CN104744355A - Method for preparing torasemide and derivative thereof - Google Patents
Method for preparing torasemide and derivative thereof Download PDFInfo
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- CN104744355A CN104744355A CN201310749982.XA CN201310749982A CN104744355A CN 104744355 A CN104744355 A CN 104744355A CN 201310749982 A CN201310749982 A CN 201310749982A CN 104744355 A CN104744355 A CN 104744355A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
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Abstract
The invention belongs to the field of medicine synthesis and provides a method for preparing torasemide and a derivative thereof. The method comprises the following steps: by taking N-alkyl-1H-imidazole-1-formamide as the raw material, reacting with 4-(m-toluene amino) pyridine-3-sulfamide to obtain the torasemide and the derivative thereof. The method for preparing the torasemide and the derivative thereof has the advantages of low toxin, low pollution, high safety, short production period and simple operation and is suitable for industrial production.
Description
Technical field
The invention belongs to technical field of medicine synthesis, be specifically related to the preparation method of a kind of torasemide and derivative thereof.
Background technology
(commodity are called torasemide
developed by Nycomed pharma company of Switzerland, be used for the treatment of acute renal failure, chronic kidney hypofunction and essential hypertension.Within 1993, first in Germany's listing, next year goes on the market in the U.S..Torasemide is high-ceiling diuretics, and the mechanism of action is similar to Furosemide, mainly acts on kidney ascending thick limb of Henle's loop, suppress the active of Cl-heavily to absorb, the heavily absorption of medullary loop ascending branch NaCl is reduced, kidney medulla osmotic pressure reduces, in tube chamber, osmotic pressure increases, the concentration process of interference urine.With other medullary loop hydragog(ue) unlike, torasemide without effect, thus can not cause the discharge of K+ to increase proximal tubule position.20 clinical application for many years confirm, torasemide indication is wide, diuretic properties is powerful rapidly and lasting, adverse reaction rate is low, is the efficient diuretic(s) of a class be worthy to be popularized clinically.
The chemical name of torasemide is N-sec.-propyl-[4-(3-MethYlphenylamino) pyridine-3-sulfoamido] methane amide.Patent documentation EP618209, US2516025, US6674794, US4244950, CA1070313A, CN1423558 etc. report the synthesis of torasemide, its intermediate and derivative thereof, other documents relating to its synthetic method also have " study on the synthesis of Novel blood pressure-reducing hydragog(ue)-torasemide " (Chinese pharmaceutical chemistry magazine, 2002,12 (4), 219-224), " torasemide study on the synthesis " (fine-chemical intermediate, 2009,39 (6), 29-30) etc.These synthetic methods are all be that raw material and intermediate 4-(m-toluino) pyridine-3-sulfuryl amine reaction generate torasemide with n-Isopropyl isocyanate, as shown below:
The shortcoming of the method is that n-Isopropyl isocyanate toxicity is very large, has intense stimulus, can cause pulmonary edema to respiratory tract, to eye and skin also irritant, can cause and burn, and its price is very expensive.N-Isopropyl isocyanate is also inflammable, brings certain potential safety hazard to production.
Therefore, a kind of method preparing torasemide developing hypotoxicity, low stain, security high is very necessary.
Summary of the invention
The object of the invention is to the defect overcoming prior art, according to the theory of Green Chemistry, provide a kind of method preparing torasemide and derivative thereof of improvement, the method hypotoxicity, low stain, security are high.
Shown in the following reaction formula of method preparing torasemide and derivative (I) thereof provided by the invention:
Wherein, R
1, R
2be selected from hydrogen, saturated or undersaturated C independently of one another
1~ C
10straight-chain alkyl, saturated or undersaturated C
1~ C
10branched hydrocarbyl, C
3~ C
6cycloalkyl, or NR
1r
2be five yuan ~ seven yuan nitrogen heterocyclics;
Preferably, R
1for hydrogen, R
2for C
1~ C
6straight or branched alkyl, or NR
1r
2be five yuan ~ seven yuan nitrogen heterocyclics;
More preferably, R
1for hydrogen, R
2for ethyl, sec.-propyl or normal-butyl, or NR
1r
2for penta azacyclo.
Described method is preferably carried out under acid binding agent exists, acid binding agent can be organic bases, as triethylamine, diethylamine, diisopropylethylamine, pyridine, 2, one or more in 6-lutidine, N-methylmorpholine, N-ethylmorpholine, DMAP (DMAP), N, N-diisopropyl ethyl amine (DIPEA); Acid binding agent can be also mineral alkali, as one or more in sodium carbonate, sodium bicarbonate, salt of wormwood, saleratus, potassium tert.-butoxide, sodium tert-butoxide, potassium hydroxide, sodium hydroxide.
