CN100457711C - Prepn of 2-methyl-3-nitrophenylalkylamine derivative or its salt - Google Patents
Prepn of 2-methyl-3-nitrophenylalkylamine derivative or its salt Download PDFInfo
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- CN100457711C CN100457711C CNB2005100271644A CN200510027164A CN100457711C CN 100457711 C CN100457711 C CN 100457711C CN B2005100271644 A CNB2005100271644 A CN B2005100271644A CN 200510027164 A CN200510027164 A CN 200510027164A CN 100457711 C CN100457711 C CN 100457711C
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Abstract
The present invention is preparation process of 2-methyl-3-nitrophenylalkylamine derivative or its salt. The material 2-methyl-3-nitrophenylalkyl acid is first reduced with metal boron as reductant in the presence of Lewis acid, and through further sulfonylation and amination, the 2-methyl-3-nitrophenylalkylamine derivative is obtained. The 2-methyl-3-nitrophenylalkylamine derivative may be further reacted with conventional acid to produce salt as required. The present invention is simple, convenient, low in cost and suitable for use in both lab and industrial production.
Description
Technical field
The present invention relates to organic chemistry filed, the preparation method of particularly a kind of 2-methyl-3-nitro phenylalkyl sulfonamide derivatives or its salt.
Background technology
2-methyl-3-nitro phenylalkyl sulfonamide derivatives (I) compound is widely used in chemical industry and field of medicaments as a kind of important organic synthesis intermediate.
In the formula
N is 1 or 2,
R
1And R
2Expression hydrogen, straight or branched C
1-C
5The phenyl that alkyl, benzyl or expression can be replaced by alkyl.
At present, the preparation method of 2-methyl-3-nitro phenylalkyl sulfonamide derivatives (I) mainly contains following several:
1) European patent EP 0113964 has been described and used borane reduction agent reducing amide in tetrahydrofuran (THF), prepares compound (I) (n=2, R
1, R
2Be hydrogen, straight or branched C
1-C
5Alkyl, benzyl).
2) document J.Med.Chem.1985,28,10,1533-1536 has described and used borane reduction agent reductase 12-methyl-3-nitro phenylformic acid in tetrahydrofuran (THF), prepares compound (III) (n=2, R
1, R
2Be the n-propane base).
With regard to industrial production, the method of above-mentioned bibliographical information has significant disadvantages: they have all been used and have cost an arm and a leg, the borane reduction agent of severe toxicity, this reductive agent self character has determined reaction needed to operate under absolute anhydrous condition, strict to reaction system, still operate in the laboratory in industrial all being difficult to.
Summary of the invention
In order to overcome the defective of prior art, the object of the present invention is to provide a kind of economy, safety and prepare the method for 2-methyl-3-nitro phenylalkyl sulfonamide derivatives (I) or its salt easily.
With 2-methyl-3-nitro phenylalkyl acid (II) is that raw material reduces through the metallo-borane reductive agent in the presence of lewis acidic, obtains intermediate 2-methyl-3-nitro phenylalkyl alcohol (III); Compound (III) obtains the 2-methyl-3-nitro octadecyloxy phenyl ester (V) of the sulfonic acid of R ' replacement through sulfonylation, compound (V) again with R
1, R
2Replacement amine (VI) takes place to replace to send out and should obtain 2-methyl-3-nitro phenylalkyl sulfonamide derivatives (I), and compound (I) can obtain corresponding salt with the conventional acid reaction as required.
The compound of 2-methyl-3-nitro phenylalkyl sulfonamide derivatives (I), n represents 1 or 2 in the formula; R
1And R
2
Represent hydrogen, straight or branched C respectively
1-C
5Alkyl, benzyl or expression phenyl or alkyl phenyl; The preparation method of compound of the present invention (I) adopts following reaction to carry out,
N, R in the formula
1And R
2Has the implication that above-claimed cpd (I) is given, R ' expression straight or branched C
1-C
4Alkyl, straight or branched C
1-C
4Haloalkyl, phenyl or alkyl phenyl, this method comprises following steps:
(1) 2-methyl-3-nitro phenylalkyl acid (II) adopts the reduction of metal boron reductive agent to obtain 2-methyl 3-nitrophenyl alkyl alcohol (III) in the presence of lewis acidic in organic solvent;
(2) compound (III) is under the effect of organic basic material and R ' SO
2Cl (IV) carries out the 2-methyl-3-nitro octadecyloxy phenyl ester (V) that sulfonylation obtains the sulfonic acid of R ' replacement in organic solvent commonly used;
(3) compound (V) and R
1, R
2The amine (VI) that replaces carries out amination reaction and obtains 2-methyl-3-nitro phenylalkyl sulfonamide derivatives (I) in organic solvent commonly used.
