQVVUBIJ-UHFFFAOYSA-N Erythromycin-B Natural products CC1C(OC2C(C(CC(C)O2)N(C)C)O)C(C)(O)CC(C)C(=O)C(C)C(O)C(C)C(CC)OC(=O)C(C)C1OC1CC(C)(OC)C(O)C(C)O1 IDRYSCOQVVUBIJ-UHFFFAOYSA-N 0.000 description 9
- IDRYSCOQVVUBIJ-PPGFLMPOSA-N erythromycin B Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@H]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)C)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 IDRYSCOQVVUBIJ-PPGFLMPOSA-N 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- 239000012535 impurity Substances 0.000 description 8
- 239000000725 suspension Substances 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- ZMZDMBWJUHKJPS-UHFFFAOYSA-M Thiocyanate anion Chemical compound [S-]C#N ZMZDMBWJUHKJPS-UHFFFAOYSA-M 0.000 description 4
- 235000012970 cakes Nutrition 0.000 description 4
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N hydrogen thiocyanate Natural products SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 229910015400 FeC13 Inorganic materials 0.000 description 2
- -1 SCN ions Chemical class 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- SOIFLUNRINLCBN-UHFFFAOYSA-N ammonium thiocyanate Chemical compound [NH4+].[S-]C#N SOIFLUNRINLCBN-UHFFFAOYSA-N 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 235000021463 dry cake Nutrition 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 1
- 0 CC[C@]([C@](C)([C@@]([C@@](C)C([C@](C)C[C@](C)([C@@]([C@](C)[C@@]([C@]1C)OC(CC2(*)OC)OC(C)C2O)OC(C2*)OC(C)CC2N(C)C)O)=O)O)O)OC1=O Chemical compound CC[C@]([C@](C)([C@@]([C@@](C)C([C@](C)C[C@](C)([C@@]([C@](C)[C@@]([C@]1C)OC(CC2(*)OC)OC(C)C2O)OC(C2*)OC(C)CC2N(C)C)O)=O)O)O)OC1=O 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 229910021578 Iron(III) chloride Inorganic materials 0.000 description 1
- HTLZVHNRZJPSMI-UHFFFAOYSA-N N-ethylpiperidine Chemical compound CCN1CCCCC1 HTLZVHNRZJPSMI-UHFFFAOYSA-N 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- JIVGDWPJJALVLG-UHFFFAOYSA-N diethylazanium;thiocyanate Chemical compound [S-]C#N.CC[NH2+]CC JIVGDWPJJALVLG-UHFFFAOYSA-N 0.000 description 1
- SPEMTLAMABUSQQ-UHFFFAOYSA-N dimethylazanium;thiocyanate Chemical compound C[NH2+]C.[S-]C#N SPEMTLAMABUSQQ-UHFFFAOYSA-N 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 1
- 239000003120 macrolide antibiotic agent Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- ODUCDPQEXGNKDN-UHFFFAOYSA-N nitroxyl Chemical compound O=N ODUCDPQEXGNKDN-UHFFFAOYSA-N 0.000 description 1
- WTBAHSZERDXKKZ-UHFFFAOYSA-N octadecanoyl chloride Chemical compound CCCCCCCCCCCCCCCCCC(Cl)=O WTBAHSZERDXKKZ-UHFFFAOYSA-N 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
- C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
- C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins
Definitions
- the present invention relates to a novel process for the liberation of Erythromycin from Erythromycin salts. More particularly, the present invention relates to a novel process for the liberation of Erythromycin from Erythromycin thiocyanate in presence of a base and using water as a solvent.
- the present invention further relates to a novel process for the preparation of Erythromycin salts like Erythromycin Stearate from Erythromycin or its salts using water as a solvent.
- Erythromycin of formula I is the most important member of the macrolide antibiotics of microbial origin. It is effective against many Gram-positive and Gram-negative bacteria and is often used for people who have an allergy to penicillin.
- Erythromycin Being bitter in taste Erythromycin has limitations when administered orally. Hence orally it is administered as Erythromycin Stearate in the form of a tablet. Erythromycin Stearate is not only palatable but also has an anti bacterial property. It is relatively stable and has high erythromycin potency.
- Erythromycin was first disclosed in U.S. patent 2,653,899 in 1952. Various prior art discloses different processes for preparation of Erythromycin.
- 497/MUM/2005 discloses preparation of Erythromycin base from Erythromycin thiocyanate in presence of halogenated solvents and ammonia. The process involves use of 6 volumes of chlorinated solvent such as dichloromethane for liberating Erythromycin from Erythromycin thiocyanate.
- 627/MUM/2005 discloses preparation of 6,9 imino ether from Erythromycin thiocyanate. As stated in this patent application, the process comprises dissolving Erythromycin thiocyanate in methylene chloride and adding liquid ammonia as a base, separating organic layer, distilling solvent from organic layer to obtain residue of Erythromycin base which further converted to the title compound.