The reaction solvent of described reaction is polar solvent, one or more in particular methanol, ethanol, Virahol, n-propyl alcohol, isopropylcarbinol, propyl carbinol, ethyl acetate, butylacetate, acetone, acetonitrile, methylene dichloride, tetrahydrofuran (THF), N, N-dimethylformamide, pyridine, dioxane, methyl-sulphoxide, water.
The temperature of reaction of described reaction is between room temperature to 100 DEG C.
Beneficial effect of the present invention: the preparation method of torasemide provided by the invention and derivative thereof with N-alkyl-1H-imidazoles-1-methane amide (III) for raw material, target product torasemide or derivatives thereof (I) is obtained by reacting with 4-(m-toluino) pyridine-3-sulphonamide (II), reaction conditions is gentle, easy and simple to handle, and the reaction times shortens greatly, production production capacity promotes greatly.Without the need to using the isocyanic ester that height is malicious, inflammable, pungency is strong in reaction process, security is high, environmental protection.Preparation method provided by the invention is applicable to industrial application.
Specific embodiment
Following embodiment is preferred embodiment in order to demonstrate the invention, the protection domain be not meant to limit the present invention.
In all embodiments, TLC is silica gel H SGF254 plate, and ultimate analysis adopts Elementar Vario ELIII type elemental analyser, and mass spectrum adopts AGILENT1100LC/MS mass spectrograph,
1h-NMR adopts BRUKER AV-500 type nuclear magnetic resonance analyser, and fusing point adopts YRT-3 melting point apparatus.
The preparation of embodiment 1N-ethyl-[4-(3-MethYlphenylamino) pyridine-3-sulfoamido] methane amide
500mL ethanol is joined in 1L there-necked flask, add N-ethyl-1H-imidazoles-1-methane amide (69.58g, 0.50 mol), 4-(3-toluino) pyridine-3-sulphonamide (105.3g, 0.40mol) successively, mix under stirring.Reflux, reaction 7-8 hour, underpressure distillation, is concentrated into dry.Residue adds strong aqua (25-28%) 125mL and purified water 500mL, and stir lower heating for dissolving, after clarifying completely, add gac 1.0g, 15-30min is stirred in insulation decolouring.Filtered while hot, filtrate cools to 40-50 DEG C, and filtrate is neutralized to PH=6-7 with Glacial acetic acid, is cooled to 10 ~ 20 DEG C, filters after crystallization 4h.Filter cake purified water washs 2 times.By wet product forced air drying 6-8 hour at 60 ~ 65 DEG C.Weigh, weight is 80g, and yield is 60.0%.ESI-MS (m/z): 335.4 [M+H]
+; Fusing point: 151.0-151.7 DEG C;
1h-NMR (DMSO
d-6, 500MHz) and δ 1.012 (3H, t), 2.143 (3H, s), 3.752 (2H, m), 7.236 (4H, m), 7.491 (1H, m), 8.227 (1H, m), 8.684 (1H, m), 3.015 (1H, s, disappears after heavy water exchanges), 5.714 (1H, s, heavy water disappears after exchanging), 9.623 (1H, s disappear after heavy water exchanges).
The preparation of embodiment 2N-ethyl-[4-(3-MethYlphenylamino) pyridine-3-sulfoamido] methane amide
500mL ethanol is joined in 1L there-necked flask, add N-ethyl-1H-imidazoles-1-methane amide (69.58g, 0.50mol), 4-(3-toluino) pyridine-3-sulphonamide (105.3g, 0.40mol) and pyridine (79.1g successively, 1.0mol), mix under stirring.Reflux, reaction 4-6 hour.TLC monitors, and after having reacted, underpressure distillation, is concentrated into dry.Residue adds strong aqua (25-28%) 125mL and purified water 500mL, and stir lower heating for dissolving, after clarifying completely, add gac 1.0g, 15-30min is stirred in insulation decolouring.Filtered while hot, filtrate cools to 40-50 DEG C, and filtrate is neutralized to PH=6-7 with Glacial acetic acid, is cooled to 10 ~ 20 DEG C, filters after crystallization 4h.Filter cake purified water washs 2 times.By wet product forced air drying 6-8 hour at 60 ~ 65 DEG C.Weigh, weight is 120.4g, and yield is 90.0%.ESI-MS (m/z): 335.4 [M+H]
+; Fusing point: 151.0-151.7 DEG C;
1h-NMR (DMSO
d-6, 500MHz) and δ 1.012 (3H, t), 2.143 (3H, s), 3.752 (2H, m), 7.236 (4H, m), 7.491 (1H, m), 8.227 (1H, m), 8.684 (1H, m), 3.015 (1H, s, disappears after heavy water exchanges), 5.714 (1H, s, heavy water disappears after exchanging), 9.623 (1H, s disappear after heavy water exchanges).