Preferably, R
1And/or R
2Be n-propyl; More preferably n represents 2.
Preferably, R ' expression p-methylphenyl, methyl or trifluoromethyl.
The first step reduction reaction, described metal boron reductive agent is selected from sodium borohydride, lithium borohydride, POTASSIUM BOROHYDRIDE, and described Lewis acid plays catalytic effect to reduction reaction, and Lewis acid commonly used is boron trifluoride or aluminum chloride; The organic solvent that reaction is adopted is lower alcohol (as: methyl alcohol, ethanol, propyl alcohol, Virahol, butanols etc.), water, aromatic hydrocarbon (as toluene, dimethylbenzene etc.), ethers (as tetrahydrofuran (THF), glycol dimethyl ether, dioxan etc.), halogenated alkane (methylene dichloride, chloroform, 1,2-ethylene dichloride etc.) etc.
The consumption of described reaction reductive agent can be the reductive agent of compound (II) use equimolar amount to the 6 times molar weight of 1 molar weight, often is adopted as the reductive agent of 1 molar weight to 3 times molar weight.
The second step sulfonylation; the compound that reduction reaction obtains (III) uses one or more organic basic materials as acid-binding agent with compound (IV) reaction; be beneficial to the carrying out that react, organic basic material commonly used is triethylamine, pyridine, N-methylmorpholine, quinoline, diisopropyl ethyl amine etc.Reaction solvent is lower alcohol (as: methyl alcohol, ethanol, propyl alcohol, Virahol, butanols etc.), ketone (as acetone etc.), aromatic hydrocarbon (as toluene, dimethylbenzene etc.), ethers (as tetrahydrofuran (THF), glycol dimethyl ether, dioxan etc.), halogenated alkane (methylene dichloride, chloroform, 1,2-ethylene dichloride etc.), dimethyl formamide, N,N-DIMETHYLACETAMIDE, dimethyl sulfoxide (DMSO), acetonitrile etc.; The ratio of the amount of reactant is that the compound (III) of 1 molar weight uses the compound (IV) that waits 1 that to measure 3 times of molar weights, is preferably the compound (IV) of 1 molar weight to 2 times molar weight.
The 3rd step amination reaction obtains compound (V) and replaces amine (VI) reaction by sulfonylation, prepares target compound (I).Reaction solvent is lower alcohol (as: methyl alcohol, ethanol, propyl alcohol, Virahol, butanols etc.), aromatic hydrocarbon (as toluene, dimethylbenzene etc.), ethers (as tetrahydrofuran (THF), glycol dimethyl ether, dioxan etc.), dimethyl formamide, N,N-DIMETHYLACETAMIDE, dimethyl sulfoxide (DMSO), acetonitrile etc.; The amount of reactant often adopts the compound (VI) of 5 molar weights to 15 molar weights than the compound (VI) of the compound that can be 1 molar weight (V) use 1 molar weight to 20 molar weight.
The derivative (I) of the present invention's preparation can obtain corresponding salt with the conventional acid prepared in reaction as required.These conventional acids can be mineral acid, example hydrochloric acid, sulfuric acid, phosphoric acid etc.; Organic acid such as toxilic acid, fumaric acid, oxalic acid, tartrate, citric acid etc.
Method of the present invention is compared with the method for above-mentioned bibliographical information, the replacement of metal boron reductive agent costs an arm and a leg, the borane reduction agent of severe toxicity owing to adopt, make operation more simple and convenient (need not absolute anhydrous condition), it is a kind of method for preparing 2-methyl-3-nitro phenylalkyl sulfonamide derivatives (I) or its salt economically, not only be fit to the laboratory and prepare on a small quantity, also be fit to large-scale industrialization production.
Specific implementation method
Further illustrate content of the present invention below in conjunction with embodiment, these embodiment are not to be restriction to the scope of the invention or spirit.
The preparation of embodiment 1 2-methyl-3-nitro phenylcarbinol
With 2-methyl-3-nitro phenylformic acid (45.3g 0.25mol) is dissolved in the 300ml tetrahydrofuran solution, and low temperature stirs down, add sodium borohydride (12.3g, 0.325mol), drip again boron trifluoride diethyl ether solution (44ml, 0.35mol).Stirring reaction is complete.Under the ice bath, in reaction solution, drip water 450mL.Tetrahydrofuran solvent is removed in decompression, with the residuum of dichloromethane extraction decompression, and the saturated common salt washing, anhydrous sodium sulfate drying removes and desolvates, and promptly obtains yellow 2-methyl-3-nitro phenylcarbinol (37.2g, 89%).
