CN101516864A - Process for the preparation of candesartan cilexetil form I - Google Patents
Process for the preparation of candesartan cilexetil form I Download PDFInfo
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- CN101516864A CN101516864A CNA2007800341466A CN200780034146A CN101516864A CN 101516864 A CN101516864 A CN 101516864A CN A2007800341466 A CNA2007800341466 A CN A2007800341466A CN 200780034146 A CN200780034146 A CN 200780034146A CN 101516864 A CN101516864 A CN 101516864A
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Abstract
The present invention provides an improved process for the manufacture of candesartan cilexetil form I. Further the present invention discloses a candesartan cilexetil preparation containing less than 0.15%, preferably less than 0.10%, of (+-)-1-Hydroxyethyl candesartan oxanyl carbonate (ester) of the following formula (V) wherein one of A, B and C is an oxygen atom and the other two are-CH2-groups.
Description
Technical field
The present invention relates to a kind of improved method, this method is used to prepare mean particle size and is lower than 25 μ m and does not have the candesartan cilexetil of agglomeration (agglomeration) tendency to come for former times ester (candesartancilexetil) crystal formation I.
Background technology
As shown in the formula the candesartan cilexetil shown in (I) come for former times ester chemically be described as (+/-)-1-[[(cyclohexyloxy) carbonyl] the oxygen base]-2-oxyethyl group-1-[[2 '-(1H-tetrazolium-5-yl)-1,1 '-xenyl-4-yl] methyl]-the 1H-benzimidazole-7-carboxylate.Another kind of expression is (+-)-1-hydroxyethyl-2-oxyethyl group-1-(right-(neighbour-1H-tetrazolium-5-base phenyl) benzyl)-7-benzoglyoxaline-carboxylic acid cyclohexyl carbonic ether, wherein Candesartan is the carboxylic acid as the basis, i.e. 2-oxyethyl group-1-(right-(neighbour-1H-tetrazolium-5-base phenyl) benzyl)-7-benzoglyoxaline carboxylic acid.
Because it suppresses the ability of angiotensin-converting enzyme, candesartan cilexetil come for former times ester be widely used in the treatment of hypertension and relative disease and symptom.As a kind of angiotensin II receptor antagonists, candesartan cilexetil come for former times ester avoided the side effect of calcium antagonist, and demonstrate high stability and tangible curative effect.At present candesartan cilexetil come for former times ester sell with racemic mixture.It is according to disclosed patent, and for example EP0720982B1 and EP0459136 produce.
In Chem.Pharm.Bull.47 (2), put down in writing two kinds of crystal formations (crystal formation I and crystal form II) and amorphous forms among the 182-186 (1999), and characterized with their DSC thermogram, X-ray diffractogram and infrared spectrogram.
US5196444 discloses candesartan cilexetil and has replaced the C-N-type waferN (crystal formation I) of former times ester to reach the method for preparing it under acidic conditions.
WO04/085426 discloses candesartan cilexetil and has come dioxane solvate for the former times ester, and two kinds of crystalline forms in addition.
WO2005/077941 discloses candesartan cilexetil and has come hydrate and solvate for the former times ester, with and preparation method thereof.
WO2006/048237 discloses candesartan cilexetil and has come multiple new polymorphic forms goods for the former times ester, with and preparation method thereof, comprise from candesartan cilexetil to prepare amorphous candesartan cilexetil and replace the former times ester for precipitating with the liquid ring hydrocarbon in the solution of former times ester chlorinated solvent.
In WO2005/123721, provide a kind of amorphous candesartan cilexetil of forming by spraying drying and precipitation to replace the preparation method of former times ester.
This shows, provide a kind of more effective and more economical preparation candesartan cilexetil to come technological method for former times ester crystal formation I with highly beneficial, it is that unique known stable candesartan cilexetil that can easily be used for pharmaceutical composition is come the polymorphic form for the former times ester that this candesartan cilexetil is come for former times ester crystal formation I.Except this polymorphic form, come for the former times ester for candesartan cilexetil, its granularity and the tendency that bonds together for authorizable preparation of drug combination and from said composition release of active ingredients have important effect.That is to say that known from prior art, because candesartan cilexetil is come for former times ester inherent low-solubility, its particle should be as far as possible little.On the other hand, this small-particle has the bonding tendency and is easy to agglomeration, and this is very undesirable in useful in preparing drug formulations.