- Other patent applications e.g. 626/MUM/2005, WO2007029266 and WO2009023191 also describe preparation of Erythromycin from Erythromycin thiocyanate in dichloromethane using aqueous ammonia.
- Polish patent PL83707 describes preparation of low melting Erythromycin base by treating Erythromycin thiocyanate with of 20% aqueous ethanol and 5% NaOH at 40- 50°C followed by filtering and treating the precipitate with water and alkali till suspension shows no reaction of SCN ions and pH becomes constant to obtain erythromycin base. Therefore, the processes reported in literature for the liberation of Erythromycin from Erythromycin thiocyanate employ organic solvents, primarily halogenated solvents which have bad impact on environment when one is dealing with industrial scale. During the recovery of chlorinated solvents, there is particular loss of solvent which can not be accounted, thus causing environment pollution and also considerable economical loss.
- Erythromycin Stearate was first disclosed in US2862921 in 1958.
- the said patent discloses Erythromycin esters as novel compounds and process for their preparation.
- the process as described comprises reaction of Erythromycin with stearoyl chloride in an inert solvent such as methylene chloride in presence of base such as 1 -ethyl piperidine. The reaction mass was kept overnight.
- US 2881 163 describes the process for preparation of Erythromycin acid addition salts from its salt such as Erythromycin acetate in presence of water miscible organic solvent.
- the process involves mixing of aqueous solution of Erythromycin acetate with acetone, 10% sodium hydroxide, sodium chloride. The mixture was heated at 45°C followed by separation of acetone phase which was reacted with steric acid. After steric acid was dissolved completely the solution was filtered and water was added at same temperature. The solution was allowed to crystallize at 18°C. Crystals are filtered, washed and dried to obtain Erythromycin Stearate.
- the inventors of the present invention have surprisingly found a novel process for the liberation of Erythromycin from Erythromycin thiocyanate using only water as a solvent in presence of a base, which has not been previously reported in any prior art as Erythromycin thiocyanate is insoluble in water. It is a common practice to obtain the product from its salt that use a solvent in which salt is soluble and product is insoluble. But process of the present invention uses water as a solvent in which Erythromycin thiocyanate is insoluble. The inventors of the present invention further found out a novel process for the preparation of Erythromycin Stearate from Erythromycin or its salts by reacting it with stearic acid in presence of water as a solvent by avoiding use of any organic solvent. Thus, the inventors of the present invention have found out a novel process wherein both Erythromycin and stearic acid are insoluble in water, however reacts to form an insoluble salt.
- An object of the present invention is to provide a novel process for the liberation of Erythromycin from Erythromycin salts. More particularly, the present invention provides a novel process for the liberation of Erythromycin from Erythromycin thiocyanate in water in presence of a base.
- Another object of the present invention is to provide a novel process for the preparation of Erythromycin with more than 95% purity and good yield.
- Another object of the present invention is to obtain Erythromycin substantially free of impurities by avoiding any purification process.
- Yet another object of the present invention is to provide simple, economic, environment friendly and industrially viable processes for liberation of
- Yet another object of the present invention is to provide a novel process wherein both Erythromycin and stearic acid are insoluble in water, however reacts to form an insoluble salt.
- Another aspect of the present invention is to provide Erythromycin with more than 95% purity without any further purification process.
- a novel process for the preparation of Erythromycin Stearate from Erythromycin salts such as Erythromycin thiocyanate via liberation of Erythromycin comprising i) reacting Erythromycin thiocyanate of formula II with base in presence of water at 30 to 80 °C to liberate Erythromycin of formula I ii) treating Erythromycin of step i) with stearic acid in presence of water to obtain Erythromycin Stearate.
- the present invention provides a novel process for the liberation of Erythromycin of Formula I from Erythromycin salts.
- the present invention further relates to a novel process for the preparation of Erythromycin Stearate from Erythromycin or its salts using water as the only solvent.
- the present invention relates to a novel process for the liberation of Erythromycin of Formula I from Erythromycin thiocyanate of Formula II
- Formula II by treating Erythromycin thiocyanate of Formula II with a base in presence of water as a solvent.
- the process of the present invention further comprises isolation of obtained Erythromycin by optional cooling, filtering and washing the product with water till it is free from thiocyanate and further drying it to get Erythromycin.
- the base used is selected from organic or inorganic base, wherein organic base is selected from dimethylamine, diethylamine or triethylamine and inorganic base is selected from ammonia, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide or potassium hydroxide.
- organic base is selected from dimethylamine, diethylamine or triethylamine
- inorganic base is selected from ammonia, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide or potassium hydroxide.
- ammonia is used.
- ammonia used can be in the form of aqueous ammonia or ammonia gas or combination thereof.
- ammonia as a base works most effectively in terms of completion of liberation of Erythromycin, yield and purity of the obtained Erythromycin than the other bases e.g. above-mentioned inorganic bases such as sodium hydroxide, sodium carbonate, sodium bicarbonate etc. Further, aqueous ammonia does not work efficiently at low temperature and same is the case with other bases.
