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CN101899067A - The preparation method of rice platinum - Google Patents

The preparation method of rice platinum Download PDF

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Publication number
CN101899067A
CN101899067A CN2010102497608A CN201010249760A CN101899067A CN 101899067 A CN101899067 A CN 101899067A CN 2010102497608 A CN2010102497608 A CN 2010102497608A CN 201010249760 A CN201010249760 A CN 201010249760A CN 101899067 A CN101899067 A CN 101899067A
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platinum
water
preparation
cyclohexanediamine
cis
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发明人公布姓名
孙艳艳
诸海滨
徐刚
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Southeast University
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Southeast University
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Abstract

本发明涉及一种米铂的制备方法，由二硝酸顺式-[(1R，2R)-1，2-环己二胺-二水]合铂(II)与肉豆蔻酸盐在溶剂中反应得到，其特征在于，所述溶剂由烷基醇和水组成，所述烷基醇为甲醇、乙醇、丙醇或异丙醇，所述肉豆蔻酸盐为肉豆蔻酸的钠盐、钾盐或铵盐，反应温度为20～80℃，二硝酸顺式-[(1R，2R)-1，2-环己二胺-二水]合铂(II)与水的质量比为1∶10-1∶100。水和烷基醇的体积比优选为1∶0.5～1∶2，更优选为1∶1。该制备方法步骤简单，反应媒介可以溶解肉豆蔻酸盐，从而使反应能够有效地进行，应用至工业化生产。The present invention relates to a kind of preparation method of rice platinum, by dinitrate cis-[(1R,2R)-1,2-cyclohexanediamine-dihydrate] platinum (II) and myristate react in a solvent Obtain, it is characterized in that, described solvent is made up of alkyl alcohol and water, and described alkyl alcohol is methanol, ethanol, propanol or isopropanol, and described myristate is the sodium salt of myristic acid, potassium salt or Ammonium salt, the reaction temperature is 20～80℃, the mass ratio of dinitrate cis-[(1R,2R)-1,2-cyclohexanediamine-dihydrate]platinum(II) to water is 1:10- 1:100. The volume ratio of water and alkanol is preferably 1:0.5-1:2, more preferably 1:1. The preparation method has simple steps, and the reaction medium can dissolve the myristate so that the reaction can be carried out effectively, and is applied to industrial production.

Description

The preparation method of rice platinum
Technical field
The present invention relates to the preparation method of antitumor medicament platinum, belong to the pharmaceutical chemistry technical field.
Background technology
Rice platinum (miriplatin) is a kind of fat-soluble platinum (II) series antineoplastic medicament, its code name is SM-11355, principal indication is a liver cancer, and the later stage was developed in 2009 by SUMITOMO CHEMICAL Pharmaceutical Co., Ltd and went on the market in Japan by the research and development of Bristol-Myers-Squibb company early stage.Formula (I) seen in the chemical structural formula of rice platinum,
Formula (I)
Preparation method's report of relevant rice platinum relates generally to following several patents method.
The one, European Patent Publication No is the method that 0193936A1 (priority date this patent JP43869/85) discloses, and its chemical equation as follows.At first remove starting raw material cis-[two chloro-(1R with Silver Nitrate, 2R)-1, the 2-cyclohexanediamine] close the chlorion in the platinum (II), obtain the dinitric acid cis-[(1R, 2R)-1,2-cyclohexanediamine-two water] close the aqueous solution of platinum (II), it is added in the aqueous suspension that contains Sodium tetradecanoate then, lucifuge reacted for three weeks, filtered out solid, a small amount of washing, drying under reduced pressure obtains a meter platinum.Because this method reaction times is very long, is not suitable for suitability for industrialized production.