Summary of the invention
Summary of the invention
First embodiment of the present invention is that candesartan cilexetil is come the preparation method for former times ester crystal formation I, and this method comprises the steps:
A) with 1-((2 '-cyano group (1,1 '-xenyl)-4-yl) methyl)-ester of 2-oxyethyl group-1H-benzimidazole-7-carboxylate is converted into corresponding candesartan Cilexetil;
B) the described candesartan Cilexetil of hydrolysis obtains Candesartan;
C) the tritylation Candesartan obtains trityl candesartan;
D) esterification trityl candesartan obtains the trityl candesartan west and comes for the former times ester;
E) in the presence of Lewis acid, make trityl candesartan go protection, obtain candesartan cilexetil and come for the former times ester;
F) the crystallization candesartan cilexetil is come for the former times ester from alcohol, obtains candesartan cilexetil and comes for the former times ester.
Preferably, the used ester with forming is an alkyl ester in the step a).The candesartan cilexetil that obtains to have little mean particle size (being lower than 25 μ m) and do not have the agglomeration tendency for former times ester crystal formation I particle." do not have agglomeration tendency " mean envrionment conditions in routine (as, 23 ℃ and relative humidity 75%) store at least one day down, preferred at least one week and more preferably at least one month, candesartan cilexetil is come for the goods of former times ester crystal formation I and its size-grade distribution of not obvious change.
On the other hand, the invention provides new isolated compound (+-)-1-hydroxyethyl Candesartan oxa-cyclohexyl (oxanyl) carbonic ether, it is that candesartan cilexetil is come the THP trtrahydropyranyl analog for the former times ester, abbreviates " the pyrans candesartan cilexetil is come for the former times ester " as at this.Its chemical structure is shown in following formula V.
In addition, the invention provides the goods that a kind of candesartan cilexetil is replaced the former times ester, it comprises less than 0.15%, preferably comes for the former times ester less than 0.10% pyrans candesartan cilexetil.Further, the invention provides the new isolating compound 1-halogenated ethyl oxa-cyclohexyl carbonic ether (" the pyrans west is come for the former times ester ") that has as shown in the formula (IV), wherein, halogen is meant Cl, Br, I.In addition, the invention provides a kind of 1-halo cyclohexyl carbonic ether (" west is come for the former times ester ") goods, wherein, halogen is meant Cl, Br, I, it contains less than 0.3%, preferably less than 0.2%, is more preferably less than 0.1% and preferably come for the former times ester less than 0.05% pyrans west again.Unless indicate in addition, all per-cents all are weight percents among the present invention.
Detailed Description Of The Invention
An object of the present invention is to prepare the candesartan cilexetil that mean particle size is lower than 25 μ m and do not have an agglomeration tendency comes for former times ester crystal formation I.
According to first embodiment of the present invention, candesartan cilexetil come for former times ester prepare by following method, this method may further comprise the steps:
A) with 1-((2 '-cyano group (1,1 '-xenyl)-4-yl) methyl)-ester of 2-oxyethyl group-1H-benzimidazole-7-carboxylate, preferably its alkyl ester is converted into a kind of ester, preferred Candesartan alkyl ester;
B) the described Candesartan of hydrolysis (alkyl) ester obtains Candesartan;
C) the tritylation Candesartan obtains trityl candesartan;
D) esterification trityl candesartan obtains the trityl candesartan west and comes for the former times ester;
E) in the presence of Lewis acid, make trityl candesartan go protection, obtain candesartan cilexetil and come for the former times ester;
F) the crystallization candesartan cilexetil is come for the former times ester from alcohol, obtains candesartan cilexetil and comes for former times ester crystal formation I, and its mean particle size is less than 25 μ m and do not have the agglomeration tendency.
Described initial compounds 1-((2 '-cyano group (1,1 '-xenyl)-4-yl) methyl)-and the ester of 2-oxyethyl group-1H-benzimidazole-7-carboxylate, can prepare the method for describing as EP459136B1 by currently known methods.
Preferably, the described initial compounds step (a) that is converted into candesartan Cilexetil is at high temperature finished by tributyl azide tin in organic solvent such as toluene and dimethylbenzene.As mentioned above, this ester is alkyl ester preferably, is more preferably C
1-6Alkyl ester most preferably is methyl ester or ethyl ester.