- inventors of the present invention provide a novel process for liberation of Erythromycin in presence of base and water as a solvent. None of the prior art teaches use of water as a solvent. For the person skilled in art it is common to get the product like Erythromycin base by liberating it from salt like Erythromycin thiocyanate in a solvent like chlorinated solvent in which the salt is soluble and the product is insoluble. However, in the process of the present invention solvent used is water in which both salt Erythromycin thiocyanate and product Erythromycin is insoluble.
- the range of suitable stoichiometries of base with respect to Erythromycin thiocyanate is between 1-10 equivalents and range of suitable stoichiometries of water solvent with respect to Erythromycin thiocyanate is between 1-5 equivalents, preferably 1.
- the process of liberation of Erythromycin is carried out at temperature ranging from 30 °C to 80 °C.
- process of the present invention provides Erythromycin base with more than 95% purity without further purification process.
- Erythromycin base obtained by the process of the present invention is substantially free of impurities.
- Erythromycin of formula I used is obtained by its process of liberation as discussed above. Erythromycin of formula I, available by commercial source also can be used. The scope of the present invention also covers the use of Erythromycin of formula I that is obtained by commercial source as described in Ex.9 and 10.
- Erythromycin Stearate can be prepared by reacting Erythromycin, obtained by the process of liberation as discussed herein above or obtained by commercial source with stearic acid in presence of water.
- a process for preparation of Erythromycin Stearate from Erythromycin thiocyanate of formula II via liberation of Erythromycin comprising steps of
- Base used in the step i) is selected from organic or inorganic base, wherein organic base is selected from dimethylamine, diethylamine or triethylamine and inorganic base is selected from ammonia, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide or potassium hydroxide. Preferably, ammonia is used.
- Erythromycin obtained in step i) is isolated by optional cooling, filtering and washing the product with water till it is free from thiocyanate. The wet cake obtained is used as such for step ii) reaction.
- Erythromycin of formula I as liberated is reacted with stearic acid at temperature ranging from 30 to 70°C.
- the molar ratio of stearic acid to Erythromycin used is 1.1 to 1.35, preferably ratio is 1.2 to 1.35.
- process of the present invention for preparation of Erythromycin Stearate avoids the use of any organic solvent. Also it avoids the extended isolation and crystallization process. Hence, it is cost-effective, environmental friendly and industrially viable process.
- Erythromycin thiocyanate HPLC analysis Erythromycin A: 84.61%, Erythromycin B: 1.37%, Erythromycin C: 1.46%
- Erythromycin base HPLC analysis Erythromycin A: 96.28%, Erythromycin B:
- Erythromycin thiocyanate (243 g) was suspended in water (200 ml). The slurry was heated up to 35°C and liquor Ammonia (200 ml) was added in half an hour. The mass was heated further up to 70°C and stirred for 1 hour. The suspension was cooled to ambient temperature and filtered. The residue was washed with water till free from ammonium thiocyanate (test with FeCl 3 solution). The product was dried at 55 to 60°C. Yield: 212 g (moisture: 5%)
- Erythromycin thiocyanate (121.5 g) was suspended in water (100 ml). The slurry was heated up to 35°C and liquor Ammonia (100 ml) was added in half an hour. The mass was heated further up to 70°C and stirred for 1 hour. The suspension was cooled to 50°C temperature and filtered. The residue was washed with water till free from ammonium thiocyanate (test with FeC3 ⁇ 4 solution). The product was dried at 55 to 60°C.
- Erythromycin thiocyanate HPLC analysis Erythromycin A: 84.61%, Erythromycin B : 1.37%, Erythromycin C: 1.46%
- Erythromycin base taken as a dry cake (25 g), stearic acid (12.5 g) and water (175 ml) were charged to a round-bottom flask. The reaction mass was heated to 35 to 40°C and stirred for 2 hours. The product was then filtered and dried at 60°C.
- Erythromycin base taken as a dry cake (25 g), stearic acid (12 g) and water (100 ml) were charged to a round-bottom flask.
- the reaction mass was heated to 35 to 40°C and stirred for 2 hours, The product was then filtered and dried at 60°C.
- Erythromycin base 25 g
- Stearic acid 13 g
- water 175 ml
- Erythromycin thiocyanate (121 g) and water (300 ml) were charged to a round-bottom flask. The suspension was heated to 35°C and liquor Ammonia (100 ml) was added in about half an hour. The reaction mass was further heated up to 70°C, stirred at 70°C for 1 hour, cooled to 50°C and filtered. The wet cake of Erythromycin is then treated with stearic acid (55.12 g) and water (125 ml). The reaction mass was heated to 35 to 40°C and stirred for 2 hours. The product was filtered and dried at 60°C.
- Erythromycin base 25 g
- Stearic acid 13 g
- water 175 ml
- the processes of the present invention avoid tedious steps such as separation of organic solvent, concentration of solvent etc during isolation of Erythromycin base and Erythromycin Stearate.
