CN103450201A - Preparation method of chiral 8-(3-aminopiperidine-1-yl)-xanthine - Google Patents
Preparation method of chiral 8-(3-aminopiperidine-1-yl)-xanthine Download PDFInfo
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- CN103450201A CN103450201A CN2012101719215A CN201210171921A CN103450201A CN 103450201 A CN103450201 A CN 103450201A CN 2012101719215 A CN2012101719215 A CN 2012101719215A CN 201210171921 A CN201210171921 A CN 201210171921A CN 103450201 A CN103450201 A CN 103450201A
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- 0 C*C=CC1CC(*)CC1 Chemical compound C*C=CC1CC(*)CC1 0.000 description 3
- AMBAWAHKHZZAAY-UHFFFAOYSA-N CCC(C)c1ccccc1C Chemical compound CCC(C)c1ccccc1C AMBAWAHKHZZAAY-UHFFFAOYSA-N 0.000 description 1
- YLYWBMFEEUIYCT-GOSISDBHSA-N Cc1c(cccc2)c2nc(CN(C(c([n]2CC#CC)c(N3C)nc2N(CCC2)C[C@@H]2N)=O)/C3=[O]\C)n1 Chemical compound Cc1c(cccc2)c2nc(CN(C(c([n]2CC#CC)c(N3C)nc2N(CCC2)C[C@@H]2N)=O)/C3=[O]\C)n1 YLYWBMFEEUIYCT-GOSISDBHSA-N 0.000 description 1
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
The invention relates to a preparation method of chiral 8-(3-aminopiperidine-1-yl)-xanthine. The preparation method comprises following steps: protecting the amino group of 3-aminopiperidine, and then subjecting 3-aminopiperidine to carry out reactions with 1-[3-nitrile-piridine-2-yl]-3-methyl-7-(2-butyne-1-yl)-8-bromine xanthine. The preparation method has a high reaction yield, guarantees the purity of 8-(3-aminopiperidine-1-yl)-xanthine, and is suitable for industrial production.
Description
Technical field
The present invention relates to a kind of synthetic method for preparing BI 1356.Another aspect of the present invention relates to a kind of intermediate for the preparation of BI 1356 and synthetic method thereof.
Background technology
BI 1356 (Linagliptin) is a kind of dipeptides kinases IV(DPPIV) inhibitor, belong to chirality 8-(3-amino piperidine-1-yl)-Xanthine compounds, there is the chemical structure as shown in the formula I:
BI 1356 is particularly suitable for prevention or treatment DPPIV active relevant disease, particularly I type or type ii diabetes or hyperglycemia.The clinical study result shows, BI 1356 can raise glucagon-like peptide (GLP-1) concentration, reduce type ii diabetes patient's blood sugar concentration, significantly reduce diabetic subject's glycolated hemoglobin (Hb1Ac) level.
Disclosing a kind of aminocompound (shown in formula b) by tertbutyloxycarbonyl (Boc) protection in WO2004018468 is intermediate, by the method for sloughing corresponding Boc protection, prepares chirality 8-(3-amino piperidine-1-yl)-Xanthine compounds:
Yet, because piperidines ammonia is used the Boc protection, when producing BI 1356 industry amplification, can introduce the impurity that difficulty is removed, be not easy to the purifying of BI 1356, reduced quality product and the productive rate of BI 1356.Whole purge process also can cause the increase of production cost.BI 1356 for the production pharmaceutical grade is totally unfavorable.
Therefore, need a kind of suitability for industrialized production that starts from, may improve the productive rate of BI 1356, ensure the new synthetic method of its product purity and quality.
Summary of the invention
The purpose of this invention is to provide a kind of yield high, purity is secure, is applicable to the synthetic method of the BI 1356 of suitability for industrialized production.
