CN105061303A - New method for preparation of netupitant key intermediate N-methyl-4-(2-methyl phenyl)-6-(4-methyl-1-piperazinyl)-3-pyridylamine - Google Patents
New method for preparation of netupitant key intermediate N-methyl-4-(2-methyl phenyl)-6-(4-methyl-1-piperazinyl)-3-pyridylamine Download PDFInfo
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- CN105061303A CN105061303A CN201510478969.4A CN201510478969A CN105061303A CN 105061303 A CN105061303 A CN 105061303A CN 201510478969 A CN201510478969 A CN 201510478969A CN 105061303 A CN105061303 A CN 105061303A
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- C—CHEMISTRY; METALLURGY
- 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
Belonging to the field of drug synthesis, the invention relates to a new method for preparation of the netupitant key intermediate N-methyl-4-(2-methyl phenyl)-6-(4-methyl-1-piperazinyl)-3-pyridylamine. The method comprises the steps of: 1) in certain solvent, subjecting 6-(4-methyl-1-piperazinyl)-4-(2-methyl phenyl)nicotinamide (formula I compound) and ROX (X=H or Na) to Hoffman degradation reaction under the condition of iodobenzene diacetate or substituted Iodobenzene diacetate, thus obtaining a formula II compound; and 2) carrying out reduction reaction on the formula II compound to obtain N-methyl-4-(2-methyl phenyl)-6-(4-methyl-1-piperazinyl)-3-pyridylamine (formula III compound). The new method for preparation of the netupitant key intermediate N-methyl-4-(2-methyl phenyl)-6-(4-methyl-1-piperazinyl)-3-pyridylamine has the advantages of easily available production raw materials, mild reaction conditions and simple operation, avoids application of strong base and controlled reagents, and provides an environment-friendly generation process.
Description
Technical field
The present invention relates to the novel method that one prepares how appropriate pyrrole smooth key intermediate N-methyl-4-(2-aminomethyl phenyl)-6-(4-methyl isophthalic acid-piperazinyl)-3-pyridine amine, belong to pharmaceutical synthesis field.
Background technology
In October, 2014, U.S. food Drug Administration (FDA) ratifies the Akynzeo(smooth netupitant of how appropriate pyrrole and Palonosetron palonosetron) be used for the treatment of and implement feeling sick and vomiting of cancer chemotherapy patients.Wherein, oral Palonosetron got the Green Light in 2008, and what after starting for preventing cancer chemotherapy, acute phase produced feels sick and vomiting; How appropriate pyrrole is smooth is a kind of new drug, belongs to 5-hydroxytryptamine receptor antagonist, for feeling sick and vomiting of producing of acute phase after preventing cancer chemotherapy and lag period.
At present, the synthetic method that appropriate pyrrole is smooth about how is less, and comprehensively analyzes discovery, and the synthetic method of bibliographical information all relates to the synthesis of key intermediate (formula III compound).Wherein, in the synthetic method of US6297375 report, N-pivaloyl group-6-(4-methyl isophthalic acid-piperazinyl)-4-(2-aminomethyl phenyl)-3-pyridine amine is through hydrolysis, acidylate, lithium aluminium hydride reduction, realizes the preparation of key intermediate (formula III compound).The method relates to the application of pyroreaction and harmful influence lithium aluminum hydride, complex operation, and yield is lower, is not suitable for suitability for industrialized production; Its reaction formula is as shown below.
Document
j.Org.Chem.2006,71 (5), 2000 and Org.pro.Res & Dev.2006, all with the preparation of 6-(4-methyl isophthalic acid-piperazinyl)-4-(2-aminomethyl phenyl) niacinamide to be precursor through Hofmann degradation, reduction reaction realize key intermediate (formula III compound) in the synthetic methods of 10 (6), 1157 reports.This technique is comparatively simple, but operation is more loaded down with trivial details, and reaction system needs Non-aqueous processing, and production cost is higher; Its reaction formula is as shown below.
In view of the preparation method about key intermediate (formula III compound) of bibliographical information all exists larger defect, the suitability for industrialized production that appropriate pyrrole is smooth to how, reduce production cost and cause considerable influence; Therefore, the great market prospect that appropriate pyrrole is smooth based on how, designs, develops a reaction conditions gentleness, easy and simple to handle, low cost, environmentally friendly production technique become the focus that everybody pays close attention to jointly.
