CN101628887B - Method for preparing mesna - Google Patents
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- CN101628887B CN101628887B CN200810132528A CN200810132528A CN101628887B CN 101628887 B CN101628887 B CN 101628887B CN 200810132528 A CN200810132528 A CN 200810132528A CN 200810132528 A CN200810132528 A CN 200810132528A CN 101628887 B CN101628887 B CN 101628887B
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- mesna
- straight
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- branched alkyl
- sour
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Abstract
The invention provides a new method for synthesizing mesna. The method is realized by the following scheme: (1) acidifying acyl mesna in hydrogen chloride alcohol solution to obtain acyl mesna acid; (2) refluxing the acyl mesna acid in alcohol for alcoholysis to obtain mesna acid; and (3) neutralizing the mesna acid with alkali to obtain the mesna. Or the mesna acid is not separated but neutralized directly by the alkali to obtain the mesna.
Description
Technical field
The present invention relates to the preparation method of the particularly antitumor medication mesna of field of medicaments (Mucofluid Sodium).
Background of invention
Mesna is the adjuvant drug of antitumour drug, can be used as the urethra protective material.The hemorrhagic cystitis that toxicants such as its meta-bolites propenal of the heavy dose of use of ifosfamide and endoxan back cause.And mesna to be by stablizing nontoxic thioether in conjunction with generating with it, thus prevention and reducing inflammation.
Its synthetic report is shown in USSR J.Applied.Chem 18 the earliest, and 718-24. (1945) Chem.Abs.40.6407. (1946) adopts the reaction of Sodium sulfhydrate and bromotrifluoromethane sodium sulfonate directly to make mesna.React as follows:
NaHS+XCH
2CH
2SO3Na→HSCH
2CH
2SO
3Na+NaX
The disclosed technology of US2694723 is: S-WAT and the reaction of dihalo-ethane make the halogenated ethyl sodium sulfonate, and again with xanthogenate reaction, product ammonia-catalyzed hydrolysis again obtains the sulfydryl ethyl sulfonic acid through IX again, obtain mesna with the sodium hydroxide neutralization.Reactions step is following:
XRX+Me
2SO3→XRSO
3Me+MeX
XRSO
3Me+R
1OCSSMe→R
1OCSSRSO
3Me+MeX
R
1OCSSRSO
3Me+NH
4OH→HSRSO
3Me+R
1OCSNH
4
HSRSO
3Me+H
+(ion exchange resin) → HSRSO
3H
HSRSO
3H+MOH→HSRSO
3M+H
2O
US2695310 and J.Am.Chem.Soc. (1955), the process step of 6231-6233 report is:
The reaction of S-WAT and ethylene dichloride is made the chloroethyl sodium sulfonate, make inner salt with the thiocarbamide reaction again, inner salt ammonia is separated, and crosses post exchange De Meisi acid then, again with sodium hydroxide neutralize mesna.
Reactions step is following:
X(CH
2)nX+Me
2SO
3→X(CH
2)nSO
3Me+MeX
X(CH
2)nSO
3Me+NH
2CSNH
2→
+(NH
2)
2CS(CH
2)nSO
3 -+MeX
+(NH2)2CS(CH2)nSO
3 -+NH
3→HS(CH
2)nSO
3 -+NH
2C(NH
2)
2
HS (CH
2) nSO
3 -+NH
2C (NH
2)
2+ H
+(ion exchange resin) → HS (CH
2) nSO
3H+ (NH
2)
2CHNH
3 +
HS(CH
2)nSO
3H+MOH→HS(CH
2)nSO
3M+H
2O
EP0263556 technology is: thiobenzoic acid and the reaction of bromotrifluoromethane sodium sulfonate, the product that obtains alkaline water again solves product.Reactions step is following:
C
6H
5COSH+NaHCO
3+Br(CH
2)
2SO
3Na→C
6H
5COS(CH
2)
2SO
3Na
C
6H
5COS(CH
2)
2SO
3Na+NH
4OH→HS(CH
2)
2SO
3Na+C
6H
5CONH
2
The CS252564 report adopts thioacetic acid potassium alkaline hydrolysis, crosses post, neutralization then.Reactions step is following:
Br(CH
2)
2SO
3Na+CH
3COSK→CH
3COSCH
2CH
2SO
3Na+KBr
CH
3COSCH
2CH
2SO
3Na+KOH→CH
3COOK+HSCH
2CH
2SO
3Na
The shortcoming of above technology is that by-product inorganic salts is too many, is difficult to purifying, and heating for multiple times concentrates, and is prone to produce two mesnas, is difficult to obtain meeting the mesna of medicinal standard; Perhaps yield is too low, and production cost is too high.