The invention provides a kind of synthetic route of BI 1356 as follows:
In above-mentioned chemical formula,
Wherein said R
1together with R
2form amino protecting group with adjacent amino cyclization.Preferred described R
1together with R
2form the group of cyclic imide structure with adjacent amino cyclization; Or R
1together with R
2form the group of cyclic lactames structure with adjacent amino cyclization.Preferred, described
comprise following shown in the group of structure:
Described R
3, R
4, R
5, R
6be hydrogen when different, be selected from respectively halogen, H, the low alkyl replaced.Preferably, R
3, R
4, R
5, R
6be chlorine or bromine, or R
3, R
4, R
5, R
6in any two be chlorine, bromine or methyl, other two is H, for example:
,
;
;
deng.
Described X is leavings group, is selected from halogen, for example fluorine, chlorine or bromine atom; Or sulphonate, such as phenylsulfonyloxy, tolysulfonyl oxygen base, sulfonyloxy methyl oxygen base or trimethyl fluoride sulfonyl oxygen base etc.X is preferably chlorine or bromine.
In said synthesis route, at first the compound shown in described formula III is reacted in suitable solvent with the chipal compounds shown in formula IV or its salt, for example, at 0-160 ℃ of temperature, preferably at 20-140 ℃ of temperature, reaction in for example tetrahydrofuran (THF) (THF), DMF (DMF), N,N-DIMETHYLACETAMIDE (DMA), METHYLPYRROLIDONE (NMP) or methyl-sulphoxide (DMSO).Subsequently amino protecting group is removed, obtained BI 1356.The method of described Deprotection, comprise acid or alkaline condition hydrolysis, or the mode of reduction.
The salt of the chipal compounds shown in described formula IV comprises tartrate, camphorate, malate, dibenzoyl tartaric acid salt etc.Preferred tartrate.
The synthetic method of BI 1356 of the present invention, adopted new amido protecting group, is particularly suitable for the protection of primary amine.Synthetic method of the present invention reduced the foreign matter content in the BI 1356 production process, avoided the racemization process of the chiral centre in BI 1356 compound potential in the reaction process, effectively improved quality product and the productive rate of BI 1356.Be particularly suitable for suitability for industrialized production.
Another object of the present invention; be to provide the synthetic method of the chiral intermediate shown in a kind of preparation formula IV or its salt; comprise racemic 3-amino piperidine in appropriate solvent and corresponding amido protecting radical reaction, further the sour salify by opticity splits the salt of 3-amino piperidine isomer of the amido protecting of (R) configuration shown in acquisition formula IV.Or further, adopt this area routine techniques means that salt is removed, obtain the compound shown in free formula IV.
In another embodiment of the present invention, the synthetic method of the chiral intermediate shown in described preparation formula IV or its salt, comprise the 3-amino piperidine of R configuration in appropriate solvent and corresponding amido protecting radical reaction preparation.Further can with opticity acid salify.
The acid of described opticity comprises D-(-) tartrate, D-dextrocamphoric acid, D-malic acid, D-dibenzoyl tartaric acid etc.Preferred D(-) tartrate.
Embodiment
The present invention is as described below is only the preferred embodiments of the present invention, not in order to limit the present invention.The raw material used in the embodiment of the present invention if not otherwise indicated, all can obtain by commercially available purchase.
The synthetic method of embodiment 1 intermediate formula IV1 compound
Step a is dissolved in 3-amino piperidine (50.1g) in the DMF of 2L, add 1,2-phenylbenzene vinylidene carbonic ether (119.1g), triethylamine (1L), be stirred to react completely (about 30min) under ice-water bath after, add the ethyl acetate extraction, merge organic layer, use anhydrous sodium sulfate drying, remove organic solvent.The product of gained is dissolved in the 1L trifluoracetic acid, stirs 2 hours under 20 ℃, vacuum concentration, remove unnecessary trifluoracetic acid, obtains the product (148.5g, productive rate 92.3%) of above formula Chinese style a.m/z：320.16。
Step b adds the formula a compound in upper step reaction in dehydrated alcohol (about 400ml), adds D-(-) tartrate (80g) stirring, reflux to mass crystallization product is separated out, cooling, and product is leached, and uses absolute ethanol washing.With ethanol and water mixed solvent recrystallization, dry formula IV1 compound 89.3g(productive rate 41.2%, the HPLC purity 99.7% of obtaining).