- the process of the present invention provides Erythromycin base with more than 95% purity by avoiding further purification process.
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- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
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- Saccharide Compounds (AREA)
Abstract
The present invention relates to a novel process for the liberation of Erythromycin from Erythromycin salts such as Erythromycin thiocyanate using water as a solvent in presence of a base. Erythromycin obtained by process of the present invention has purity of more than 95%. The present invention further relates to a novel process for the preparation of Erythromycin Stearate by reacting Erythromycin or its salts with stearic acid in presence of water.
Description
A Novel Process of Liberation of Erythromycin
And Preparation of its Salts
FIELD OF INVENTION
The present invention relates to a novel process for the liberation of Erythromycin from Erythromycin salts. More particularly, the present invention relates to a novel process for the liberation of Erythromycin from Erythromycin thiocyanate in presence of a base and using water as a solvent.
The present invention further relates to a novel process for the preparation of Erythromycin salts like Erythromycin Stearate from Erythromycin or its salts using water as a solvent. BACKGROUND OF INVENTION
Erythromycin of formula I is the most important member of the macrolide antibiotics of microbial origin. It is effective against many Gram-positive and Gram-negative bacteria and is often used for people who have an allergy to penicillin.
Formula I
Being bitter in taste Erythromycin has limitations when administered orally. Hence orally it is administered as Erythromycin Stearate in the form of a tablet. Erythromycin Stearate is not only palatable but also has an anti bacterial property. It is relatively stable and has high erythromycin potency.
Erythromycin was first disclosed in U.S. patent 2,653,899 in 1952. Various prior art discloses different processes for preparation of Erythromycin.
497/MUM/2005 discloses preparation of Erythromycin base from Erythromycin thiocyanate in presence of halogenated solvents and ammonia. The process involves use of 6 volumes of chlorinated solvent such as dichloromethane for liberating Erythromycin from Erythromycin thiocyanate.
627/MUM/2005 discloses preparation of 6,9 imino ether from Erythromycin thiocyanate. As stated in this patent application, the process comprises dissolving Erythromycin thiocyanate in methylene chloride and adding liquid ammonia as a base, separating organic layer, distilling solvent from organic layer to obtain residue of Erythromycin base which further converted to the title compound. Other patent applications e.g. 626/MUM/2005, WO2007029266 and WO2009023191, also describe preparation of Erythromycin from Erythromycin thiocyanate in dichloromethane using aqueous ammonia.
Polish patent PL83707 describes preparation of low melting Erythromycin base by treating Erythromycin thiocyanate with of 20% aqueous ethanol and 5% NaOH at 40- 50°C followed by filtering and treating the precipitate with water and alkali till suspension shows no reaction of SCN ions and pH becomes constant to obtain erythromycin base.
Therefore, the processes reported in literature for the liberation of Erythromycin from Erythromycin thiocyanate employ organic solvents, primarily halogenated solvents which have bad impact on environment when one is dealing with industrial scale. During the recovery of chlorinated solvents, there is particular loss of solvent which can not be accounted, thus causing environment pollution and also considerable economical loss.
Erythromycin Stearate was first disclosed in US2862921 in 1958. The said patent discloses Erythromycin esters as novel compounds and process for their preparation. The process as described comprises reaction of Erythromycin with stearoyl chloride in an inert solvent such as methylene chloride in presence of base such as 1 -ethyl piperidine. The reaction mass was kept overnight.
US 2881 163 describes the process for preparation of Erythromycin acid addition salts from its salt such as Erythromycin acetate in presence of water miscible organic solvent. The process involves mixing of aqueous solution of Erythromycin acetate with acetone, 10% sodium hydroxide, sodium chloride. The mixture was heated at 45°C followed by separation of acetone phase which was reacted with steric acid. After steric acid was dissolved completely the solution was filtered and water was added at same temperature. The solution was allowed to crystallize at 18°C. Crystals are filtered, washed and dried to obtain Erythromycin Stearate.
Thus, there are very few prior art references which disclose preparation of Erythromycin Stearate. All the reported processes are carried out in presence of organic solvents. The processes are lengthy and involve extended work up process which makes them costly and difficult to handle on large scale and environment unfriendly.
The inventors of the present invention have surprisingly found a novel process for the liberation of Erythromycin from Erythromycin thiocyanate using only water as a solvent in presence of a base, which has not been previously reported in any prior art as Erythromycin thiocyanate is insoluble in water. It is a common practice to obtain the product from its salt that use a solvent in which salt is soluble and product is insoluble.
But process of the present invention uses water as a solvent in which Erythromycin thiocyanate is insoluble. The inventors of the present invention further found out a novel process for the preparation of Erythromycin Stearate from Erythromycin or its salts by reacting it with stearic acid in presence of water as a solvent by avoiding use of any organic solvent. Thus, the inventors of the present invention have found out a novel process wherein both Erythromycin and stearic acid are insoluble in water, however reacts to form an insoluble salt.