Summary of the invention
For above-mentioned defect, the object of the invention is to provide one to prepare the novel method of how appropriate pyrrole smooth key intermediate N-methyl-6-(4-methyl isophthalic acid-piperazinyl)-4-(2-aminomethyl phenyl)-3-pyridine amine, to make that the raw material of this production technique is easy to get, reaction conditions is gentle, easy and simple to handle, avoids the application of highly basic, control reagent; Meanwhile, to provide a kind of environmentally friendly generating process.
The present invention is achieved in that
One prepares the novel method of how appropriate pyrrole smooth key intermediate N-methyl-6-(4-methyl isophthalic acid-piperazinyl)-4-(2-aminomethyl phenyl)-3-pyridine amine (formula III compound), comprises the following steps:
1) in certain solvent, there is hoffman degradation reaction at iodobenzene diacetate or under replacing iodobenzene diacetate condition in 6-(4-methyl isophthalic acid-piperazinyl)-4-(2-aminomethyl phenyl) niacinamide (type I compound) and ROX (X=H or Na), prepares formula II compound;
2) formula II compound issues raw reduction reaction in reductive agent effect, prepares N-methyl-4-(2-aminomethyl phenyl)-6-(4-methyl isophthalic acid-piperazinyl)-3-pyridine amine (formula III compound);
Reaction formula described in step 1 of the present invention and 2 is as follows:
, wherein, R=H, straight-chain paraffin base, branched alkane alkyl or containing other substituent alkyls; X=H or Na.
When preparing intermediate formula II compound, in prior art, first there is bromo-reaction in 6-(4-methyl isophthalic acid-piperazinyl)-4-(2-aminomethyl phenyl) niacinamide (type I compound), then hofmann rearrangement production formula II compound occurs in the basic conditions under the effect of NBS reagent.The hoffman degradation reaction yield participated in due to NBS reagent is lower, and aftertreatment is comparatively loaded down with trivial details, and therefore this synthetic route is unsuitable for suitability for industrialized production.
And 6-(4-methyl isophthalic acid-piperazinyl)-4-(2-aminomethyl phenyl) niacinamide (type I compound) in above-mentioned steps 1 of the present invention iodobenzene diacetate or replace iodobenzene diacetate, ROX effect under there is hoffman degradation reaction, reset and generate formula II compound, thus the use of NBS reagent of avoiding knowing clearly, this synthetic route operates without the need to anhydrous and oxygen-free, reaction conditions is gentle, reagent price is all relatively cheap, and the productive rate of formula II compound prepared by this synthetic route is significantly improved.
Preferably, above-mentioned R=H, C
1-C
10direct-connected alkyl, C
1-C
10branched alkane alkyl or containing other substituent C
1-C
10alkyl.Such as: R is methyl, ethyl, propyl group, sec.-propyl, normal-butyl, isobutyl-or phenmethyl etc.
In the present invention, the described solvent in step 1 selects ketones solvent, alkane solvents, aromatic hydrocarbon solvent, ether solvent, nitrile solvents, amide solvent or sulfoxide type solvents.
In the present invention, the described solvent selected from acetone in step 1, methylethylketone, normal hexane, hexanaphthene, toluene, dimethylbenzene, ether, dipropyl ether, acetonitrile, benzyl cyanide, DMF, N, N N,N-DIMETHYLACETAMIDE or dimethyl sulfoxide (DMSO).
In the present invention, the described ROX in step 1 is RONa, and described RONa is selected from sodium methylate, sodium ethylate, sodium tert-butoxide etc.
In the present invention, the described ROX in step 1 is ROH, and described ROH as solvent, and can react.As preferably, ROH is selected from methyl alcohol, ethanol, Virahol etc.
Above-mentioned ROX can be RONa can be also ROH, is preferably ROH.When ROX used is ROH, it not only can as solvent, and meanwhile, it can also participate in reaction as raw material, thus reduces addition step, makes operation more simple, convenient; And the yield of formula II compound can be made to be further enhanced.
In the present invention, the described replacement iodobenzene diacetate in step 1 is phenyl ring or/and ethanoyl is substituted the monosubstituted or polysubstituted iodobenzene diacetate of base.