The synthetic method of embodiment 2 intermediate formula IV2 compounds
Step a mixes tetrachlorophthalic tetrachlorophthalic anhydrid (142g) and 3-amino piperidine (50.1g), adds 400ml toluene and triethylamine (59.8g), reflux water-dividing 48 hours, and steaming desolventizes.Resistates adds water and ethyl acetate, then adds triethylamine (about 60g), is stirred to dissolving, ethyl acetate extraction, the compound (163g, productive rate 88.6%) of acquisition above formula b.m/z：367.9。
Step b adds the compound of formula b in dehydrated alcohol (about 500ml), adds D-(-) tartrate (84g) stirring, reflux to mass crystallization product is separated out, cooling, and product is leached, and uses absolute ethanol washing.With ethanol and water mixed solvent recrystallization, dry formula IV2 compound 88.3g(productive rate 38.5%, the HPLC purity 99.8% of obtaining).
Embodiment 3
Adopt the method for embodiment 2, the compound that two chloro-phthalic anhydrides of take are raw material preparation formula IV3, productive rate approximately 40.2%, HPLC purity 99.8%).The m/z of formula c compound is 298.0.
Embodiment 4
Step a mixes 2,3-diphenyl maleic anhydride (125g) and 3-amino piperidine (50.1g), adds the 1L methylene dichloride, and stirring at room 1 hour, except desolventizing.Resistates adds in aceticanhydride and sodium-acetate mixture, and reflux 2 hours is after reacting completely, cooling, adds water and ethyl acetate extraction, obtains the compound (150.5g, productive rate 90.6%) of above formula d.m/z：332.1。
Step b adds the compound of formula d in dehydrated alcohol (about 400ml), adds D-(-) tartrate (82g) stirring, reflux to mass crystallization product is separated out, cooling, and product is leached, and uses absolute ethanol washing.With ethanol and water mixed solvent recrystallization, dry formula IV4 compound 94.2g(productive rate 43.1%, the HPLC purity 99.8% of obtaining).
Embodiment 5
Step a mixes by two (oxyethyl group thiocarbonyl) sulfide (114g) and 3-amino piperidine (50.1g) the ethanol water mixed liquid (1:1) that is placed in 1L, in ice bath, stirs, and drips gradually the aqueous sodium hydroxide solution of 4N, until the mixture clarification.Stirring at room 24 hours, remove solvent, and the gained solid is placed in methylene dichloride-pyridine mixed solution (1:1,500ml), stirs 1 hour, adds aceticanhydride 500ml to stir and spend the night.Steaming desolventizes, dry, the product of gained is dissolved in anhydrous acetonitrile, add chloroformyl SULPHURYL CHLORIDE (62.7ml) under anhydrous condition, stirring at room 4 hours, reaction solution dilutes with methylene dichloride, successively with sodium bicarbonate, water and salt solution washing, dry concentrated, obtain the compound (99.6g, yield 90.4%) shown in formula e.m/z：218.0。
Step b adds the compound of formula e in dehydrated alcohol (about 300ml), adds D-(-) tartrate (86g) stirring, reflux to mass crystallization product is separated out, cooling, and product is leached, and uses absolute ethanol washing.With ethanol and water mixed solvent recrystallization, dry formula IV5 compound 68.1g(productive rate 41%, the HPLC purity 99.8% of obtaining).
Raw material two in the present embodiment (oxyethyl group thiocarbonyl) sulfide can be by the preparation of the disclosed method of prior art, such as adopting the people such as Oliva at Heterocyclic Communications, and 14 (5), 329-335; Disclosed method preparation in 2008.
Embodiment 6
Step a is 3-amino piperidine (50.1g), 2,5-hexanedione (110ml), and toluene 200ml mixes, and nitrogen protection is stirred, and reflux divides water to react completely (approximately 6 hours).Cooling, reaction solution is processed with ether, concentrated, obtains the compound 82.8g(productive rate 93.1% shown in formula f), m/z:178.2.