BE842665 adopt tert-butyl mercaptan and chloroethyl sodium sulfonate react t-butylthio ethylsulfonic acid sodium, this product (6N hydrochloric acid) hydrolysis under acidic conditions then obtains mesna.
Reactions step is following:
Iso-butylene that hydrolysis generates and hydrogen sulfide reaction can generate tert-butyl mercaptan, and be recyclable.Shortcoming is that the raw material tert-butyl mercaptan is a liquid, high volatility, and the smell cacosmia, production plant area and surrounding environment can't be stood.In addition, the hydrolysis of thioether is difficult, and condition is more violent, and product is prone to oxidation and generates two mesnas, has a strong impact on quality product.
Hydrolysis obtains this step reaction of mesna for sulfocompound, and mostly in the alkaline condition hydrolysis, only patent BE842665 adopts mineral acid catalytic hydrolysis, this method shortcoming such as above-mentioned.
Summary of the invention
The invention provides a kind of novel method of synthetic mesna, this method realizes through following scheme: (1), with the acyl group mesna with the acidifying of hydrogenchloride alcoholic solution, obtain the acid of the U.S. department of acyl group;
(2), with the U.S. department of the acyl group acid alcoholysis that in alcohol, refluxes, obtain the acid of U.S. department;
(3), the acid of U.S. department obtains mesna with the alkali neutralization.Reactions step is following:
Wherein: R
1Be C
1-C
6Alkyl, C
3-C
8Cycloalkyl group, phenyl or substituted-phenyl, phenyl substituent is selected from methyl, ethyl, methoxyl group, chlorine, bromine, nitro etc., preferred C
1-C
4Straight-chain paraffin, most preferable.
R
2Be C
1-C
6Alkyl, C
3-C
8Cycloalkyl group, benzyl, preferred C
1-C
4Straight or branched alkane.
R
3Be H or C
1-C
4Straight or branched alkyl, preferred C
1-C
4Straight or branched alkane.
In the inventive method embodiment preferred, (1), with acyl group mesna (II) with the acidifying of hydrogenchloride alcoholic solution, filtering reacting liquid, the filtering insoluble solids, filtrating concentrate to be steamed to desolventize and is obtained the U.S. department's acid of acyl group (III); (2), the acid of the U.S. department of acyl group is dissolved in the alcohol, alcoholysis forms U.S. department's acid (IV), and U.S. department's acid (IV) does not separate in alcoholysis liquid, directly obtains mesna (I) with the alkali neutralization.Reactions step is following:
Wherein: R
1Be C
1-C
6Alkyl, C
3-C
8Naphthenic base, phenyl or substituted-phenyl, phenyl substituent is selected from methyl, ethyl, methoxyl group, chlorine, bromine, nitro etc., preferred R
1Be C
1-C
4Straight chained alkyl, most preferable.
R
2Be C
1-C
6Alkyl, C
3-C
8Naphthenic base, benzyl, preferred C
1-C
4The straight or branched alkyl.
R
3Be H or C
1-C
4The straight or branched alkyl, preferred C
1-C
4Straight or branched alkane.
In further preferred embodiment of the present invention:
1, in the first step reaction:
The concentration of hydrogenchloride in alcoholic solution is: 0.5N～6N, preferred concentration: 2N;
The volume of hydrogenchloride alcoholic solution (L) with the ratio of acyl group mesna amount of substance (mol) is:
0.5: 1～6: 1, preferred proportion: 2: 1～3: 1;
Temperature of reaction: 0 ℃～50 ℃, preferred temperature: 0 ℃～30 ℃.
2, in the reaction of second step:
Alcohol R
2The volume of OH (L) with the ratio of acyl group mesna amount of substance (mol) is:
0.5: 1～3: 1, preferred proportion: 1: 1～2: 1;
Temperature of reaction: 60 ℃～120 ℃, preferred temperature: reflux temperature.
3, in three-step reaction:
The concentration of sodium alkoxide: 0.5N～4N, preferred concentration: 2N;
The temperature that drips :-15 ℃～35 ℃, preferred temperature :-5 ℃～5 ℃.
In another embodiment preferred of the present invention, preferably the reaction of (1) in the such scheme and (2) step is incorporated in " one pot " and accomplishes.That is: (1), acyl group mesna (II) carry out acidifying and alcoholysis simultaneously under the alcoholic solution condition of hydrogenchloride, filtering reacting liquid, and the filtering insoluble solids obtains U.S. department's acid (IV) behind the concentrated evaporate to dryness of will filtrating; (2) U.S. department acid (IV) is dissolved in the alcohol obtain mesna (I) with the alkali neutralization.Reactions step is following:
R wherein
1Be C
1-C
6Alkyl, C
3-C
8Naphthenic base, phenyl or substituted-phenyl, phenyl substituent is selected from methyl, ethyl, methoxyl group, chlorine, bromine, nitro etc., preferred C
1-C
4Straight chained alkyl, most preferable.