Preferably, described hydrolysing step (b) is finished in the presence of alkali and by means of alkali such as NaOH or KOH.Replace the quality of former times ester in order to improve the finished product candesartan cilexetil, importantly candesartan Cilexetil as far as possible fully is hydrolyzed to Candesartan (the Candesartan ester content in the Candesartan is below 0.10%).The alkyl ester of Candesartan almost can not or even remove for the former times ester from candesartan cilexetil by chromatography by crystallization.
The tritylation of Candesartan (c) can be by Candesartan and trityl chloride at alkali such as triethylamine, diisopropylethylamine and K
2CO
3Exist reaction down to finish.
Preferably, esterif iotacation step (d) is reacted in the presence of alkali such as salt of wormwood and solvent such as N,N-DIMETHYLACETAMIDE by trityl candesartan and 1-halogenated ethyl cyclohexyl carbonic ether and is finished.Be meant Cl, Br or I in this used term halogen.The trityl candesartan west replaces the separation of former times ester to realize by following steps: add water and extract with ester such as isopropyl acetate then, the washing organic phase, concentrate organic phase, add a kind of ether such as t-butyl methyl ether, and come for the former times ester with the trityl candesartan west of high yield (at least 95%) and high purity (the trityl candesartan west replaces the HPLC area % of former times ester to be at least 98%) precipitation separation.
Preferably, go to protect Lewis acid used in the step to be selected from, but be not limited to trifluoromethanesulfonic acid zinc (II), zinc acetate (II), tin (II) salt such as SnX
2, wherein X represents F, Cl, Br or I, or tin (II) salt and the BX of organic acid such as acetate and trifluoromethanesulfonic acid
3, wherein X represents F, Cl, Br or I.Describedly go to protect step in organic solvent such as methylene dichloride and methyl alcohol, to finish.
Used alcohol is selected from the mixture of methyl alcohol, ethanol, Virahol, n-propyl alcohol and alcohols and water in crystallisation step (f), is preferably Virahol.
It is that candesartan cilexetil replaces the small-particle of the stable crystal formation I of former times ester very economical mode to produce that candesartan cilexetil of the present invention is replaced the preparation method's of former times ester major advantage, and its mean particle size is preferably less than 25 μ m, 10-20 μ m more preferably, be preferably again less than 10 μ m, and do not have the agglomeration tendency.
Known when particle forms agglomerate in the pharmaceutical composition release of activeconstituents slow its specific surface area is littler than little elongated piece simultaneously.Be surprisingly found out that in crystallization candesartan cilexetil from alcohol and replace in the former times ester process that the solution that obtains forms big agglomerate 25 ℃ of following nucleation, this means needs disintegrating process to obtain pharmaceutically acceptable size-grade distribution.According to a preferred implementation of the inventive method, described nucleation is 40 ℃ according to appointment of comparatively high tempss, finishes under preferred about 35 ℃, and the mean particle size that is obtained is lower than 25 μ m, does not form agglomerate.Alternatively, can cause that nucleus forms by adding crystal seed under a little more than 35 ℃ temperature.Therefore, in the embodiment of present invention further optimization, provide the preparation method who replaces former times ester crystal formation I as candesartan cilexetil claimed in the claim, wherein do not carry out pulverising step.
In crystallisation procedure does and in filtration procedure, can form candesartan cilexetil and replace the solvate of former times ester.
The candesartan cilexetil that is obtained by method of the present invention is come identical for former times ester crystal formation I and in being documented in Chem.Pharm.Bull.47 (2) 182-186 (1999).
In step (d), preferably come for former times ester (II) existing N,N-DIMETHYLACETAMIDE (DMA) to prepare the trityl candesartan west by trityl candesartan (III) and 1-chloroethyl cyclohexyl carbonic ether under as the condition of alkali as solvent and salt of wormwood.