Step b adds the compound of formula e in dehydrated alcohol (about 300ml), adds D-(-) tartrate (88g) stirring, reflux to mass crystallization product is separated out, cooling, and product is leached, and uses absolute ethanol washing.With ethanol and water mixed solvent recrystallization, dry formula IV6 compound 62.0g(productive rate 40.0%, the HPLC purity 99.8% of obtaining).
Embodiment 7
Step a is dissolved in 1,2-bis-(chloromethyl is silica-based) ethane (112.5g) in the 200ml anhydrous methylene chloride, adds wherein the 400ml anhydrous methylene chloride solution that contains 3-amino piperidine (50.1g) and triethylamine (101g).Nitrogen protection, the stirring at room reaction, to complete (approximately 2 hours), imports reaction solution in the biphosphate sodium water solution, steams solvent, obtains formula g compound 115.4g(yield 95.4%), m/z:242.1.
Step b adds the compound of formula g in dehydrated alcohol (about 300ml), adds D-(-) tartrate (91g) stirring, reflux to mass crystallization product is separated out, cooling, and product is leached, and uses absolute ethanol washing.With ethanol and water mixed solvent recrystallization, dry formula IV7 compound 70.2g(productive rate 37.6%, the HPLC purity 99.8% of obtaining).
Embodiment 8
Adopt the method for embodiment 7, with, the compound that 2-bis-(dimethylsilyl) benzene is raw material preparation formula IV8, productive rate 36.8%, HPLC purity 99.8%.
The preparation method of embodiment 9 BI 1356s
Embodiment 9-1
Step a is by 1-[3-itrile group-pyridine of 103g-2-yl]-3-methyl-7-(2-butine-1-yl)-compound shown in the formula IV1 of 8-bromine xanthine (preparing according to the disclosed method of WO2004018468), 176g adds in the METHYLPYRROLIDONE (NMP) of 500ml, be heated to 140 ℃, drip gradually the 250ml diisopropylethylamine, after dropwising, be stirred to react completely (approximately 3 hours) under 140 ℃.Reaction mixture is cooling, add water after adding methyl alcohol dilution, be cooled to room temperature, filter, obtain solid 164g(productive rate 95%)
Step b is the product obtained in step a, 10% palladium carbon (40g), and ethanol mixture, be stirred well to and react completely under room temperature, filter, the filtrate concentrate drying, the crude product recrystallizing methanol, obtain BI 1356 107.8g, productive rate 96.1%, the ee value > 99%, HPLC purity 99.8%.
Embodiment 9-2
Step a is by 1-[3-itrile group-pyridine of 103g-2-yl]-3-methyl-7-(2-butine-1-yl)-compound shown in the formula IV2 of 8-bromine xanthine (preparing according to the disclosed method of WO2004018468), 129g adds in the METHYLPYRROLIDONE (NMP) of 500ml, be heated to 80 ℃, drip gradually the 250ml diisopropylethylamine, after dropwising, under 140 ℃, be stirred to and react completely.Reaction mixture is cooling, add water after adding methyl alcohol dilution, be cooled to room temperature, filter, obtain solid 174g(productive rate 94.1%)
Step b mixes the product and the quadrol (40g) that obtain in step a, be placed in tetrahydrofuran (THF) (300ml), reflux, to react completely (approximately 2 hours), adds water treatment, uses chloroform extraction, anhydrous sodium sulfate drying, steaming desolventizes, and the crude product recrystallizing methanol obtains BI 1356 102g productive rate 92.0%, the ee value > 99%, HPLC purity 99.8%.
Embodiment 9-3
Method according to embodiment 9-2 prepares BI 1356, gained BI 1356 productive rate 95.5%, ee value > 99%, HPLC purity 99.8%.