R
2Be C
1-C
6Alkyl, C
3-C
8Naphthenic base, benzyl, preferred C
1-C
4The straight or branched alkyl.
R
3Be H or C
1-C
4The straight or branched alkyl.
In the further preferred scheme of this embodiment:
1, in the first step reaction:
The concentration of hydrogenchloride is: 0.5N～6N, preferred concentration: 2N;
The volume of hydrogenchloride alcoholic solution (L) with the ratio of acyl group mesna amount of substance (mol) is:
0.5: 1～6: 1, preferred proportion: 2: 1～3: 1;
Temperature of reaction: 60 ℃～120 ℃, preferred temperature: reflux temperature.
2, in the reaction of second step:
Alcohol R
2The volume of OH (L) with the ratio of acyl group mesna amount of substance (mol) is: 0.5: 1～3: 1, and preferred proportion: 1: 1～2: 1;
The concentration of sodium alkoxide: 0.5N～4N, preferred concentration: 2N;
The temperature that drips :-15 ℃～35 ℃, preferred temperature :-5 ℃～5 ℃.
In this method: scheme 1 makes the acid of the U.S. department of acyl group earlier, utilizes the acid directly catalyzed alcoholysis of the U.S. department of midbody acyl group acid self then, does not need to add in addition other acid as catalyst, and finished product is prone to purify; Scheme 2 is accomplished one step of two-step reaction, and the reaction times is short, and is simple to operate.U.S. department acid direct neutralization in alcoholic solution can be separated out mesna.
With data by MoM and MEI, the product purity that this method obtains is high, and yield is high, and cost is low, operates also comparatively simple.
Embodiment
Further specify the present invention through embodiment below.The preparation method who it should be understood that the embodiment of the invention is only used for explaining the present invention, rather than limitation of the present invention, under design prerequisite of the present invention, preparing method's of the present invention simple modifications is all belonged to the present invention and requires the scope protected.
Embodiment 1:
With 20.6g ethanoyl mesna, the ethanol solution of hydrogen chloride of 200ml2N joins in the there-necked flask; Stirred overnight under nitrogen protection, filtration filtering solid, filtrating concentrating steamed and desolventized to such an extent that the lurid ethanoyl of 14.5g U.S.A takes charge of sour thick liquid; Add the 100ml absolute ethyl alcohol, after heating reflux reaction under the nitrogen protection was complete, it was about 5 that this sour ethanolic soln of U.S. department uses the methanol solution of sodium methylate of 2N to be neutralized to PH in ice-water bath; Separate out white mesna solid, filter, the solid that leaches gets 12.3 gram products in room temperature vacuum-drying; Yield 75.0% (in the ethanoyl mesna, down together).Product purity reaches 96%.
Embodiment 2:
With 20.6g ethanoyl mesna, the 200ml2N isopropanol solution of hydrogen chloride joins in the there-necked flask; Stirred overnight under nitrogen protection, filtration filtering solid, filtrating concentrating steamed and desolventized to such an extent that the lurid ethanoyl of 14.3g U.S.A takes charge of sour thick liquid; Add the 100ml Virahol, after heating reflux reaction under the nitrogen protection was complete, it was about 5 that this sour aqueous isopropanol of U.S. department uses the methanol solution of sodium methylate of 2N to be neutralized to PH in ice-water bath; Separate out white mesna solid, filter, the solid that leaches gets the 13.1g product in room temperature vacuum-drying; Yield 79.9%, purity is more than 96%.
Embodiment 3:
With 20.6g ethanoyl mesna, the ethanol solution of hydrogen chloride of 200ml2N joins in the there-necked flask; Stirred overnight under nitrogen protection, filtration filtering solid, filtrating concentrating steamed and desolventized to such an extent that the lurid ethanoyl of 14.5g U.S.A takes charge of sour thick liquid; Add the 150ml absolute ethyl alcohol, in heating reflux reaction under the nitrogen protection fully after, this sour ethanolic soln of U.S. department uses the 4N sodium hydroxide solution to be neutralized to PH in ice-water bath to be about 5 (is to use the sodium hydroxide solution of 0.5N at 2 o'clock instead to pH value); Separate out white mesna solid, filter, the solid that leaches is in room temperature vacuum-drying; Get the 11.8g product, yield 72.0%, purity is more than 96%.