The preparation of embodiment 2 2-methyl-3-nitro phenylcarbinols
With 2-methyl-3-nitro phenylformic acid (48g, 0.265mol) be dissolved in the 300ml diethylene glycol dimethyl ether solution, cold going under the stirring, add sodium borohydride (12.5g, 0.33mol), when treating that temperature is reduced to 5 ℃, drip aluminum chloride (16.8g, 0.126mol) diethylene glycol dimethyl ether 60mL solution, add the back stirring at room up to reacting completely.Removal of solvent under reduced pressure after the cooling, is poured in the frozen water of the 500mL that contains the 70mL concentrated hydrochloric acid, separates out solid, filters, and washing gets crude product, and ethyl alcohol recrystallization obtains yellow 2-methyl-3-nitro phenylcarbinol (38g, 86%).
The preparation of embodiment 3 methylsulfonic acid 2-methyl-3-nitro benzyl esters
With 2-methyl-3-nitro phenylcarbinol (36g 0.22mol) dissolves in the 300mL methylene dichloride, and add triethylamine (43.9mL, 0.33mol).Ice bath stirs down, and the dropping methylsulfonyl chloride (18.8mL, 0.24mol), stirring at room 0.5 hour.Add an amount of saturated ammonium chloride solution cancellation reaction, layering, water layer with an amount of dichloromethane extraction once merges organic layer.Washing, 5% sodium bicarbonate is washed, saturated common salt washing, anhydrous sodium sulfate drying.Remove and to desolvate, oil pump drain methylsulfonic acid 2-methyl-3-nitro benzyl ester (47.4g, 88%).
Embodiment 4 N, the preparation of N-di-(2-methyl-3-nitro) benzylamine
With methylsulfonic acid 2-methyl-3-nitro benzyl ester (47g 0.19mol) is suspended in the 25mL ethanol, and add di-n-propylamine (262mL, 1.9mol), reflux 2.5h.Steam solvent, residuum is dissolved in an amount of ethyl acetate, washing, and 5% sodium bicarbonate is washed, saturated common salt washing, anhydrous sodium sulfate drying.Concentrate the back column chromatography for separation, obtain N, N-di-(2-methyl-3-nitro) benzylamine (38.0g, 80%)
Embodiment 5 N, the preparation of N-di-(2-methyl-3-nitro) benzylamine hydrochloride
With N, (35g 0.14mol) is dissolved in the aqueous hydrochloric acid that 50mL concentration is 3N N-di-(2-methyl-3-nitro) benzylamine, and stirring, filtration, drying obtain N, N-di-(2-methyl-3-nitro) benzylamine hydrochloride (34.9g, 87%).
Embodiment 6 N, the preparation of N-di-(2-methyl-3-nitro) benzylamine tartrate
With N, and N-di-(2-methyl-3-nitro) benzylamine (18g, 0.072mol) and tartrate (12g, 0.08mol) be dissolved in the 25mL ethanolic soln, stirring, filtration, drying obtain N, N-di-(2-methyl-3-nitro) benzylamine tartrate (23.9g, 83%).
The preparation of embodiment 7 2-(2-methyl-3-nitro phenyl) alcoholic acid
(40.0g 0.2mol) is dissolved in the 250mL tetrahydrofuran (THF), cold going under the stirring with 2-(2-methyl-3-nitro phenyl) acetate, the adding sodium borohydride (10g, 0.26mol), when treating after adding that temperature is reduced to 5 ℃, the diethyl ether solution of dropping boron trifluoride (35.2ml, 0.28mol).The postcooling that reacts completely drips 400 water mL in reaction solution.Tetrahydrofuran (THF) is removed in decompression, with the residuum of dichloromethane extraction decompression, and the saturated common salt washing, anhydrous sodium sulfate drying removes and desolvates, and promptly obtains light yellow oil 2-(2-methyl-3-nitro phenyl) ethanol (37g, 99%).
The preparation of embodiment 8 methylsulfonic acid 2-(2-methyl-3-nitro phenyl) ethyl ester
With 2-(2-methyl-3-nitro phenyl) ethanol (22.12g 0.122mol) dissolves in the 200mL methylene dichloride, and add triethylamine (25.5mL, 0.183mol).Ice bath stirs down, and (10.45mL 0.134mol), after stirring at room reacts completely, adds an amount of saturated ammonium chloride solution cancellation reaction, layering, an amount of dichloromethane extraction of water layer, merging organic layer to drip methylsulfonyl chloride.Washing, 5% sodium bicarbonate is washed, saturated common salt washing, anhydrous sodium sulfate drying.Remove and desolvate, oven dry obtains methylsulfonic acid 2-(2-methyl-3-nitro phenyl) ethyl ester (29.38g, 93%).