Figure BDA0000024290650000012
The 2nd, international monopoly WO9414470 reported method, its chemical equation is as follows.Cis-[two iodo-(1R, 2R)-1,2-cyclohexanediamine] are closed platinum (II) and tetradecanoic acid silver are suspended in the chloroform and react, remove the Silver iodide of formation after, concentrating filter liquor is handled and is obtained a meter platinum.Because the starting raw material cis-and [two iodo-(1R, 2R)-1,2-cyclohexanediamine] close platinum (II) and tetradecanoic acid silver is almost insoluble in chloroform, and it is extremely slow to cause this reaction to be carried out.Only need 24 hours although adopt this method to use valeric acid silvery to be equipped with relevant platinum complex, but experiment shows that when adopting tetradecanoic acid silvery to be equipped with rice platinum, the reaction times increases to more than 48 hours and also do not react completely, and product purity is lower, so this method also is not suitable for industrial preparation.
The 3rd, Japanese Patent JP2004083508 disclosed method, its chemical equation is as follows.In water, earlier remove starting raw material cis-[two chloro-(1R with Silver Nitrate, 2R)-1, the 2-cyclohexanediamine] close the chlorion in the platinum (II), obtaining dinitric acid cis-[(1R, 2R)-1,2-cyclohexanediamine-two water] closes the aqueous solution of platinum (II), add tetradecanoic acid, chloroform and potassium hydroxide reaction then, aftertreatment obtains a meter platinum.Because tetradecanoic acid is dissolved in chloroform and is insoluble in the water, so reaction is to carry out in two-phase basically, the reaction times is longer, and adds multiple solvent again, causes the aftertreatment trouble.
Figure BDA0000024290650000022
Summary of the invention
Deficiency at the existing open antitumor medicament platinum preparation method who reports, the present invention aims to provide the preparation method of a kind of meter platinum, and this preparation method's step is simple, and reaction media can dissolve myristate, thereby reaction can be carried out effectively, be applied to suitability for industrialized production.
The preparation method of rice platinum of the present invention is, by dinitric acid cis-[(1R, 2R)-1,2-cyclohexanediamine-two water] close platinum (II) and myristate and in solvent, react and obtain, it is characterized in that, described solvent is made up of the alkyl alcohol and water, described alkyl alcohol is methyl alcohol, ethanol, propyl alcohol or Virahol, described myristate is sodium salt, sylvite or the ammonium salt of tetradecanoic acid, temperature of reaction is 20～80 ℃, the mass ratio that dinitric acid cis-[(1R, 2R)-1,2-cyclohexanediamine-two water] closed platinum (II) and water is 1: 10-1: 100.
Experiment shows that myristate solubleness in the water below 50 ℃ is less, the general suspension that forms when being higher than 50 ℃, and temperature reduces and can solidify once again.Because myristate is insoluble in the organic solvent, thereby adopts single solvent not help the carrying out that reacts.The present inventor finds that at a certain temperature, the mixed solvent that a certain proportion of water and lower alkyl alcohol are formed can dissolve tetradecanoic acid salt formation settled solution fully, thereby helps the carrying out that react.
Employed alkyl alcohol can be methyl alcohol, ethanol, propyl alcohol or Virahol among the present invention, is preferably ethanol or Virahol; In the reaction soln system, the volume ratio of water and alkyl alcohol is preferably 1: 0.5～and 1: 2, more preferably 1: 1.
Temperature of reaction is preferably 50～60 ℃.Reaction times can be definite through testing by those skilled in the art, is preferably 24～48h, more preferably 24～36h.
The mole dosage that myristate and dinitric acid cis-[(1R, 2R)-1,2-cyclohexanediamine-two water] closed platinum (II) is 2: 1 by the chemical reaction metering.
Dinitric acid cis-[(1R, 2R)-1,2-cyclohexanediamine-two water] closes platinum (II) and can prepare its aqueous solution according to known technology, need not further to purify, and promptly can be used for the present invention, and preferred scheme is:
Closing platinum (II) with the cis of structure shown in the formula (II)-[dihalo--(1R, 2R)-1,2-cyclohexanediamine] reacts in water with Silver Nitrate, remove by filter the silver halide of generation, obtain the dinitric acid cis-[(1R, 2R)-1,2-cyclohexanediamine-two water] close the aqueous solution of platinum (II), add tetradecanoic acid salt formation suspension then, add alkyl alcohol again, react, be cooled to room temperature, filter, drying obtains the rice platinum of structure shown in the formula (I);
Figure BDA0000024290650000031
Formula (I) formula (II)
The preparation method of rice platinum of the present invention, its chemical equation is seen formula (III):
Formula (III)
Wherein, X is the halogen ion, is chlorion, bromide anion or iodide ion; CH 3(CH 2) 12COOM is a myristate, and M is a monovalent cation, is sodium ion, potassium ion or ammonium ion; ROH be can be miscible with water alkyl alcohol, be methyl alcohol, ethanol, propyl alcohol or Virahol.