The preparation of embodiment 3N-sec.-propyl-[4-(3-MethYlphenylamino) pyridine-3-sulfoamido] methane amide
500mL acetone is joined in 1L there-necked flask, add N-sec.-propyl-1H-imidazoles-1-methane amide (76.60g, 0.50mol), 4-(3-toluino) pyridine-3-sulphonamide (105.3g, 0.40mol) and triethylamine (101.2g successively, 1.0mol), mix under stirring.Be heated to 40-50 DEG C, reaction 4-6 hour.TLC monitors, and after reacting completely, underpressure distillation, is concentrated into dry.Residue adds strong aqua (25-28%) 125mL and purified water 500mL, and stir lower heating for dissolving, after clarifying completely, add gac 1.0g, 15-30min is stirred in insulation decolouring.Filtered while hot, filtrate cools to 40-50 DEG C, and filtrate is neutralized to PH=6-7 with Glacial acetic acid, is cooled to 10 ~ 20 DEG C, filters after crystallization 4h.Filter cake purified water washs 2 times.By wet product forced air drying 6-8 hour at 60 ~ 65 DEG C.Weigh, weight is 127.3g, and yield is 91.3%.ESI-MS (m/z): 349.4 [M+H]
+; Fusing point: 163.5-164.1 DEG C;
1h-NMR (DMSO
d-6, 500MHz) and δ 1.043 (6H, d), δ 2.337 (3H, s), δ 3.688 (1H, m), δ 6.579 (1H, s disappear after heavy water exchanges), 7.012 (1H, d), 7.112 (3H, m), 7.366 (1H, m), 8.247 (1H, d), 8.680 (1H, s), 9.001 (1H, s, heavy water disappears after exchanging), 11.191 (1H, s disappear after heavy water exchanges).
The preparation of embodiment 4N-normal-butyl-[4-(3-MethYlphenylamino) pyridine-3-sulfoamido] methane amide
500mL acetonitrile is joined in the there-necked flask of 1L, add N-positive definite base-1H-imidazoles-1-methane amide (83.60g, 0.50mol), 4-(m-toluino) pyridine-3-sulphonamide (105.3g, 0.40mol) and DMAP(122.2g, 1.0mol), mix under stirring.Then 90-100 DEG C is heated to, reaction 4-6 hour.TLC monitors, and after reacting completely, underpressure distillation, is concentrated into dry.Residue adds strong aqua (25-28%) 125mL and purified water 500mL, and stir lower heating for dissolving, after clarifying completely, add gac 1.0g, 15-30min is stirred in insulation decolouring.Filtered while hot, filtrate cools to 40-50 DEG C, and filtrate is neutralized to PH=6-7 with Glacial acetic acid, is cooled to 10 ~ 20 DEG C, filters after crystallization 4h.Filter cake purified water washs 2 times.By wet product at 60 ~ 65 DEG C, forced air drying 6-8 hour.Weigh, weight is 128.0g.Yield 88.3%.ESI-MS (m/z): 363.4 [M+H]
+;
1h-NMR (DMSO
d-6, 500MHz) and δ 0.886 (3H, m), 1.198 (2H, m), 1.238 (2H, m), 1.439 (2H, m), 2.372 (3H, s), 6.936-7.345 (5H, m), 8.032 (1H, d), 8.566 (1H, s), 3.089 (2H, s disappear after heavy water exchanges), 9.204 (1H, s disappear after heavy water exchanges).
Embodiment 5N-pyrrolidyl--the preparation of [4-(3-MethYlphenylamino) pyridine-3-sulfoamido] methane amide
500mL acetonitrile is joined in the there-necked flask of 1L, add (1H-imidazoles-1-base) (pyrrolidin-1-yl) ketone (82.60g, 0.50mol), 4-(m-toluino) pyridine-3-sulphonamide (105.3g, 0.40mol) with triethylamine (101.2g, 1.0mol), mix under stirring.Then 90-100 DEG C is heated to, reaction 4-6 hour.TLC monitors, and after reacting completely, underpressure distillation, is concentrated into dry.Residue adds strong aqua (25-28%) 125mL and purified water 500mL, and stir lower heating for dissolving, after clarifying completely, add gac 1.0g, 15-30min is stirred in insulation decolouring.Filtered while hot, filtrate cools to 40-50 DEG C, and filtrate is neutralized to PH=6-7 with Glacial acetic acid, is cooled to 10 ~ 20 DEG C, filters after crystallization 4h.Filter cake purified water washs 2 times.By wet product at 60 ~ 65 DEG C, forced air drying 6-8 hour.Weigh, weight is 122.5g.Yield 85.0%.ESI-MS (m/z): 361.1 [M+H]
+;
1h-NMR (DMSO
d-6, 500MHz) and δ 1.697 (4H, m), 2.254 (3H, s), 3.187 (4H, m), (6.890-7.510 5H, m), 8.498 (1H, d), 8.754 (1H, s), 3.769 (1H, s disappear after heavy water exchanges), 9.315 (1H, s disappear after heavy water exchanges).