The preparation of embodiment 9 tosic acid 2-(2-methyl-3-nitro phenyl) ethyl ester
With 2-(2-methyl-3-nitro phenyl) ethanol (20g 0.11mol) dissolves in the 200mL methylene dichloride, and add pyridine (44.4mL, 0.55mol).Ice bath stirs down, and the dropping Tosyl chloride (25.3g, 0.132mol), stirred overnight at room temperature.Add an amount of saturated ammonium chloride solution cancellation reaction, layering, water layer with an amount of dichloromethane extraction once merges organic layer.Washing, 5% sodium bicarbonate is washed, saturated common salt washing, anhydrous sodium sulfate drying.Remove and to desolvate, oil pump drain tosic acid 2-(2-methyl-3-nitro phenyl) ethyl ester (31g, 84%).
The preparation of embodiment 10 trifluoromethanesulfonic acid 2-(2-methyl-3-nitro phenyl) ethyl ester
With 2-(2-methyl-3-nitro phenyl) ethanol (18.1g 0.1mol) dissolves in the 200mL methylene dichloride, and add pyridine (40.4mL, 0.5mol).Ice bath stirs down, and (28.5g 0.11mol), after stirring at room reacts completely, adds an amount of saturated ammonium chloride solution cancellation reaction, layering, an amount of dichloromethane extraction of water layer, merging organic layer to drip trifluoromethanesulfchloride chloride.Washing, 5% sodium bicarbonate is washed, saturated common salt washing, anhydrous sodium sulfate drying.Remove and to desolvate, oil pump drain trifluoromethanesulfonic acid 2-(2-methyl-3-nitro phenyl) ethyl ester (23.8g, 76%).
Embodiment 11 N, the preparation of N-di-2-(2-methyl-3-nitro phenyl) ethamine
With methylsulfonic acid 2-methyl-3-nitro benzyl ester (29.38g 0.113mol) is suspended in the 15mL ethanol, and add di-n-propylamine (156mL, 1.13mol).Heating reflux reaction steams solvent, and residuum is dissolved in an amount of ethyl acetate, washing, and 5% sodium bicarbonate is washed, saturated common salt washing, anhydrous sodium sulfate drying.Concentrate the back underpressure distillation, collect 140-145 ℃/0.6mmHg cut, obtain N, N-di-2-(2-methyl-3-nitro phenyl) ethamine (24.0g, 85%).
The preparation of embodiment 12 N-n-propyl-2-(2-methyl-3-nitro phenyl) ethamine
With methylsulfonic acid 2-methyl-3-nitro phenylethylester (20g 0.077mol) is suspended in the 20mL ethanol, and add Tri N-Propyl Amine (64mL, 0.77mol), reflux 10h.Steam solvent, residuum is dissolved in an amount of ethyl acetate, washing, and 5% sodium bicarbonate is washed, saturated common salt washing, anhydrous sodium sulfate drying.After concentrating, the post separation obtains N-n-propyl-2-(2-methyl-3-nitro phenyl) ethamine (13.8g, 81%)
The preparation of embodiment 13 N-benzyl-N-n-propyl-2-(2-methyl-3-nitro phenyl) ethamine
With N-benzyl Tri N-Propyl Amine (25.7g, 0.17mol) and methylsulfonic acid 2-methyl-3-nitro phenylethylester (21.68g, 0.0837mol) dissolve in the 100mL dehydrated alcohol, reflux 18h, primitive reaction is complete, removes and desolvates, and post separates, obtain light yellow oil N-benzyl-N-n-propyl-2-(2-methyl-3-nitro phenyl) ethamine (20.1g, 77%).
Embodiment 14 N, the preparation of N-di-2-(2-methyl-3-nitro phenyl) ethamine
With tosic acid 2-(2-methyl-3-nitro phenyl) ethyl ester (29g 0.087mol) is suspended in the 15mL ethanol, and add di-n-propylamine (119mL, 0.87mol).Reflux is spent the night.Steam solvent, residuum is dissolved in an amount of ethyl acetate, washing, and 5% sodium bicarbonate is washed, saturated common salt washing, anhydrous sodium sulfate drying.Concentrate the back underpressure distillation, collect 140-145 ℃/0.6mmHg cut, obtain N, N-di-2-(2-methyl-3-nitro phenyl) ethamine (16.53g, 76%).