In order to obtain to meet the product of medical standard, can adopt recrystallization method to obtain highly purified rice platinum, the recrystallization solvent of use is common chloroparaffin or acetone.
Adopt the rice platinum of the inventive method preparation, confirm, meet the structure shown in the formula (I) through infrared spectra, nucleus magnetic hydrogen spectrum and mass-spectrometric data.The ultimate analysis and the thermogravimetric analysis of sample show that gained rice platinum contains a part crystal water.
Starting raw material cis used in the present invention-[dihalo--(1R, 2R)-1, the 2-cyclohexanediamine] close platinum (II) by early stage literature method acquisition, employed water is distilled water.
Embodiment
The present invention obtains further instruction by following embodiment, but these explanations are not restriction the present invention.
Embodiment 1. Sodium tetradecanoates solubility experiment in water under differing temps
A certain amount of Sodium tetradecanoate is added in the water of certain volume, under differing temps, observe its solubleness, concrete experiment content and the results are shown in Table 1.Along with the rising of temperature, Sodium tetradecanoate solubleness in water increases, and solvability is better during temperature 〉=50 ℃.
Table 1. Sodium tetradecanoate is the solvability in water under differing temps
Figure BDA0000024290650000041
Embodiment 2. Sodium tetradecanoates are the solubility experiment in water and alkyl alcohol mixed solvent under uniform temp
In a certain amount of water and alcohol (volume ratio 1: 1) mixed solvent, under uniform temp, observe its dissolving power, concrete experiment content and the results are shown in Table 2 to Sodium tetradecanoate.Experimental result shows that 30 ℃ of following Sodium tetradecanoates have certain dissolubility in water and pure mixed solvent, and mixed solvent solubleness size order is: water-Virahol (1: 1)＞water-ethanol (1: 1)＞water-methanol (1: 1).
Table 2. Sodium tetradecanoate is the solvability in water and alkyl alcohol mixed solvent under uniform temp
Figure BDA0000024290650000051
Embodiment 3. Sodium tetradecanoates are at the water of different ratios and the solubility experiment in the alcohol mixed solvent
Under uniform temp, in the water and alcohol mixed solvent of different ratios, observe its dissolving power, concrete experiment content and the results are shown in Table 3 to Sodium tetradecanoate.Experimental result shows no matter increase or reduce the ratio of ethanol in mixed solvent under the uniform temp, and the solubleness of Sodium tetradecanoate is reduced, and Sodium tetradecanoate dissolved optimal proportions in water and alcohol mixed solvent is 1: 1.
Table 3. Sodium tetradecanoate is in the water of different ratios and the solvability in the alcohol mixed solvent
Figure BDA0000024290650000061
Embodiment 4. cis-[(two chloro-(1R, 2R)-1,2-cyclohexanediamine] closed the preparation (PtC of platinum (II) 6H 14Cl 2N 2)
Under the lucifuge, 6.23g (15.0mmol) potassium tetrachloroplatinate is dissolved in the 60ml water, stirs adding 1.71g (15.0mmol) (1R down, 2R)-1, the 30ml aqueous solution of 2-cyclohexanediamine stirs under the room temperature and spends the night, filtration, vacuum-drying get yellow solid, the 5.18g that weighs (productive rate 91%).
Embodiment 5. cis-[(two iodo-(1R, 2R)-1,2-cyclohexanediamine] closed the preparation (PtC of platinum (II) 6H 14I 2N 2)
Under the lucifuge, 2.08g (5.0mmol) potassium tetrachloroplatinate and 6.64g (40.0mmol) potassiumiodide are dissolved in the 50mL water stirring at room 20 minutes, add 0.57g (5.0mmol) (1R then, 2R)-1, the 30ml aqueous solution of 2-cyclohexanediamine continues to stir 30 minutes.Filter, use less water, ethanol and ether washing precipitation successively, 60 ℃ of following vacuum-dryings get the safran solid, the 2.67g that weighs (productive rate 95%).