Embodiment 4:
With 20.6g ethanoyl mesna, the 200ml2N ethanol solution of hydrogen chloride joins in the there-necked flask; Stirred overnight under nitrogen protection, filtration filtering solid, filtrating concentrating steamed and desolventized to such an extent that the lurid ethanoyl of 14.3g U.S.A takes charge of sour thick liquid; Add the 100ml Virahol, in heating reflux reaction under the nitrogen protection fully after, this sour aqueous isopropanol of U.S. department uses the sodium hydroxide solution of 4N to be neutralized to PH in ice-water bath to be about 5 (is to use the sodium hydroxide solution of 0.5N at 2 o'clock instead to pH value); Separate out white mesna solid, filter, the solid that leaches is in room temperature vacuum-drying; Get the 12.5g product, yield 76.2%, purity is more than 96%.
Embodiment 5:
With 20.6g ethanoyl mesna, the 200ml2N ethanol solution of hydrogen chloride joins in the there-necked flask, stirs; Logical nitrogen 30 minutes, reflux 5 hours, cooling; Filtration filtering solid, filtrating to concentrate to steam desolventizes to such an extent that the lurid U.S.A of 13.9g takes charge of sour thick liquid, and it is about 5 that adding 150ml ethanol uses the methanol solution of sodium methylate of 2N to be neutralized to PH in ice-water bath; Separate out white mesna solid, filter, the solid that leaches is in room temperature vacuum-drying; Get the 12.4g product, yield 75.6%, purity is more than 96%.
Embodiment 6:
With 20.6g ethanoyl mesna, the 200ml2N isopropanol solution of hydrogen chloride joins in the there-necked flask, stirs; Logical nitrogen 30 minutes, reflux 5 hours, cooling; Filtration filtering solid, filtrating to concentrate to steam desolventizes to such an extent that the lurid U.S.A of 14.0g takes charge of sour thick liquid, and it is about 5 that adding 100ml Virahol uses the methanol solution of sodium methylate of 2N to be neutralized to PH in ice-water bath; Separate out white mesna solid, filter, the solid that leaches is in room temperature vacuum-drying; Get the 13.5g product, yield 82.3%, purity is more than 96%.
Embodiment 7:
With 20.6g ethanoyl mesna, the 200ml2N ethanol solution of hydrogen chloride joins in the there-necked flask, stirs; Logical nitrogen 30 minutes, reflux 5 hours, cooling; Filter the filtering solid, filtrating concentrating steam desolventize the sour thick liquid of the lurid U.S. department of 13.9g, add 200ml ethanol and in ice-water bath, use the sodium hydroxide solution of 4N to be neutralized to PH to be about 5 (is to use the sodium hydroxide solution of 0.5N at 2 o'clock instead to pH value); Separate out white mesna solid, filter, the solid that leaches is in room temperature vacuum-drying; Get the 12.0g product, yield 73.2%, purity is more than 96%.
Embodiment 8:
With 20.6g ethanoyl mesna, the 200ml2N isopropanol solution of hydrogen chloride joins in the there-necked flask, stirs; Logical nitrogen 30 minutes, reflux 5 hours, cooling; Filter the filtering solid, filtrating concentrating steam desolventize the sour thick liquid of the lurid U.S. department of 14.0g, add the 150ml Virahol and in ice-water bath, use the sodium hydroxide solution of 4N to be neutralized to PH to be about 5 (is to use the sodium hydroxide solution of 0.5N at 2 o'clock instead to pH value); Separate out white mesna solid, filter, the solid that leaches is in room temperature vacuum-drying; Get 13.2g white solid product, yield 80.5%, purity is more than 96%.
Claims (11)
1. method for preparing mesna comprises:
(1) acyl group mesna II obtains the U.S. sour III of department of acyl group with the alcoholic solution acidifying of hydrogenchloride;
(2) the sour III alcoholysis of the U.S. department of acyl group obtains the U.S. sour IV of department;
(3) the U.S. sour IV of department obtains mesna formula I with the alkali neutralization
R wherein
1Be naphthenic base, phenyl or the substituted phenyl of 1 to 6 carbon atom straight chain or branched-chain alkyl, 3 to 8 carbon atoms, the substituting group of phenyl is selected from methyl, ethyl, methoxyl group, chlorine, bromine and nitro;
R
2Be the straight or branched alkyl of 1 to 6 carbon atom, the naphthenic base or the benzyl of 3 to 8 carbon atoms;
R
3Be H or C
1-C
4The straight or branched alkyl.