Thus, the processes of the present invention are cost effective, operationally simple, industrially feasible and environment friendly.
OBJECT OF INVENTION i) An object of the present invention is to provide a novel process for the liberation of Erythromycin from Erythromycin salts. More particularly, the present invention provides a novel process for the liberation of Erythromycin from Erythromycin thiocyanate in water in presence of a base.
Another object of the present invention is to provide a novel process for the preparation of Erythromycin with more than 95% purity and good yield.
Another object of the present invention is to obtain Erythromycin substantially free of impurities by avoiding any purification process.
Another object of the present invention is to provide a novel process for the preparation of Erythromycin salts like Erythromycin Stearate from Erythromycin using only water as a solvent. Thus, process of the present invention avoids the use of any organic solvent.
Yet another object of the present invention is to provide a novel process for the preparation of Erythromycin Stearate from Erythromycin salts such as Erythromycin thiocyanate via liberation of Erythromycin. Entire process is carried out in presence of only water without using any organic solvent.
Yet another object of the present invention is to provide simple, economic, environment friendly and industrially viable processes for liberation of
Erythromycin and preparation of its salts like Erythromycin Stearate from liberated Erythromycin or via liberation of Erythromycin.
Yet another object of the present invention is to provide a novel process wherein both Erythromycin and stearic acid are insoluble in water, however reacts to form an insoluble salt.
SUMMARY OF INVENTION
In first aspect of the present invention, there is provided a novel process for the liberation of Erythromycin of Formula I from Erythromycin salts such as Erythromycin thiocyanate
Formula I
by treating Erythromycin thiocyanate of Formula II
Formula II
with a base in presence of water as a solvent.
Another aspect of the present invention is to provide Erythromycin with more than 95% purity without any further purification process.
In second aspect of the present invention, there is provided a novel process for the preparation of Erythromycin Stearate from Erythromycin by reacting it with stearic acid in presence of water as a solvent.
In third aspect of the present invention, there is provided a novel process for the preparation of Erythromycin Stearate from Erythromycin salts such as Erythromycin thiocyanate via liberation of Erythromycin comprising i) reacting Erythromycin thiocyanate of formula II with base in presence of water at 30 to 80 °C to liberate Erythromycin of formula I ii) treating Erythromycin of step i) with stearic acid in presence of water to obtain Erythromycin Stearate.
Thus, the processes of the present invention are simple and avoid the use of any organic solvent.
DETAILED DESCRIPTION OF INVENTION
The present invention provides a novel process for the liberation of Erythromycin of Formula I from Erythromycin salts.
Formula I
The present invention further relates to a novel process for the preparation of Erythromycin Stearate from Erythromycin or its salts using water as the only solvent. In one aspect, the present invention relates to a novel process for the liberation of Erythromycin of Formula I from Erythromycin thiocyanate of Formula II
Formula II
by treating Erythromycin thiocyanate of Formula II with a base in presence of water as a solvent.
In another aspect, the process of the present invention further comprises isolation of obtained Erythromycin by optional cooling, filtering and washing the product with water till it is free from thiocyanate and further drying it to get Erythromycin.
In an embodiment of the present invention, the base used is selected from organic or inorganic base, wherein organic base is selected from dimethylamine, diethylamine or triethylamine and inorganic base is selected from ammonia, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide or potassium hydroxide. Preferably, ammonia is used.
In another embodiment of the present invention, ammonia used can be in the form of aqueous ammonia or ammonia gas or combination thereof.
It has been observed by inventors of the present invention that ammonia as a base works most effectively in terms of completion of liberation of Erythromycin, yield and purity of the obtained Erythromycin than the other bases e.g. above-mentioned inorganic bases such as sodium hydroxide, sodium carbonate, sodium bicarbonate etc. Further, aqueous ammonia does not work efficiently at low temperature and same is the case with other bases.
Thus, inventors of the present invention provide a novel process for liberation of Erythromycin in presence of base and water as a solvent. None of the prior art teaches use of water as a solvent. For the person skilled in art it is common to get the product like Erythromycin base by liberating it from salt like Erythromycin thiocyanate in a solvent like chlorinated solvent in which the salt is soluble and the product is insoluble. However, in the process of the present invention solvent used is water in which both salt Erythromycin thiocyanate and product Erythromycin is insoluble.
In another embodiment of the present invention, the range of suitable stoichiometries of base with respect to Erythromycin thiocyanate is between 1-10 equivalents and range of suitable stoichiometries of water solvent with respect to Erythromycin thiocyanate is between 1-5 equivalents, preferably 1.
In another embodiment of the present invention, the process of liberation of Erythromycin is carried out at temperature ranging from 30 °C to 80 °C.
In yet another embodiment, process of the present invention provides Erythromycin base with more than 95% purity without further purification process. Thus, Erythromycin base obtained by the process of the present invention is substantially free of impurities.