Preparation (the PtC of 6. meters platinum of embodiment 34H 68N 2O 4.H 2O)
Under the lucifuge, with 0.57g (1.50mmol) cis-[(two chloro-1R, 2R)-1, the 2-cyclohexanediamine] close platinum (II) and place the 250ml flask, adding 40ml distilled water stirs, the solution that then 0.51g (3.00mmol) Silver Nitrate is dissolved in 10ml distilled water adds above-mentioned suspension, lucifuge stirring at room reaction 24h.The diatomite aided filter is removed silver nitride precipitation, gets light yellow settled solution.Above-mentioned filtrate adds 0.71g (2.85mmol) Sodium tetradecanoate under lucifuge stirs, and then adds 50ml ethanol, 55 ℃ of lucifuge stirring reactions 36 hours, cooling is filtered, light yellow solid, vacuum-drying, the 0.94g that weighs (productive rate 80%).
Preparation (the PtC of 7. meters platinum of embodiment 34H 68N 2O 4.H 2O)
Under the lucifuge, with 1.00g (2.60mmol) cis-[(two chloro-1R, 2R)-1, the 2-cyclohexanediamine] close platinum (II) and place the 250ml flask, adding 40ml distilled water stirs, the solution that then 0.89g (5.20mmol) Silver Nitrate is dissolved in 10ml distilled water adds above-mentioned suspension, lucifuge stirring at room reaction 24h.The diatomite aided filter is removed silver nitride precipitation, gets light yellow settled solution.Above-mentioned filtrate adds 1.30g (5.20mmol) Sodium tetradecanoate under lucifuge stirs, and then adds the 50ml Virahol, 50 ℃ of lucifuge stirring reactions 24 hours, cooling is filtered, light yellow solid, vacuum-drying, the 1.60g that weighs (productive rate 79%).
Preparation (the PtC of 8. meters platinum of embodiment 34H 68N 2O 4.H 2O)
Under the lucifuge, with 0.84g (1.50mmol) cis-[(two iodo-1R, 2R)-1, the 2-cyclohexanediamine] close platinum (II) and place the 250ml flask, adding 50ml distilled water stirs, the solution that then 0.51g (3.00mmol) Silver Nitrate is dissolved in 10ml distilled water adds above-mentioned suspension, lucifuge stirring at room reaction 24h.The diatomite aided filter is removed the Silver iodide precipitation, gets light yellow settled solution.Above-mentioned filtrate adds 0.71g (2.85mmol) Sodium tetradecanoate under lucifuge stirs, and then adds the 40ml dehydrated alcohol, 55 ℃ of lucifuge stirring reactions 48 hours, cooling is filtered, light yellow solid, vacuum-drying, the 0.88g that weighs (productive rate 75%).
Preparation (the PtC of 9. meters platinum of embodiment 34H 68N 2O 4.H 2O)
Under the lucifuge, 19.0g (50mmol) dichloro cyclohexanediamine is closed platinum place the 1000ml flask, add 200ml distilled water and stir, 16.2g (95mmol) AgNO 3The solution that is dissolved in 50ml distilled water adds above-mentioned suspension, lucifuge stirring at room reaction 24 hours.The diatomite aided filter is removed silver nitride precipitation, gets light yellow settled solution.Under lucifuge, stir, 25.0g (100mmol) Sodium tetradecanoate and 250ml ethanol added in the above-mentioned filtrate, 50 ℃ of lucifuge stirring reactions 36 hours, cooling is filtered, light yellow solid, vacuum-drying, the 34.3g that weighs (productive rate 88%).
The recrystallization of 10. meters platinum of embodiment
1.60g rice platinum crude product adds 20mlCH 2Cl 2In, be heated to dissolving under the lucifuge, add small amount of activated, stirring and refluxing 0.5 hour, filter pale yellow solution, filtrate concentrates postcooling and places and spend the night, and separates out white solid, filters vacuum-drying, the 1.33g that weighs (productive rate 83%, purity: 99.83%).