When coming for former times ester (I) by the method for preparing candesartan cilexetil, detected impurity level obviously improves in final material.The purity that is surprisingly found out that initial compounds 1-chloroethyl cyclohexyl carbonic ether or its any other halogen (Br, I) derivative to have a significant impact for the impurity level in the former times ester (I) to the candesartan cilexetil that finally obtains.That is to say, if find that initial compounds comprises 1-halogenated ethyl oxa-cyclohexyl carbonic ether, promptly a kind of compound with formula (IV),
Wherein, be Sauerstoffatom one of among A, B and the C, two are-CH in addition
2-group, and wherein X represents Cl, Br or I, then can come for the compound that detects in the former times ester material (I) as the formula V of impurity in final candesartan cilexetil, promptly (+-)-1-hydroxyethyl Candesartan oxa-cyclohexyl carbonic ether,
Be Sauerstoffatom one of among A, B and the C wherein, two are-CH in addition
2-group.Should note candesartan cilexetil come for former times ester and the difference of the compound of formula V only be that among residue A, B and the C each all is a methylene group.The shortcoming of the impurity of formula V is that it is difficult to separate for the former times ester from the finished product candesartan cilexetil with known ordinary method.Only having the initial compounds 1-halogenated ethyl cyclohexyl carbonic ether (wherein halogen be meant Cl, Br, I) relevant with relevant material/impurity suitable quality can obtain the finished product candesartan cilexetil that quality meets the Ph.Eur./ICH guide and come for the former times ester.Therefore, consider that resulting final activeconstituents candesartan cilexetil comes the impurity profile for the former times ester, in candesartan cilexetil is come for the synthesis path of former times ester, when occurring, detect and differentiate extremely important when the impurity of not expecting.In addition, it is extremely important that the impurity of having differentiated is remained on alap level, perhaps if possible, is more preferably and fundamentally avoids its formation.And known have only separation and sign impurity just can guarantee the better control of preparation process and can easily set limiting the quantity of of impurity.
Used in the present invention " the pyrans west was come for former times " is meant the compound of formula (IV).
The another kind of method for expressing of formula (IV) is
Wherein, X represents Cl, Br or I, and the O atom can be at the ortho position, a position or contraposition.
Used " the pyrans candesartan cilexetil is come for the former times ester " refers to the compound of formula V among the present invention.
The another kind of method for expressing of formula V is
Wherein, the O atom can be at the ortho position, a position or contraposition.
Therefore, another embodiment of the invention is that candesartan cilexetil is come for the former times ester, and it comprises less than 0.15%, and preferably less than the compound of 0.10% formula V, promptly the pyrans candesartan cilexetil is come for the former times ester.
The invention provides new isolating impurity pyrans candesartan cilexetil and come for the former times ester, it characterizes by LC-MS (liquid chromatography-mass spectrography).This impurity is controlled to be RRT (residence time relatively) about 0.569 by HPLC (high performance liquid chromatography).This chromatography specifically is documented among the embodiment 14a.
Another embodiment of the invention is the goods of material 1-halogenated ethyl cyclohexyl carbonic ether, wherein halogen refers to Cl, Br, I, it comprises less than 0.3%, preferably less than 0.2%, be more preferably less than 0.1% and preferably come for former times (the 1-halogenated ethyl oxa-cyclohexyl carbonic ether of formula (IV)) again less than 0.05% pyrans west.
The present invention also provides new isolating impurity pyrans west to come for former times, and it can pass through LC-MS (liquid chromatography-mass spectrography) and characterize.This impurity by vapor-phase chromatography be controlled to be RRT be about 1.478 and RRT be about the summation of 1.486 impurity.This chromatography is documented among the embodiment 14b.
Description of drawings
Fig. 1 and Fig. 2 are that the expression candesartan cilexetil is come for the granularity of former times ester crystal formation I and the photo of crystal formation.
Fig. 1 represents that the known candesartan cilexetil of prior art comes for former times ester crystal formation I.
Fig. 2 represents that candesartan cilexetil of the present invention comes for former times ester crystal formation I.
Embodiment
The present invention describes by following infinite embodiment.
Fusing point is measured on Koffler fusing point instrument, and infrared spectra is measured on Paragon 100 Perkin-ElmerFT-IR spectrographs.Granularity is measured on Malvern Mastersizer Apparatus MS 2000.
Embodiment
A) candesartan cilexetil of the present invention is come the preparation for former times ester crystal formation I
Embodiment 1: the preparation of Candesartan (step a, step b)
0.85g (2mmol) 1-((2 '-cyanobiphenyl base-4-yl) methyl)-mixture of 2-oxyethyl group-1H-benzo [d] imidazoles-7-carboxylic acid, ethyl ester, 2.6g (8mmol) tributyl azide tin and 7ml toluene heated 2 days under reflux temperature.After reaction is finished, cool off this mixture, add 10ml 1M NaOH then and this mixture was refluxed 1 hour at least.After finishing hydrolysis reaction, cool off this mixture and separate each phase.Water adds 1M HCl then and makes the pH of water estimate to reach 3 to 4 with toluene (15ml) extraction.The product of filtering-depositing and dry (0.79g).This product is with methyl alcohol or acetone recrystallization.MP：199-211℃。
Embodiment 2: the preparation (step c) of trityl candesartan
In containing the dichloromethane solution of 0.88g (2mmol) Candesartan, 4ml adds 0.66g (2.4mmol) trityl chloride and 0.34ml (2.4mmol) triethylamine.At room temperature stirred the mixture 1 hour, and with 5ml water washing (twice).The evaporation organic phase also joins t-butyl methyl ether in the residue.Separated product and dry (1.2g).