In second aspect of the present invention, there is provided a novel process for the preparation of Erythromycin Stearate from Erythromycin of formula I, by reacting it with stearic acid in presence of water.
Erythromycin of formula I used is obtained by its process of liberation as discussed above. Erythromycin of formula I, available by commercial source also can be used. The scope of the present invention also covers the use of Erythromycin of formula I that is obtained by commercial source as described in Ex.9 and 10. Thus, according to process of the present invention Erythromycin Stearate can be prepared by reacting Erythromycin, obtained by the process of liberation as discussed herein above or obtained by commercial source with stearic acid in presence of water. In third aspect of the present invention, there is provided a process for preparation of Erythromycin Stearate from Erythromycin thiocyanate of formula II via liberation of Erythromycin comprising steps of
i) reacting Erythromycin thiocyanate of formula II with a base in presence of water at 30 to 80 °C to liberate Erythromycin of formula I
ii) treating Erythromycin obtained in step i) with stearic acid in presence of water
iii) filtering the reaction mass obtained in step ii) followed by drying the product to obtain desired Erythromycin Stearate
Base used in the step i) is selected from organic or inorganic base, wherein organic base is selected from dimethylamine, diethylamine or triethylamine and inorganic base is selected from ammonia, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide or potassium hydroxide. Preferably, ammonia is used. Erythromycin obtained in step i) is isolated by optional cooling, filtering and washing the product with water till it is free from thiocyanate. The wet cake obtained is used as such for step ii) reaction.
Erythromycin of formula I, as liberated is reacted with stearic acid at temperature ranging from 30 to 70°C.
According to another embodiment of the present invention, the molar ratio of stearic acid to Erythromycin used is 1.1 to 1.35, preferably ratio is 1.2 to 1.35. Thus, process of the present invention for preparation of Erythromycin Stearate avoids the use of any organic solvent. Also it avoids the extended isolation and crystallization process. Hence, it is cost-effective, environmental friendly and industrially viable process.
The detail of the invention provided in the following example is given by the way of illustration only and should not be construed to limit the scope of the present invention.
EXAMPLES AND COMPARATIVE EXAMPLES
Comparative Example 1
For comparison purposes. Erythromycin base was prepared by process as known in the art
100 g active Erythromycin thiocyanate was suspended in dichloromethane (560 ml). To it, a solution of NaOH (8.8 g in 154 ml water) was added and the mass was refluxed for 1 hour. Cooled to room temperature and separated the aqueous and organic phases. The organic phase was washed with water (5 xlOO ml). Then it was concentrated partially to dehydrate, chilled to 0 to 5°C, stirred for 1 hour and filtered. Washed the cake with chilled MDC (50 ml). Wet cake was then dried at 50 to 55°C.
Dry weight: 92 to 94 g (Moisture: 5%).
HPLC purity:
Erythromycin thiocyanate HPLC analysis: Erythromycin A: 84.61%, Erythromycin B: 1.37%, Erythromycin C: 1.46%
Erythromycin base HPLC analysis: Erythromycin A: 96.28%, Erythromycin B:
0.17%, Erythromycin C: 0.71%
Experimental Example 1
Preparation of Erythromycin according to present invention.
Erythromycin thiocyanate (243 g) was suspended in water (200 ml). The slurry was heated up to 35°C and liquor Ammonia (200 ml) was added in half an hour. The mass was heated further up to 70°C and stirred for 1 hour. The suspension was cooled to ambient temperature and filtered. The residue was washed with water till free from ammonium thiocyanate (test with FeCl3 solution). The product was dried at 55 to 60°C. Yield: 212 g (moisture: 5%)
Erythromycin thiocyanate HPLC analysis: Erythromycin A: 84.61%, Erythromycin B: 1.37%, Erythromycin C: 1.46%
Erythromycin base HPLC analysis: Erythromycin A: 96.34%, Erythromycin B: 0.68%, Erythromycin C: 1.15%
Experimental Example 2
Preparation of Erythromycin according to present invention.
Erythromycin thiocyanate (121.5 g) was suspended in water (100 ml). The slurry was heated up to 35°C and liquor Ammonia (100 ml) was added in half an hour. The mass was heated further up to 70°C and stirred for 1 hour. The suspension was cooled to 50°C temperature and filtered. The residue was washed with water till free from ammonium thiocyanate (test with FeC¾ solution). The product was dried at 55 to 60°C.
Yield: 106 g
Erythromycin thiocyanate HPLC analysis: Erythromycin A: 84.61%, Erythromycin B: 1.37%, Erythromycin C: 1.46% Erythromycin base HPLC analysis: Erythromycin A: 96.58%, Erythromycin B: 0.69%, Erythromycin C: 1.03%
Experimental Example 3
Preparation of Erythromycin according to present invention. To a suspended solution of Erythromcyin thiocyanate (32 g) in water (100 ml) was charged 19 ml Dimethyl amine (40%) and the mass was heated at 70°C for 3 hours. The suspension was cooled to 50°C , filtered and washed with water till free from dimethyl ammonium thiocyanate (test with FeC13 solution). The product was dried at 55 to 60°C.