The spectrum data of gained rice platinum is as follows, meets the structure shown in the formula (I):
IR(KBr，cm -1)：3434，3186，3106，2921，2852，1603，1468，1379，1113，720；
1H?NMR(d 6-CDCl 3/TMS，ppm)：δ0.886(t，6H)，δ1.136-1.253(m，44H)，δ1.506(m，6H)，δ1.784(m，2H)，δ1.994(m，2H)，δ2.135-2.161(t，4H)，δ2.782(br，2H，H 2O)，δ4.964(m，2H，NH 2)，δ5.847(m，2H，NH 2)；
ESI-MS：m/z[M-H] -＝763(10％)。

Claims (8)

1.一种米铂的制备方法，由二硝酸顺式-[(1R，2R)-1，2-环己二胺-二水]合铂(II)与肉豆蔻酸盐在溶剂中反应得到，其特征在于，所述溶剂由水和烷基醇组成，所述烷基醇为甲醇、乙醇、丙醇或异丙醇，所述肉豆蔻酸盐为肉豆蔻酸的钠盐、钾盐或铵盐，反应温度为20～80℃，二硝酸顺式-[(1R，2R)-1，2-环己二胺-二水]合铂(II)与水的质量比为1∶10-1∶100。1. a preparation method of rice platinum, obtained by the reaction of dinitrate cis-[(1R, 2R)-1,2-cyclohexanediamine-dihydrate] platinum (II) and myristate in a solvent , it is characterized in that, described solvent is made up of water and alkyl alcohol, and described alkyl alcohol is methanol, ethanol, propanol or isopropanol, and described myristate is the sodium salt of myristic acid, potassium salt or Ammonium salt, the reaction temperature is 20～80℃, the mass ratio of dinitrate cis-[(1R,2R)-1,2-cyclohexanediamine-dihydrate]platinum(II) to water is 1:10- 1:100. 2.如权利要求1所述的米铂的制备方法，其特征在于，水和烷基醇的体积比为1∶0.5～1∶2。2. the preparation method of rice platinum as claimed in claim 1 is characterized in that, the volume ratio of water and alkyl alcohol is 1: 0.5～1: 2. 3.如权利要求2所述的米铂的制备方法，其特征在于，水和烷基醇的体积比为1∶1。3. the preparation method of rice platinum as claimed in claim 2 is characterized in that, the volume ratio of water and alkyl alcohol is 1: 1. 4.如权利要求1所述的米铂的制备方法，其特征在于，所述烷基醇为乙醇或异丙醇。4. the preparation method of rice platinum as claimed in claim 1 is characterized in that, described alkyl alcohol is ethanol or Virahol. 5.如权利要求1-4中任一项所述的米铂的制备方法，其特征在于，反应温度为50～60℃。5. The preparation method of rice platinum as described in any one of claims 1-4, it is characterized in that, reaction temperature is 50～60 ℃. 6.如权利要求1-4中任一项所述的米铂的制备方法，其特征在于，反应时间为24～48h。6. The preparation method of miplatin according to any one of claims 1-4, characterized in that the reaction time is 24 to 48 hours. 7.如权利要求1-4中任一项所述的米铂的制备方法，其特征在于，反应时间为24～36h。7. The preparation method of miplatin according to any one of claims 1-4, characterized in that the reaction time is 24 to 36 hours. 8.如权利要求1-4中任一项所述的米铂的制备方法，其特征在于，以式(II)所示结构的顺式-[二卤-(1R，2R)-1，2-环己二胺]合铂(II)与硝酸银在水中反应，过滤除去生成的卤化银，得到二硝酸顺式-[(1R，2R)-1，2-环己二胺-二水]合铂(II)的水溶液，然后加入肉豆蔻酸盐形成悬浮液，再加入烷基醇，进行反应，冷却至室温，过滤，干燥，得到式(I)所示结构的米铂；8. the preparation method of the rice platinum as described in any one in claim 1-4 is characterized in that, with the cis-[dihalogen-(1R, 2R)-1 of structure shown in formula (II), 2 -Cyclohexanediamine] platinum (II) reacts with silver nitrate in water, and the silver halide generated is removed by filtration to obtain dinitrate cis-[(1R,2R)-1,2-cyclohexanediamine-dihydrate] The aqueous solution of combined platinum (II), then add myristate to form a suspension, add alkyl alcohol again, carry out reaction, cool to room temperature, filter, dry, obtain the rice platinum of structure shown in formula (I);