In the present invention, the described replacement iodobenzene diacetate in step 1 is two (trifluoroacetic acid) iodobenzene.
In the present invention, the reaction system of step 1 is preferably alkali reaction system; Alkali selected by described alkali reaction system is mineral alkali or organic bases.
In the present invention, described mineral alkali is selected from potassium hydroxide, sodium hydroxide, lithium hydroxide, salt of wormwood, sodium carbonate, cesium carbonate.
In the present invention, described organic bases is selected from triethylamine, diisopropylethylamine, pyridine, sodium methylate, sodium ethylate, potassium tert.-butoxide, sodium tert-butoxide.
In the present invention, the described reductive agent in step 2 is selected from red aluminium, lithium aluminum hydride or borine.
When preparation formula III compound, when adopting lithium aluminium hydride reduction formula II compound, need to keep anhydrous and oxygen-free condition, it is relatively stricter to operational requirement, and aftertreatment is very loaded down with trivial details, and therefore, preferred red aluminium or borine are as reductive agent.When adopting red aluminium or borane reduction II compound, its reaction temperature and, simple to operate, and the yield of formula III compound preparing gained can reach more than 60%, comparatively adopt the yield of lithium aluminium hydride reduction preparation formula III compound to be significantly improved.
Beneficial effect of the present invention:
The novel method of the how appropriate pyrrole of preparation provided by the present invention smooth key intermediate N-methyl-6-(4-methyl isophthalic acid-piperazinyl)-4-(2-aminomethyl phenyl)-3-pyridine amine, make that the raw material of production technique is easy to get, reaction conditions is gentle, easy and simple to handle, avoid the application of highly basic, control reagent, and provide a kind of environmentally friendly generating process.
Accompanying drawing explanation
Fig. 1 is the high resolution mass spectrum figure of N-methoxycarbonyl base-6-(4-methyl isophthalic acid-piperazinyl)-4-(2-aminomethyl phenyl)-3-pyridine amine (formula II compound);
Fig. 2 is the hydrogen nuclear magnetic resonance spectrogram of N-methoxycarbonyl base-6-(4-methyl isophthalic acid-piperazinyl)-4-(2-aminomethyl phenyl)-3-pyridine amine (formula II compound);
Fig. 3 is the high resolution mass spectrum figure of N-methyl-6-(4-methyl isophthalic acid-piperazinyl)-4-(2-aminomethyl phenyl)-3-pyridine amine (formula III compound);
Fig. 4 is N-methyl-6-(4-methyl isophthalic acid-piperazinyl)-4-(2-aminomethyl phenyl)-3-pyridine amine (formula III compound) hydrogen nuclear magnetic resonance spectrogram.
Fig. 5 is the high resolution mass spectrum figure how appropriate pyrrole is smooth.
Embodiment
Following embodiment can make explanation specifically to content of the present invention, but subject area of the present invention is not limited to following specific embodiment, and every technology, technique realized based on content of the present invention all belongs to scope of the present invention.
Embodiment 1
Prepared by N-methoxycarbonyl base-6-(4-methyl isophthalic acid-piperazinyl)-4-(2-aminomethyl phenyl)-3-pyridine amine (formula II compound):
6-(4-methyl isophthalic acid-piperazinyl)-4-(2-aminomethyl phenyl) niacinamide 70g is added in single port flask, after being dissolved with anhydrous methanol 1L, stir cooling under ice bath after, add 80g iodobenzene diacetate and 26g potassium hydroxide, stirring reaction 1 hour under ice bath.TLC monitoring reacts completely.After concentrated, add 1L water successively, extraction into ethyl acetate 3 times in reaction solution, organic layer merges, and after then washing twice with saturated nacl aqueous solution, organic over anhydrous dried over sodium sulfate, filters, concentrated, obtains yellow oil 65g.Yield 85%.
1H-NMR（CDCl
3,400MHz）：
δ=8.81(brs,1H),7.34~7.25(m,3H),7.12(d,
J=8Hz),6.46(s,1H),5.92(s,1H),3.67(s,3H),3.55~3.54(m,4H),2.55(t,
J=4Hz,4H),2.35(s,3H),2.12(s,3H)ppm;HRMS-ESI(m/z):341.1970(M+H
+)。
Reaction formula is as follows:
。
The KOH of the present embodiment can also adopt other mineral alkalis or organic bases to replace, such as: sodium hydroxide, lithium hydroxide, salt of wormwood, sodium carbonate, cesium carbonate, triethylamine, diisopropylethylamine, pyridine, sodium methylate, sodium ethylate, potassium tert.-butoxide or sodium tert-butoxide etc.