Embodiment 3: the preparation (step d) for the former times ester is come in the trityl candesartan west
20.40g (30mmol) trityl candesartan, 30ml N,N-DIMETHYLACETAMIDE (DMA), 4.95g (235.9mmol) K
2CO
3And 10.2g (49.4mmol) 1-chloroethyl cyclohexyl carbonic ether was 60 ℃ of heating 4 hours.With the reaction mixture cool to room temperature, add 240ml isopropyl acetate and 240ml water.Water is separated with organic phase, and with 240ml isopropyl acetate aqueous phase extracted once more.Organic phase after merging with 2 * 240ml water washing is filtered then, and evaporating volatile component in a vacuum.Adding the 150ml t-butyl methyl ether to the oiliness residue also at room temperature stirred the mixture 15 hours at least.Filtering precipitate and in vacuum drier 40 ℃ dry 2 hours down.Obtain 25.09g (98%) compound (II) (HPLC: surpass 98%).
Embodiment 4: candesartan cilexetil is come the preparation (step e) for the former times ester
Embodiment 4a:
Former times ester, 60ml MeOH, 240ml methylene dichloride and 2.39g (17.5mmol) ZnCl are replaced in 17.06g (20mmol) trityl candesartan west
2Reflux 4 hours.Finishing reaction postcooling reaction mixture to about 30 ℃, add 200ml water, separate organic phase and water and, use NaSO then with 2 * 200ml water washing organic phase
4Below 0.3%, the evaporating volatile component obtains 18g oiliness residue to drying until water content.Gained oiliness residue is dissolved in the 60ml isopropyl acetate and in room temperature (between 15 ℃ and 25 ℃) to descend to stir this mixture about 7 hours.Filtering precipitate and 45 ℃ of dryings 2 hours.Obtain the partly wet product of 10.7g, further at room temperature in the 107ml t-butyl methyl ether, suspended 1 hour.Product at room temperature dry night.
Embodiment 4b:
Former times ester, 5.6ml MeOH, 23ml methylene dichloride and 0.23ml (1.8mmol) BF are replaced in 1.6g (1.88mmol) trityl candesartan west
3Etherate stirred 5 hours down at 0 to 10 ℃.After reaction is finished, add 19ml water, separate organic phase and water, organic phase is with 2 * 19ml water washing and use NaSO
4Be dried to water content below 0.3%, thereby the evaporating volatile component obtains 1.7g oiliness residue.Gained oiliness residue is dissolved in the 5.6ml isopropyl acetate and in room temperature (between 15 ℃ and 25 ℃) to descend to stir this mixture about 7 hours.Filtering precipitate is also following dry 2 hours at 45 ℃.Obtain the partly wet product of 0.95g, further this product was at room temperature suspended 1 hour in the 10ml t-butyl methyl ether.The product that obtains at room temperature dry night.
Embodiment 4c:
1.6g (1.88mmol) former times ester, 5.6ml MeOH, 23ml methylene dichloride and 0.31g (1.6lmmol) SnCl are replaced in the trityl candesartan west
2Heating is 3.5 hours under reflux temperature.After reaction is finished, add 19ml water, separate organic phase and water, organic phase is with 2 * 19ml water washing and use MgSO
4Be dried to water content below 0.3%, thereby the evaporating volatile component obtains 1.7g oiliness residue.Gained oiliness residue is dissolved in the 5.6ml isopropyl acetate and in room temperature (between 15 ℃ and 25 ℃) to descend to stir this mixture about 7 hours.Filtering precipitate is also following dry 2 hours at 45 ℃.Obtain the partly wet product of 0.85g, further this product was at room temperature suspended 1 hour in the 10ml t-butyl methyl ether.The product that obtains at room temperature dry night.