Figure FDA0000024290640000011
Figure FDA0000024290640000011
 式(I)                            式(II)Formula (I) Formula (II)
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Cited By (10)

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CN102127119A (en) * 2011-01-11 2011-07-20 济南利民制药有限责任公司 Preparation method of miboplatin
CN102225954A (en) * 2011-05-05 2011-10-26 昆明贵研药业有限公司 Method for purifying platinum
CN102516311A (en) * 2011-11-03 2012-06-27 南京优科生物医药有限公司 Preparation method of miriplatin hydrate
CN102746342A (en) * 2012-04-26 2012-10-24 江苏奥赛康药业股份有限公司 Miriplatin crystal form and preparation method thereof
CN102766169A (en) * 2012-08-01 2012-11-07 昆明贵研药业有限公司 New method for synthesizing anti-tumor drug miboplatin
CN103910762A (en) * 2014-04-16 2014-07-09 北京美迪康信医药科技有限公司 Preparation method of miriplatin
CN104031091A (en) * 2014-04-11 2014-09-10 神威药业集团有限公司 Preparation method for fat-soluble platinum complex
CN104119387A (en) * 2013-04-24 2014-10-29 正大天晴药业集团股份有限公司 Preparation method for miriplatin
CN104597157A (en) * 2015-01-17 2015-05-06 神威药业集团有限公司 Method for measuring fat-soluble platinum complex and preparation related substances thereof
CN116970006A (en) * 2023-07-31 2023-10-31 石家庄智时医药科技有限公司 A kind of preparation method of platinum

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Publication number Priority date Publication date Assignee Title
CN102127119B (en) * 2011-01-11 2012-03-14 济南利民制药有限责任公司 Preparation method of miboplatin
CN102127119A (en) * 2011-01-11 2011-07-20 济南利民制药有限责任公司 Preparation method of miboplatin
CN102225954B (en) * 2011-05-05 2013-07-31 昆明贵研药业有限公司 Method for purifying platinum
CN102225954A (en) * 2011-05-05 2011-10-26 昆明贵研药业有限公司 Method for purifying platinum
CN102516311A (en) * 2011-11-03 2012-06-27 南京优科生物医药有限公司 Preparation method of miriplatin hydrate
CN102516311B (en) * 2011-11-03 2014-05-28 南京优科生物医药有限公司 Preparation method of miriplatin hydrate
CN102746342A (en) * 2012-04-26 2012-10-24 江苏奥赛康药业股份有限公司 Miriplatin crystal form and preparation method thereof
CN102766169A (en) * 2012-08-01 2012-11-07 昆明贵研药业有限公司 New method for synthesizing anti-tumor drug miboplatin
CN102766169B (en) * 2012-08-01 2015-04-22 昆明贵研药业有限公司 New method for synthesizing anti-tumor drug miboplatin
CN104119387A (en) * 2013-04-24 2014-10-29 正大天晴药业集团股份有限公司 Preparation method for miriplatin
CN104119387B (en) * 2013-04-24 2017-08-18 正大天晴药业集团股份有限公司 A kind of preparation method of Miboplatin
CN104031091A (en) * 2014-04-11 2014-09-10 神威药业集团有限公司 Preparation method for fat-soluble platinum complex
CN103910762A (en) * 2014-04-16 2014-07-09 北京美迪康信医药科技有限公司 Preparation method of miriplatin
CN104597157A (en) * 2015-01-17 2015-05-06 神威药业集团有限公司 Method for measuring fat-soluble platinum complex and preparation related substances thereof
CN116970006A (en) * 2023-07-31 2023-10-31 石家庄智时医药科技有限公司 A kind of preparation method of platinum

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