Yield: 24.6 g (moisture :5.92%)
Erythromycin thiocyanate HPLC analysis: Erythromycin A: 76.63%, Erythromycin B :3.02%, Erythromycin C:0.77%
Erythromycin base HPLC analysis: Erythromycin A: 81.37%, Erythromycin
B: 4.85%, Erythromycin C: 1.01% Experimental Example 4
Preparation of Erythromycin according to present invention.
To a suspended solution of Erythromcyin thiocyanate (32 g) in water(80 ml) was charged Diethyl amine (9.2 g) and the mass was heated at 70°C for 2 hours. The suspension was cooled to 50°C ,filtered and washed with water till free from diethyl ammonium thiocyanate (test with FeC13 solution). The product was dried at 55 to 60°C.
Yield : 19.1 g (moisture :5.45%)
Erythromycin thiocyanate HPLC analysis: Erythromycin A: 84.61%, Erythromycin B : 1.37%, Erythromycin C: 1.46%
Erythromycin base HPLC analysis: Erythromycin A: 95.28%, Erythromycin B: 1.15%, Erythromycin C: 0.98% Example 5
Preparation of Erythromycin Stearate from Erythromycin obtained by the process of liberation of the present invention
Erythromycin base taken as a dry cake (25 g), stearic acid (12.5 g) and water (175 ml) were charged to a round-bottom flask. The reaction mass was heated to 35 to 40°C and stirred for 2 hours. The product was then filtered and dried at 60°C.
Yield: 36.4 g
Moisture: 2.60% (complies limit of NMT 4%)
HPLC (Erythromycin A + B + C) (on anhydrous basis): 65.6% (complies limit of NLT 60.5%)
Free Stearic acid: 6.94% (complies limit of NMT 14%)
Total impurities: 3.38% (complies limit of NMT 6%)
Example 6
Preparation of Erythromycin Stearate from Erythromycin obtained by the process of liberation of the present invention Erythromycin base taken as a dry cake (25 g), stearic acid (12 g) and water (100 ml) were charged to a round-bottom flask. The reaction mass was heated to 35 to 40°C and stirred for 2 hours, The product was then filtered and dried at 60°C.
Yield: 35.2 g
Moisture 2.72%
HPLC (Erythromycin A + B + C) (on anhydrous basis): 68.6%
Free Stearic acid: 4.52%
Total impurities: 2.698%
Example 7
Preparation of Erythromycin Stearate from Erythromycin obtained by the process of liberation of the present invention
Erythromycin base (25 g), Stearic acid (13 g) and water (175 ml) were charged to a round-bottom flask. The reaction mass was heated up to 35 to 40°C and stirred for 2 hours. The product was filtered and dried at 60°C.
Yield: 36.2 g
Moisture: 2.42%
HPLC (Erythromycin A + B + C) (on anhydrous basis): 65.2%
Free Stearic acid: 5.21%
Total impurities: 2%
Example 8
Preparation of Erythromycin Stearate from Erythromycin thiocyanate via liberation of Erythromycin
Erythromycin thiocyanate (121 g) and water (300 ml) were charged to a round-bottom flask. The suspension was heated to 35°C and liquor Ammonia (100 ml) was added in about half an hour. The reaction mass was further heated up to 70°C, stirred at 70°C for 1 hour, cooled to 50°C and filtered. The wet cake of Erythromycin is then treated with stearic acid (55.12 g) and water (125 ml). The reaction mass was heated to 35 to 40°C and stirred for 2 hours. The product was filtered and dried at 60°C.
Yield: 159 g
Moisture: 2.64%
HPLC (Erythromycin A + B + C) (on anhydrous basis): 66.32%
Free Stearic acid: 6.97%
Total impurities: 3.5%
Example 9
Preparation of Erythromycin Stearate from commercially available Erythromycin
Erythromycin base (25 g), Stearic acid (13 g) and water (175 ml) were charged to a round-bottom flask. The reaction mass was heated up to 50 to 55°C and stirred for 2 hours. The product was filtered and dried at 60°C.
Yield: 36.2 g
Moisture: 2.54%
HPLC (Erythromycin A + B + C) (on anhydrous basis): 60.64%
Free Stearic acid: 6.03%
Total impurities: 4.91%
Example 10
Preparation of Erythromycin Stearate from commercially available Erythromycin
Erythromycin base (25 g), Stearic acid (13 g) and water (175 ml) were charged to a round-bottom flask. The reaction mass was heated to 60 to 65°C and stirred for 2 hours, The product was filtered and dried at 60°C.
Yield: 36.2 g
Moisture: 2.60%
HPLC (Erythromycin A + B + C) (on anhydrous basis): 60.75%
Free Stearic acid: 10.9%
Total impurities: 5.16%
Advantages of the novel processes of the present invention for the preparation of Erythromycin and Erythromycin Stearate are
1. The processes of the present invention are carried out in water as a solvent. Thus, present invention avoids use of any organic solvent especially chlorinated solvents.