Embodiment 4d:
1.6g (1.88mmol) former times ester, 5.6ml MeOH, 23ml methylene dichloride and 0.35g (1.6lmmol) Zn (CH are replaced in the trityl candesartan west
3COO)
2Heating is 24 hours under reflux temperature.After reaction is finished, add 19ml water, separate organic phase and water, organic phase is with 2 * 19ml water washing and use MgSO
4Be dried to water content below 0.3%, thereby the evaporating volatile component obtains 1.7g oiliness residue.Gained oiliness residue is dissolved in the 5.6ml isopropyl acetate and in room temperature (between 15 ℃ and 25 ℃) to descend to stir this mixture about 7 hours.Filtering precipitate is also following dry 2 hours at 45 ℃.Obtain the partly wet product of 0.9g, further this product was at room temperature suspended 1 hour in the 10ml t-butyl methyl ether.The product that obtains at room temperature dry night.
Embodiment 4e:
1.6g (1.88mmol) the trityl candesartan west replaces former times ester, 5.6ml MeOH, 23ml methylene dichloride and 0.58g (1.61mmol) trifluoromethanesulfonic acid zinc to heat 4.5 hours under reflux temperature.After reaction is finished, add 19ml water, separate organic phase and water, organic phase is with 2 * 19ml water washing and use MgSO
4Be dried to water content below 0.3%, thereby the evaporating volatile component obtains 1.7g oiliness residue.The oiliness residue that obtains is dissolved in the 5.6ml isopropyl acetate and in room temperature (between 15 ℃ and 25 ℃) to descend to stir this mixture about 7 hours.Filtering precipitate is also following dry 2 hours at 45 ℃.Obtain the partly wet product of 0.92g, further this product was at room temperature suspended 1 hour in the 10ml t-butyl methyl ether.The product that obtains at room temperature dry night.
Embodiment 5: candesartan cilexetil is come the crystallization (step f) for the former times ester
Embodiment 5a:
10.4g candesartan cilexetil come for former times ester and the 52ml Virahol mix and be heated to whole candesartan cilexetil and come for former times ester dissolving.Filter this solution, cool to room temperature also stirred 12 hours under the temperature between 15 ℃ and 25 ℃.Filtering precipitate, washing is also following dry 2 hours at 35 ℃ in instrument air dryer.Obtaining the pure candesartan cilexetil of 9.3g comes for former times ester crystal formation I.
HPLC area %: candesartan cilexetil is come for the former times ester: 99.66%, and candesartan cilexetil is come the alkyl ester for the former times ester: 0.05%, the pyrans candesartan cilexetil is come for the former times ester: 0.05%, the trityl candesartan west is come for the former times ester: 0.08%.
Embodiment 5b:
Candesartan cilexetil comes to be dissolved under 60-65 ℃ in the Virahol (900ml) for former times ester (60g).With the solution heat filtering in reactor and be cooled fast to 35 ℃.Under this temperature, come to cause nucleus formation and add strong mixing for former times ester crystal formation I with the 300mg candesartan cilexetil.Suspension in 1 hour, be cooled to 30 ℃ and under this temperature high degree of agitation 5 hours again.Reduce the stirring dynamics then and suspension was cooled to 20 ℃ in 8 hours.Filtration product is with washed with isopropyl alcohol and following dry 2 hours at 38 ℃.Obtaining the 48.7g candesartan cilexetil comes for former times ester crystal formation I.
HPLC area %: candesartan cilexetil is come for the former times ester: 99.73%, candesartan cilexetil is come the alkyl ester 0.08% for the former times ester, the pyrans candesartan cilexetil come for former times ester be below 0.05%, the trityl candesartan west is come for former times ester 0.09%.
Mean particle size: 19 μ m do not have agglomeration (referring to Fig. 2) to occur.