2. technology for preparing mesna comprises:
(1) acyl group mesna II filters the filtering solid with the alcoholic solution acidifying of hydrogenchloride, after filtrating concentrates evaporate to dryness, obtains the U.S. sour III of department of acyl group;
(2) the U.S. sour III of department of the acyl group that obtains in the step (1) is dissolved in alcoholysis forms the U.S. sour IV of department in the alcohol; The U.S. sour IV of department does not separate in alcoholysis liquid, directly with the alkali neutralization, obtains mesna I
Wherein: R
1Be C
1-C
6Straight or branched alkyl, C
3-C
8Naphthenic base, phenyl or substituted phenyl, the substituting group of phenyl is selected from methyl, ethyl, methoxyl group, chlorine, bromine and nitro;
R
2Be C
1-C
6Straight or branched alkyl, C
3-C
8Cycloalkyl group or benzyl;
R
3Be H or C
1-C
4The straight or branched alkyl.
3. according to the method for claim 1 or 2, R wherein
1Be C
1-C
4Straight chained alkyl.
4. according to the method for claim 1 or 2, R wherein
1Be methyl.
5. according to the method for claim 1 or 2, R wherein
2Be C
1-C
4The straight or branched alkyl.
6. according to the method for claim 1 or 2, R wherein
3Be C
1-C
4The straight or branched alkyl.
7. technology for preparing mesna comprises:
(1) with acyl group mesna II alcoholysis in the alcoholic solution of hydrogenchloride, filter the filtering solid, after filtrating concentrates evaporate to dryness, obtain the U.S. sour IV of department;
(2) the sour IV of U.S. department is dissolved in the alcohol, obtains mesna I with the alkali neutralization;
R wherein
1Be C
1-C
6Straight or branched alkyl, C
3-C
8Naphthenic base, phenyl or substituted phenyl, the substituting group of phenyl is selected from methyl, ethyl, methoxyl group, chlorine, bromine and nitro;
R
2Be C
1-C
6Straight or branched alkyl, C
3-C
8Naphthenic base or benzyl;
R
3Be H or C
1-C
4The straight or branched alkyl.
8. according to the method for claim 7, R wherein
1Be C
1-C
4Straight chained alkyl.
9. according to Claim 8 method, wherein R
1Be methyl.
10. according to the method for claim 7, R wherein
2Be C
1-C
4The straight or branched alkyl.
11. according to the method for claim 7, wherein R
3Be C
1-C
4The straight or branched alkyl.
Priority Applications (1)
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|---|---|---|---|
| CN200810132528A CN101628887B (en) | 2008-07-16 | 2008-07-16 | Method for preparing mesna |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200810132528A CN101628887B (en) | 2008-07-16 | 2008-07-16 | Method for preparing mesna |
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| Publication Number | Publication Date |
|---|---|
| CN101628887A CN101628887A (en) | 2010-01-20 |
| CN101628887B true CN101628887B (en) | 2012-10-03 |
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ID=41574186
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Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN109232337B (en) * | 2017-07-11 | 2021-02-05 | 四川科瑞德凯华制药有限公司 | Process for the purification of mesna |
| CN111187189A (en) * | 2020-03-10 | 2020-05-22 | 姚文刚 | Method for preparing mercapto carboxylic acid or derivatives thereof by aminolysis of thiourea carboxylic acid or derivatives thereof |
| CN115215776B (en) * | 2022-08-04 | 2023-10-03 | 江苏梦得新材料科技有限公司 | Preparation method and application of sodium polydithio-di-ethane sulfonate |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BE842665A (en) * | 1976-06-08 | 1976-12-08 | PROCESS FOR THE PREPARATION OF THIALKANE ALKALINE SULPHONATES | |
| CS252564B1 (en) * | 1985-06-17 | 1987-09-17 | Jiri Jary | Method of 2-mercapoethaneulphonic acid production |
-
2008
- 2008-07-16 CN CN200810132528A patent/CN101628887B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BE842665A (en) * | 1976-06-08 | 1976-12-08 | PROCESS FOR THE PREPARATION OF THIALKANE ALKALINE SULPHONATES | |
| CS252564B1 (en) * | 1985-06-17 | 1987-09-17 | Jiri Jary | Method of 2-mercapoethaneulphonic acid production |
Non-Patent Citations (2)
| Title |
|---|
| 赵平等.美司钠合成工艺的改进.《贵阳医学院学报》.2006,第31卷(第6期), * |
| 韩玲玲,成秀俊.2-巯基乙磺酸钠的制备方法.《中国现代应用药学》.1996,第13卷(第2期), * |
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