2. The processes of the present invention are thus environmentally friendly.
3. The processes of the present invention avoid tedious steps such as separation of organic solvent, concentration of solvent etc during isolation of Erythromycin base and Erythromycin Stearate.
4. The processes of the present invention are thus economically and industrially viable.
5. The process of the present invention provides Erythromycin base with more than 95% purity by avoiding further purification process.
Claims
We claim
Formula II
by treating Erythromycin thiocyanate of Formula II with a base in presence of water as a solvent
2. The process for liberation of Erythromycin as claimed in claim 1, further comprises isolation of obtained Erythromycin by optional cooling, filtering and washing the product with water
3. The process for liberation of Erythromycin as claimed in claim 1, wherein the base used is selected from organic or inorganic base, wherein organic base is selected from dimethylamine, diethylamine or triethylamine and inorganic base is selected from ammonia, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide or potassium hydroxide, preferably ammonia is used
4. The process for liberation of Erythromycin as claimed in claim 3, wherein ammonia used can be in the form of aqueous ammonia or ammonia gas or combination thereof
5. The process for liberation of Erythromycin as claimed in claim 1 or 3, wherein the range of suitable stoichiometries of the base with respect to the Erythromycin thiocyanate is between 1 to 10 equivalents
6. The process for liberation of Erythromycin as claimed in claim 1, wherein the said process is carried out at temperature ranging from 30 °C to 80 °C
7. The process for liberation of Erythromycin as claimed in claim 1, wherein the range of suitable stoichiometries of water solvent with respect to Erythromycin thiocyanate is between 1 to 5 equivalents, preferably 1
8. A novel process for the preparation of Erythromycin Stearate by reacting Erythromycin with stearic acid in presence of water
9. A novel process for the preparation of Erythromycin Stearate from Erythromycin thiocyanate comprising steps of
i) reacting Erythromycin thiocyanate with a base in presence of water at 30 to 80
°C to liberate Erythromycin
ii) treating Erythromycin obtained in step i) with stearic acid in presence of water iii) filtering the reaction mass obtained in step ii) followed by drying the product to obtain desired Erythromycin Stearate 10. The process as claimed in claim 8 or 9, wherein Erythromycin is reacted with stearic acid at temperature ranging from 30 to 70° C
1 1. The process as claimed in claim 8 or 9, wherein the molar ratio of stearic acid to Erythromycin used is 1.1 to 1.35, preferably ration is 1.2 to 1.35
12. The process as claimed in claim 9, wherein base used in the step i) is selected from organic or inorganic base, wherein organic base is selected from dimethylamine, diethylamine or triethylamine and inorganic base is selected from ammonia, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide or potassium hydroxide. Preferably, ammonia is used.
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| IN1129/MUM/2013 | 2013-03-26 | ||
| IN1129MU2013 | 2013-03-26 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106176613A (en) * | 2016-08-30 | 2016-12-07 | 瑞普（天津）生物药业有限公司 | A kind of slow release erythromycin thiocyanate soluble powder for animals and preparation method thereof |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2862921A (en) * | 1953-08-13 | 1958-12-02 | Upjohn Co | Erythromycin esters |
| US2881163A (en) * | 1953-11-16 | 1959-04-07 | Abbott Lab | Process of preparing salts |
| US4599326A (en) * | 1984-01-06 | 1986-07-08 | Orion-Yhtyma Oy | Acetyl erythromycin stearate, and compositions containing it |
| EP0853087A1 (en) * | 1997-01-10 | 1998-07-15 | Biochemie S.A. | A process for the purification of erythromycin |
| US6140479A (en) * | 1997-03-24 | 2000-10-31 | Taisho Pharmaceuticals Co., Ltd. | Erythromycin a derivatives |
-
2013
- 2013-05-13 WO PCT/IB2013/053860 patent/WO2014140699A1/en active Application Filing
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2862921A (en) * | 1953-08-13 | 1958-12-02 | Upjohn Co | Erythromycin esters |
| US2881163A (en) * | 1953-11-16 | 1959-04-07 | Abbott Lab | Process of preparing salts |
| US4599326A (en) * | 1984-01-06 | 1986-07-08 | Orion-Yhtyma Oy | Acetyl erythromycin stearate, and compositions containing it |
| EP0853087A1 (en) * | 1997-01-10 | 1998-07-15 | Biochemie S.A. | A process for the purification of erythromycin |
| US6140479A (en) * | 1997-03-24 | 2000-10-31 | Taisho Pharmaceuticals Co., Ltd. | Erythromycin a derivatives |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106176613A (en) * | 2016-08-30 | 2016-12-07 | 瑞普（天津）生物药业有限公司 | A kind of slow release erythromycin thiocyanate soluble powder for animals and preparation method thereof |
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