B) candesartan cilexetil is replaced the detection of impurity in the former times ester
Embodiment 6
Detecting candesartan cilexetil by HPLC replaces the pyrans candesartan cilexetil in the former times ester to come for the former times ester
HPLC (external perimysium reference method) carries out according to following explanation:
Post: Zorbax Eclipse XDB-C18,50mm * 4.6mm i.d., 1.8 μ m particles
Elutriant A:0.01M NaH
2PO
4, pH 2.5
Elutriant B: acetonitrile
The elutriant gradient:
| Time (min) | Elutriant A (%) | Elutriant B (%) |
| 0 | 55 | 45 |
| 12 | 5 | 95 |
| 20 | 5 | 95 |
| 21 | 55 | 45 |
| 25 | 55 | 45 |
Flow velocity: about 1.2ml/min
Diluent: second cyanogen: water=70: 30 (V/V)
Detect: UV, wavelength 225nm
Injection volume: 5 μ l
Column temperature: 50 ℃
Self-actuated sampler temperature: 7 ℃
Embodiment 7
Come for former times by the pyrans west that GC detects in the 1-chloroethyl cyclohexyl carbonic ether
GC/FID (area percentage method) moves according to following explanation:
Post: kapillary (fused quartz) AT-WAX or suitable
Length: 30m
ID： 0.32mm
Thickness: 0.25 μ m
Carrier gas: helium
Flow rate of carrier gas: 2.0ml/min
Separate ratio: 10: 1
Air velocity: 400ml/min
Hydrogen flow rate: 40ml/min
Supplemental air flow N
2Flow velocity: 25ml/min
Column temperature: 100 ℃ of (0min) → 10 ℃/min → 200 ℃ (10min or necessity
Shi Yanchang)
Injector temperature: 210 ℃
Detector temperature: 250 ℃
Injection volume: 1 μ l
Thinner: acetonitrile, chromatographic grade
Chromatographic system adaptability
The letter of the 1-chloroethyl cyclohexyl carbonic ether/ratio of making an uproar: be not less than 10
Claims (24)
1. candesartan cilexetil is come the preparation method for former times ester crystal formation I, comprises the steps:
A) 1-((2 '-cyano group (1,1 '-xenyl)-4-yl) methyl)-alkyl ester of 2-oxyethyl group-1H-benzimidazole-7-carboxylate is converted into the Candesartan alkyl ester;
B) the described Candesartan alkyl ester of hydrolysis obtains Candesartan;
C) the tritylation Candesartan obtains trityl candesartan;
D) esterification trityl candesartan obtains the trityl candesartan west and comes for the former times ester;
E) in the presence of Lewis acid, make the trityl candesartan west come for former times ester go protection, obtain candesartan cilexetil and replace the former times ester;
F) the crystallization candesartan cilexetil is come for the former times ester from alcohol.
2. candesartan cilexetil as claimed in claim 1 is come the preparation method for former times ester crystal formation I, and wherein said step of converting is at high temperature finished by tributyl azide tin in organic solvent.
3. candesartan cilexetil as claimed in claim 1 or 2 is come the preparation method for former times ester crystal formation I, and wherein the described ester in the step a) is methyl ester or ethyl ester.
4. the described candesartan cilexetil of arbitrary as described above claim is come the preparation method for former times ester crystal formation I, wherein after step b) in the Candesartan amount of candesartan Cilexetil be lower than 0.10wt.%.
5. the described candesartan cilexetil of arbitrary as described above claim is come the preparation method for former times ester crystal formation I, esterif iotacation step d wherein) finished by trityl candesartan and 1-halogenated ethyl cyclohexyl carbonate reaction in N,N-DIMETHYLACETAMIDE in the presence of salt of wormwood, wherein halogen is Cl, Br or I.
6. the described candesartan cilexetil of arbitrary as described above claim is come the preparation method for former times ester crystal formation I, wherein esterif iotacation step d) also comprise and separating and the former times ester is replaced in crystallization trityl candesartan west.
7. candesartan cilexetil as claimed in claim 6 is come the preparation method for former times ester crystal formation I, wherein said isolating trityl candesartan west come for former times ester by crystallization purifying at least 98% (HPLC area %).
8. the described candesartan cilexetil of arbitrary as described above claim is come the preparation method for former times ester crystal formation I, wherein crystallisation step f) be included in nucleation under 35 ℃ or the higher temperature.
9. the described candesartan cilexetil of arbitrary as described above claim is come the preparation method for former times ester crystal formation I, wherein goes to protect Lewis acid used in the step e) to be selected from trifluoromethanesulfonic acid zinc (II), zinc acetate (II), tin (II) salt and BX
3, wherein X refers to F, Cl, Br or I.
10. candesartan cilexetil as claimed in claim 9 is come the preparation method for former times ester crystal formation I, and wherein said tin (II) salt is selected from SnX
2, wherein X refers to F, Cl, Br or I, and organic acid tin (II) salt, is selected from acetate and fluoroform sulphonate.
11. the described candesartan cilexetil of arbitrary as described above claim is come the preparation method for former times ester crystal formation I, wherein crystallisation step f) in used alcohol be selected from the mixture of methyl alcohol, ethanol, Virahol, n-propyl alcohol and alcohol and water.
12. the described candesartan cilexetil of arbitrary as described above claim is come the preparation method for former times ester crystal formation I, wherein used alcohol is Virahol in the crystallisation step.