Embodiment 15 N, the preparation of N-di-2-(2-methyl-3-nitro phenyl) ethylamine hydrochloride
With N, (29.38g 0.113mol) is dissolved in the aqueous hydrochloric acid that 40mL concentration is 3N N-di-2-(2-methyl-3-nitro phenyl) ethamine, and stirring, filtration, drying obtain N, N-di-2-(2-methyl-3-nitro phenyl) ethylamine hydrochloride (24.0g, 85%).
Embodiment 16 N, the preparation of N-di-2-(2-methyl-3-nitro phenyl) ethamine tartrate
With N-(2-methyl-3-nitro phenylethyl)-N-propyl group-1-propylamine (28g, 0.106mol) and tartrate (16.5g, 0.11mol) be dissolved in the 50mL ethanolic soln, stirring, filtration, drying obtain N, N-di-2-(2-methyl-3-nitro phenyl) ethamine tartrate (35.5g, 81%).
Claims (5)
1.2-the preparation method of methyl-3-nitro phenylalkyl sulfonamide derivatives (I) or its salt,
In the formula
N represents 1 or 2,
R
1And R
2Represent hydrogen, straight or branched C respectively
1-C
5Alkyl, benzyl or expression phenyl or alkyl phenyl, this method comprises following steps:
(1) 2-methyl-3-nitro phenylalkyl acid (II) is adopted metal boron reductive agent to carry out reduction reaction in organic solvent in the presence of Lewis acid and is obtained 2-methyl-3-nitro phenylalkyl alcohol (III);
(2) compound (III) is under the effect of organic basic material and R ' SO
2Cl (IV) carries out the 2-methyl-3-nitro octadecyloxy phenyl ester (V) that sulfonylation obtains the sulfonic acid of R ' replacement in organic solvent commonly used, wherein, and R ' expression straight or branched C
1-C
4Alkyl, straight or branched C
1-C
4Haloalkyl, phenyl or alkyl phenyl;
(3) compound (V) and R
1, R
2The amine (VI) that replaces carries out amination reaction and obtains 2-methyl-3-nitro phenylalkyl sulfonamide derivatives (I) in organic solvent commonly used;
(4) as required, compound (I) is carried out to reactant salt.
2. method according to claim 1, the Lewis acid in the described step (1) is boron trifluoride or aluminum chloride.
3. method according to claim 1 and 2, wherein, R ' is p-methylphenyl, methyl or trifluoromethyl.
4. method according to claim 1, wherein, R
1And/or R
2Be n-propyl.
5. method according to claim 1, wherein, n is 2.
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|---|---|---|---|
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|---|---|---|---|
| CNB2005100271644A CN100457711C (en) | 2005-06-27 | 2005-06-27 | Prepn of 2-methyl-3-nitrophenylalkylamine derivative or its salt |
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|---|---|
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| CN100457711C true CN100457711C (en) | 2009-02-04 |
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| ZA200707888B (en) * | 2005-02-15 | 2009-01-28 | Alembic Ltd | Process for the preparation of indolone derivative |
| CN103130704B (en) * | 2013-03-11 | 2019-03-22 | 上海奥博生物医药技术有限公司 | It is a kind of to prepare 4- (2- ethoxy) -1,3- dihydro -2H- indol-2-one new method |
| CN103145604A (en) * | 2013-03-19 | 2013-06-12 | 上海奥博生物医药技术有限公司 | Method for preparing ropinirole key intermediate |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4452808A (en) * | 1982-12-07 | 1984-06-05 | Smithkline Beckman Corporation | 4-Aminoalkyl-2(3H)-indolones |
-
2005
- 2005-06-27 CN CNB2005100271644A patent/CN100457711C/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4452808A (en) * | 1982-12-07 | 1984-06-05 | Smithkline Beckman Corporation | 4-Aminoalkyl-2(3H)-indolones |
Non-Patent Citations (2)
| Title |
|---|
| . J.Med.Chem.,Vol.28 No.10. 1985 |
| . J.Med.Chem.,Vol.28 No.10. 1985 * |
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Address after: Room 304, building 1, 538 Cailun Road, China (Shanghai) pilot Free Trade Zone, Pudong New Area, Shanghai, 201203 Patentee after: Shanghai Aobo biomedical Co.,Ltd. Patentee after: ZHEJIANG HUAHAI PHARMACEUTICAL Co.,Ltd. Address before: 201203, room 1011, 601 Harley Road, Zhangjiang hi tech park, Shanghai Patentee before: Shanghai Aobo Biomedical Technology Co.,Ltd. Patentee before: ZHEJIANG HUAHAI PHARMACEUTICAL Co.,Ltd. |