The iodobenzene diacetate of the present embodiment can also select replacement iodobenzene diacetate, is preferably two (trifluoroacetic acid) iodobenzene.
Methyl alcohol in the present embodiment can also select other alcohol to replace, such as: ethanol, Virahol, propyl carbinol or isopropylcarbinol etc.
Embodiment 2
Prepared by N-methoxycarbonyl base-6-(4-methyl isophthalic acid-piperazinyl)-4-(2-aminomethyl phenyl)-3-pyridine amine (formula II compound):
Under condition of ice bath, 4g iodobenzene diacetate is joined in batches and is dissolved with 3g6-(4-methyl isophthalic acid-piperazinyl)-4-(2-aminomethyl phenyl) niacinamide and 4gCH
3in the chloroformic solution of ONa, add rear continuation and maintain stirring reaction 3h under ice bath; TLC monitoring reacts completely.In reaction solution, add 10mL shrend to go out reaction, chloroform extraction 3 times, organic layer merges, and after then washing twice with saturated nacl aqueous solution, organic over anhydrous dried over sodium sulfate, filters, concentrated, obtains yellow oil 2.4g, yield 62%.
The solvent of the present embodiment can also adopt other kind solvents to replace, such as: acetone, DMF, dimethyl sulfoxide (DMSO), methyl alcohol etc.
Embodiment 3
The preparation of N-methyl-6-(4-methyl isophthalic acid-piperazinyl)-4-(2-aminomethyl phenyl)-3-pyridine amine (formula III compound):
Be dissolved in 1.5L toluene by formula II compound 40g, be placed in ice-water bath, dropping 1L toluene dissolves the red aluminum solutions of 200ml, and in dropping process, reaction is violent, keeps temperature to be no more than 50 DEG C.After dropwising, be placed in 50 DEG C of oil bath reacting by heating, TLC monitoring reacts completely.Slowly be added drop-wise to by reaction solution in the 1NNaOH solution under ice bath, then add extraction into ethyl acetate aqueous phase, organic layer is extremely neutral with saturated nacl aqueous solution washing again, and with anhydrous sodium sulfate drying, filtering and concentrating obtains pale tan oil 30.5g, yield: 62%.
1H-NMR（CDCl
3,400MHz）：
δ=7.74(s,1H),7.31~7.13(m,4H),6.47(s,1H),3.44~3.40(m,4H),2.77(s,3H),2.57(t,
J=4Hz,4H),2.35(s,3H),2.14(s,3H)ppm;HRMS-ESI(m/z):297.2076(M+H
+)。
Reaction formula is as follows:
。
The present embodiment can also select other reductive agents to replace red aluminium, such as: lithium aluminum hydride or borine.
Embodiment 4
How the preparation that appropriate pyrrole is smooth:
Under condition of ice bath, 12g2-(3 will be dissolved with, 5-is two-trifluoromethyl-phenyl) and the dichloromethane solution 10mL of-2-methyl-propionyl chloride slowly joins in the dichloromethane solution being dissolved with 10gN-methyl-6-(4-methyl isophthalic acid-piperazinyl)-4-(2-aminomethyl phenyl)-3-pyridine amine (formula III compound) and 9mL diisopropylethylamine, under maintaining condition of ice bath, stirring reaction is after 1 hour, slowly be warming up to room temperature, TLC detection reaction is complete.Add shrend to go out reaction, extraction separatory, organic layer successively by 10% sodium hydroxide solution, saturated nacl aqueous solution washing, dried over sodium sulfate, concentrate, obtain an off-white color solid.Ethyl alcohol recrystallization obtains off-white color solid and is about 15.7g, yield: 80%.HRMS-ESI(m/z):578.2482(M+H
+)。
Claims (10)
1. prepare a novel method for how appropriate pyrrole smooth key intermediate N-methyl-4-(2-aminomethyl phenyl)-6-(4-methyl isophthalic acid-piperazinyl)-3-pyridine amine, it is characterized in that, comprise the following steps:
1) in certain solvent, there is hoffman degradation reaction at iodobenzene diacetate or under replacing iodobenzene diacetate condition in 6-(4-methyl isophthalic acid-piperazinyl)-4-(2-aminomethyl phenyl) niacinamide (type I compound) and ROX (X=H or Na), prepares formula II compound;
2) formula II compound issues raw reduction reaction in reductive agent effect, prepares N-methyl-4-(2-aminomethyl phenyl)-6-(4-methyl isophthalic acid-piperazinyl)-3-pyridine amine (formula III compound);
, wherein, R=H, straight-chain paraffin base, branched alkane alkyl or containing other substituent alkyls; X=H or Na.