Embodiment 9-4
Step a is by 1-[3-itrile group-pyridine of 103g-2-yl]-3-methyl-7-(2-butine-1-yl)-compound shown in the formula IV4 of 8-bromine xanthine (preparing according to the disclosed method of WO2004018468), 120g adds in the METHYLPYRROLIDONE (NMP) of 500ml, be heated to 140 ℃, drip gradually the 250ml diisopropylethylamine, after dropwising, under 140 ℃, be stirred to and react completely.Reaction mixture is cooling, add water after adding methyl alcohol dilution, be cooled to room temperature, filter, obtain solid 161.9(productive rate 92%)
Step b is by the product of step a under nitrogen protection, and oxammonium hydrochloride (247g) and triethylamine (346ml) are placed in the mixed solution (800ml:200ml) of second alcohol and water, and reflux only reacts completely.Keep nitrogen protection, reaction solution is cooling in ice bath, slowly adds sodium hydroxide (200g), at room temperature stirs 24 hours; filter, filtrate is concentrated, the crude product recrystallizing methanol; obtain BI 1356 104.2g(productive rate 96%), the ee value > 99%, HPLC purity 99.8%.
Embodiment 9-5
Step a is by 1-[3-itrile group-pyridine of 103g-2-yl]-3-methyl-7-(2-butine-1-yl)-compound shown in the formula IV5 of 8-bromine xanthine (preparing according to the disclosed method of WO2004018468), 90g adds in the METHYLPYRROLIDONE (NMP) of 500ml, be heated to 80 ℃, drip gradually the 250ml diisopropylethylamine, after dropwising, be stirred to react completely (approximately 3 hours) under 80 ℃.Reaction mixture is cooled to 75 ℃, adds water after adding methyl alcohol dilution, be cooled to room temperature, filter, obtain solid 139g(productive rate 94.3%)
The compound that step b makes step a is dissolved in anhydrous chloroform (500ml), adds gradually sodium borohydride (40g), is stirred to react completely (about 15min).Reaction adds water after finishing, filters, and collected organic layer, concentrated, recrystallizing methanol, obtain BI 1356 104g(productive rate 94%), the ee value > 99%, HPLC purity 99.8%.
Embodiment 9-6
Step a is by 1-[3-itrile group-pyridine of 103g-2-yl]-3-methyl-7-(2-butine-1-yl)-compound shown in the formula IV6 of 8-bromine xanthine (preparing according to the disclosed method of WO2004018468), 82g adds in the METHYLPYRROLIDONE (NMP) of 300ml, be heated to 100 ℃, drip gradually the 250ml diisopropylethylamine, after dropwising, under 100 ℃, be stirred to and react completely.Reaction mixture is cooled to 75 ℃, adds water after adding methyl alcohol dilution, be cooled to room temperature, filter, obtain solid 126g(productive rate 92%)
Step b is with reference to the method for embodiment 9-4 step b, and the product of step a of take prepares BI 1356, productive rate 96.1%, ee value as raw material > 99%, HPLC purity 99.8%.
Embodiment 9-7
Step a is by 1-[3-itrile group-pyridine of 103g-2-yl]-3-methyl-7-(2-butine-1-yl)-compound shown in the formula IV7 of 8-bromine xanthine (preparing according to the disclosed method of WO2004018468), 98g adds in the METHYLPYRROLIDONE (NMP) of 300ml, be heated to 80 ℃, drip gradually the 250ml diisopropylethylamine, after dropwising, under 80 ℃, be stirred to and react completely.Reaction mixture is cooled to 75 ℃, adds water after adding methyl alcohol dilution, be cooled to room temperature, filter, obtain solid 147g(productive rate 96%)
Step b is dissolved in the product of step a in tetrahydrofuran (THF), adds aqueous acetic acid, and stirring at room is to reacting completely, concentrated, filters, and uses recrystallizing methanol, obtains 106g(productive rate 94%), the ee value > 99%, HPLC purity 99.8%.
Claims (10)
1. the method for compound shown in a preparation formula (I),
Comprise following synthesis step:
1) compound shown in formula (III) is reacted to the compound shown in acquisition formula (II) with the compound or its salt shown in formula (IV):
Wherein, described R1 forms amino protecting group together with R2 and adjacent amino cyclization; X is halogen or sulphonate;
2) compound shown in formula (II) is removed to protection, the compound shown in acquisition formula (I).
2. method according to claim 1, is characterized in that, described R1 forms the group of cyclic imide structure together with R2 and adjacent amino cyclization; Or R1 forms the group of cyclic lactames structure together with R2 and adjacent amino cyclization.