Claims (9)
1. prepare a method for torasemide and derivative (I) thereof, it is characterized in that the compound shown in the compound shown in Formula Il I and formula II is reacted:
Wherein, R
1, R
2be selected from hydrogen, saturated or undersaturated C independently of one another
1~ C
10straight-chain alkyl, saturated or undersaturated C
1~ C
10branched hydrocarbyl, C
3~ C
6cycloalkyl, or NR
1r
2be five yuan ~ seven yuan nitrogen heterocyclics.
2. method according to claim 1, is characterized in that R
1for hydrogen, R
2for sec.-propyl, ethyl or normal-butyl.
3. method according to claim 1, is characterized in that NR
1r
2for penta azacyclo.
4. method according to claim 1, is characterized in that reaction is carried out under acid binding agent exists.
5. method according to claim 1, it is characterized in that acid binding agent is organic bases, preferred triethylamine, diethylamine, diisopropylethylamine, pyridine, 2, one or more in 6-lutidine, N-methylmorpholine, N-ethylmorpholine, DMAP (DMAP), N, N-diisopropyl ethyl amine (DIPEA).
6. method according to claim 1, is characterized in that acid binding agent is mineral alkali, one or more in preferred sodium carbonate, sodium bicarbonate, salt of wormwood, saleratus, potassium tert.-butoxide, sodium tert-butoxide, potassium hydroxide, sodium hydroxide.
7. method according to claim 1, is characterized in that reacting and carries out in polar solvent.
8. method according to claim 7, it is characterized in that one or more that polar solvent is selected from methyl alcohol, ethanol, Virahol, n-propyl alcohol, isopropylcarbinol, propyl carbinol, ethyl acetate, butylacetate, acetone, acetonitrile, methylene dichloride, tetrahydrofuran (THF), N, N-dimethylformamide, pyridine, dioxane, methyl-sulphoxide, water.
9. method according to claim 1, is characterized in that described reaction is carried out under any condition between room temperature to 100 DEG C.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110054647A (en) * | 2019-05-23 | 2019-07-26 | 上海勋和医药科技有限公司 | Torasemide phosphoric acid ester prodrug, preparation method and composition |
| CN115010659A (en) * | 2022-06-22 | 2022-09-06 | 南京正科医药股份有限公司 | New impurity reference substance of torasemide and preparation method thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102702089A (en) * | 2012-06-30 | 2012-10-03 | 连云港杰瑞药业有限公司 | Method for preparing high-purity torasemide and crystal form I thereof |
-
2013
- 2013-12-31 CN CN201310749982.XA patent/CN104744355A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102702089A (en) * | 2012-06-30 | 2012-10-03 | 连云港杰瑞药业有限公司 | Method for preparing high-purity torasemide and crystal form I thereof |
Non-Patent Citations (2)
| Title |
|---|
| MICHAEL P. WINTERS ET AL.: "Carboxylic acid bioisosteres acylsulfonamides, acylsulfamides, and sulfonylureas as novel antagonists of the CXCR2 receptor", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
| 许小聪等: "N,N’-羰基二咪唑作为活化剂在高分子合成中的研究进展", 《高分子通报》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110054647A (en) * | 2019-05-23 | 2019-07-26 | 上海勋和医药科技有限公司 | Torasemide phosphoric acid ester prodrug, preparation method and composition |
| WO2020233289A1 (en) * | 2019-05-23 | 2020-11-26 | 上海勋和医药科技有限公司 | Torasemide phosphate prodrug, preparation method therefor and composition having same |
| CN110054647B (en) * | 2019-05-23 | 2021-06-15 | 上海勋和医药科技有限公司 | Torasemide phosphate prodrugs, preparation method and composition thereof |
| CN115010659A (en) * | 2022-06-22 | 2022-09-06 | 南京正科医药股份有限公司 | New impurity reference substance of torasemide and preparation method thereof |
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