2. novel method as claimed in claim 1, it is characterized in that, the described solvent in step 1 selects ketones solvent, alkane solvents, aromatic hydrocarbon solvent, ether solvent, nitrile solvents, amide solvent or sulfoxide type solvents.
3. novel method as claimed in claim 2, it is characterized in that, solvent selected from acetone described in step 1, methylethylketone, normal hexane, hexanaphthene, toluene, dimethylbenzene, ether, dipropyl ether, acetonitrile, benzyl cyanide, DMF, N,N-dimethylacetamide or dimethyl sulfoxide (DMSO).
4. novel method as claimed in claim 1, it is characterized in that, the described ROX in step 1 is ROH, and described ROH as solvent, and can react.
5. novel method as claimed in claim 1, is characterized in that, the described replacement iodobenzene diacetate in step 1 is phenyl ring or/and ethanoyl is substituted the monosubstituted or polysubstituted iodobenzene diacetate of base.
6. novel method as claimed in claim 5, it is characterized in that, the described replacement iodobenzene diacetate in step 1 is two (trifluoroacetic acid) iodobenzene.
7. the novel method as described in any one of claim 1-6, is characterized in that, the reaction system of step 1 is preferably alkali reaction system; Alkali selected by described alkali reaction system is mineral alkali or organic bases.
8. the novel method as described in claims 7, is characterized in that, described mineral alkali is selected from potassium hydroxide, sodium hydroxide, lithium hydroxide, salt of wormwood, sodium carbonate, cesium carbonate.
9. novel method as claimed in claim 7, it is characterized in that, described organic bases is selected from triethylamine, diisopropylethylamine, pyridine, sodium methylate, sodium ethylate, potassium tert.-butoxide, sodium tert-butoxide.
10. novel method as claimed in claim 1, it is characterized in that, the described reductive agent in step 2 is selected from red aluminium, lithium aluminum hydride or borine.
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| CN201510478969.4A CN105061303A (en) | 2015-08-03 | 2015-08-03 | New method for preparation of netupitant key intermediate N-methyl-4-(2-methyl phenyl)-6-(4-methyl-1-piperazinyl)-3-pyridylamine |
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|---|---|---|---|
| CN201510478969.4A CN105061303A (en) | 2015-08-03 | 2015-08-03 | New method for preparation of netupitant key intermediate N-methyl-4-(2-methyl phenyl)-6-(4-methyl-1-piperazinyl)-3-pyridylamine |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1270959A (en) * | 1999-02-24 | 2000-10-25 | 弗·哈夫曼-拉罗切有限公司 | 4-phenyl pyridine derivatives |
| CN1297887A (en) * | 1999-11-29 | 2001-06-06 | 弗·哈夫曼-拉罗切有限公司 | Process for producing pyridine derivate |
| CN104053652A (en) * | 2011-11-29 | 2014-09-17 | 赫尔辛医疗股份公司 | Substituted 4-phenyl-pyridines for the treatment of NK-1 receptor related diseases |
-
2015
- 2015-08-03 CN CN201510478969.4A patent/CN105061303A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1270959A (en) * | 1999-02-24 | 2000-10-25 | 弗·哈夫曼-拉罗切有限公司 | 4-phenyl pyridine derivatives |
| CN1297887A (en) * | 1999-11-29 | 2001-06-06 | 弗·哈夫曼-拉罗切有限公司 | Process for producing pyridine derivate |
| CN104053652A (en) * | 2011-11-29 | 2014-09-17 | 赫尔辛医疗股份公司 | Substituted 4-phenyl-pyridines for the treatment of NK-1 receptor related diseases |
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