3. method according to claim 2, is characterized in that, described R1 together with R2 and adjacent amino cyclization form comprise following shown in the group of structure:
4. method according to claim 2, is characterized in that, described R1 together with R2 and adjacent amino cyclization form following shown in the group of structure:
Wherein said R3, R4, R5, R6 is hydrogen when different, is selected from respectively halogen, H, the low alkyl replaced.
5. the intermediate of the piperidines for the preparation of BI 1356 or its salt are selected from the compound with following structure:
6. the salt of intermediate according to claim 5, comprising: tartrate, camphorate, malate, dibenzoyl tartaric acid salt.
7. the chiral intermediate shown in a preparation formula (IV) or the synthetic method of its salt, comprise the steps:
1) by racemic 3-amino piperidine, in appropriate solvent, with amino protecting group, reaction forms cyclic imide or lactan;
2) split by the sour salify that adds opticity, separate the salt of the compound shown in acquisition formula (IV);
Described ring-type lactim or lactan structure refer to comprise following shown in the group of structure:
8. method according to claim 7, is characterized in that, the acid of described opticity is D-(-) tartrate, D-dextrocamphoric acid, D-malic acid or D-dibenzoyl tartaric acid.
9. described method according to Claim 8, is characterized in that, described opticity acid is D-(-) tartrate.
10. the chiral intermediate shown in a preparation formula (IV) or the synthetic method of its salt, comprise the 3-amino piperidine of R configuration in appropriate solvent and amino protecting group reaction formation cyclic imide or lactan.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105272982A (en) * | 2015-11-23 | 2016-01-27 | 齐鲁制药有限公司 | New Trajenta crystal form and preparation method thereof |
| EP2885302A4 (en) * | 2012-08-17 | 2016-03-09 | Glenmark Pharmaceuticals Ltd | Process for the preparation of dipeptidylpeptidase inhibitors |
| WO2016207364A1 (en) * | 2015-06-25 | 2016-12-29 | Boehringer Ingelheim International Gmbh | Process for the preparation of a xanthine-based compound |
| US20220009949A1 (en) * | 2020-07-10 | 2022-01-13 | Shin-Etsu Chemical Co., Ltd. | Organosilicon compound having cyclic silazane structure, composition containing the same, and method for producing the same |
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| CN101048409A (en) * | 2004-11-05 | 2007-10-03 | 贝林格尔·英格海姆国际有限公司 | Method for producing chiral 8-(3-amino-piperidin-1-yl)-xanthines |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2885302A4 (en) * | 2012-08-17 | 2016-03-09 | Glenmark Pharmaceuticals Ltd | Process for the preparation of dipeptidylpeptidase inhibitors |
| WO2016207364A1 (en) * | 2015-06-25 | 2016-12-29 | Boehringer Ingelheim International Gmbh | Process for the preparation of a xanthine-based compound |
| JP2018522862A (en) * | 2015-06-25 | 2018-08-16 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Process for the preparation of xanthine-based compounds |
| US10253026B2 (en) | 2015-06-25 | 2019-04-09 | Boenringer Ingelheim International GmbH | Process for the preparation of (r)-8-(3-aminopiperidin-1-yl)-7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-3,7-dihydro-1h-purine-2,6-dione |
| EP3974431A1 (en) * | 2015-06-25 | 2022-03-30 | Boehringer Ingelheim International GmbH | Process for the preparation of a xanthine-based compound |
| CN105272982A (en) * | 2015-11-23 | 2016-01-27 | 齐鲁制药有限公司 | New Trajenta crystal form and preparation method thereof |
| US20220009949A1 (en) * | 2020-07-10 | 2022-01-13 | Shin-Etsu Chemical Co., Ltd. | Organosilicon compound having cyclic silazane structure, composition containing the same, and method for producing the same |
| US11634439B2 (en) * | 2020-07-10 | 2023-04-25 | Shin-Etsu Chemical Co., Ltd. | Organosilicon compound having cyclic silazane structure, composition containing the same, and method for producing the same |
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