13. the candesartan cilexetil that the described method of arbitrary as described above claim obtains is come for the former times ester, its mean particle size is lower than 25 μ m and does not have the agglomeration tendency.
14. candesartan cilexetil as claimed in claim 13 is come for the former times ester, its mean particle size is 10-20 μ m.
15. candesartan cilexetil as claimed in claim 13 is come for the former times ester, its mean particle size is below the 10 μ m.
16. a candesartan cilexetil is come for the former times ester articles, it contains less than 0.15%, preferably less than (+-) with following formula V-1-hydroxyethyl Candesartan oxa-cyclohexyl carbonic ether of 0.10%,
Wherein one of among A, B and the C Sauerstoffatom and two other is-CH
2-group.
17. the candesartan cilexetil as claimed in claim 16 that is used for the treatment of in the method for human body is come for the former times ester articles.
18. a pharmaceutical composition comprises candesartan cilexetil as claimed in claim 16 and comes for the former times ester articles.
19. the candesartan cilexetil as claimed in claim 16 that is used for the treatment of in the method for hypertension and relative disease is come for the former times ester articles.
20. candesartan cilexetil as claimed in claim 16 is come for the purposes of former times ester articles in the medicine of preparation treatment hypertension and relative disease.
21. 1-halogenated ethyl cyclohexyl carbonic ether goods, wherein halogen refers to Cl, Br or I, and these goods comprise less than 0.3wt%, preferably less than 0.2wt%, be more preferably less than 0.1wt%, preferred again 1-halogenated ethyl oxa-cyclohexyl carbonic ether with formula (IV) less than 0.05wt%
Wherein one of among A, B and the C Sauerstoffatom and two other is-CH
2-group, and X refers to Cl, Br or I.
22. 1-halogenated ethyl cyclohexyl carbonic ether goods as claimed in claim 21 come for the purposes in the former times ester in synthetic candesartan cilexetil.
23. the compound with formula (IV),
Wherein one of among A, B and the C Sauerstoffatom and two other is-CH
2-group, and X refers to Cl, Br or I.
24. the compound with formula V,
Wherein one of among A, B and the C Sauerstoffatom and two other is-CH
2-group.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SIP200600176 | 2006-07-28 | ||
| SI200600176A SI22340A (en) | 2006-07-28 | 2006-07-28 | Processes for preparation of amorphous and crystalline forms of candesartan cilexetil |
| SIP200700068 | 2007-03-20 | ||
| SIP200700126 | 2007-05-30 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101516864A true CN101516864A (en) | 2009-08-26 |
Family
ID=39357032
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2007800341466A Pending CN101516864A (en) | 2006-07-28 | 2007-07-27 | Process for the preparation of candesartan cilexetil form I |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN101516864A (en) |
| SI (1) | SI22340A (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103396407A (en) * | 2013-08-07 | 2013-11-20 | 迪沙药业集团有限公司 | Preparation method of candesartan cilexetil crystal |
| CN106866633A (en) * | 2017-02-20 | 2017-06-20 | 威海迪素制药有限公司 | A kind of preparation method of candesartan cilexetil in high purity crystal formation I |
| CN110501449A (en) * | 2019-07-26 | 2019-11-26 | 威海迪素制药有限公司 | A kind of detection method of candesartan Cilexetil genotoxicity impurity |
| CN111943937A (en) * | 2020-09-26 | 2020-11-17 | 浙江金立源药业有限公司 | Synthesis method of triphenyl candesartan |
-
2006
- 2006-07-28 SI SI200600176A patent/SI22340A/en not_active IP Right Cessation
-
2007
- 2007-07-27 CN CNA2007800341466A patent/CN101516864A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103396407A (en) * | 2013-08-07 | 2013-11-20 | 迪沙药业集团有限公司 | Preparation method of candesartan cilexetil crystal |
| CN106866633A (en) * | 2017-02-20 | 2017-06-20 | 威海迪素制药有限公司 | A kind of preparation method of candesartan cilexetil in high purity crystal formation I |
| CN110501449A (en) * | 2019-07-26 | 2019-11-26 | 威海迪素制药有限公司 | A kind of detection method of candesartan Cilexetil genotoxicity impurity |
| CN111943937A (en) * | 2020-09-26 | 2020-11-17 | 浙江金立源药业有限公司 | Synthesis method of triphenyl candesartan |
Also Published As
| Publication number | Publication date |
|---|---|
| SI22340A (en) | 2008-02-29 |
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