CN107698500A - A kind of preparation method of Netupitant - Google Patents
A kind of preparation method of Netupitant Download PDFInfo
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- CN107698500A CN107698500A CN201710965011.7A CN201710965011A CN107698500A CN 107698500 A CN107698500 A CN 107698500A CN 201710965011 A CN201710965011 A CN 201710965011A CN 107698500 A CN107698500 A CN 107698500A
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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
- C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
Abstract
The invention discloses a kind of preparation method of Netupitant, belong to pharmaceutical compound field.The aminopyridine of 2 chlorine 5 and formic acid are condensed by the present invention; then through reduction, Boc protections, iodo; then it is condensed after being coupled, being deprotected with 2 (3,5 bis trifluoromethyl phenyl) 2 methylpropanoic acids, Netupitant is obtained after finally substituting with N methyl piperazines.Each step side reaction of preparation technology provided by the invention is few, high income, and post processing is simple, and environmental pollution is small, obtains product purity height, single miscellaneous low.
Description
Technical field
The invention belongs to pharmaceutical compound field, and in particular to a kind of preparation method of Netupitant.
Background technology
Netupitant chemistry is entitled：2- [double (trifluoromethyl) phenyl of 3,5-]-N, 2- dimethyl-N -s [4- (2- methylbenzenes
Base) -6- (4- methyl piperazines) -1- bases) pyridin-3-yl] propionamide, chemical constitution is as follows：
Netupitant is generally used for preventing the nausea and vomiting during cancer chemotherapy starts rear Acute Phase and postpones both phases.
At present, in the synthetic method of Netupitant, methyl is generally introduced on amide nitrogen by methylating reagent of iodomethane,
For example synthetic route disclosed in patent US8426450 comprises the following steps：
Above-mentioned reaction is also easy to produce double methylated by-products, reduces reaction yield, and post processing purifying is also relatively difficult.
First amido protecting, iodine substitute, methylated, being deprotected, being coupled, amidatioon, finally substituting in US20130231315
To finished product.Specific route is as follows：
Wherein, it is active relatively low due to acid by during 6 to 7, it is condensed again using acid is made into acyl chlorides.
This process toxicity is big, complex operation.
First passed through in US7211579 amide hydrolysis then again amidatioon, methylate, be coupled and obtain finished product.Specific route
It is as follows, wherein being also to replace acid to carry out amidatioon using acyl chlorides, the problem of same be present：
Therefore, need badly and a kind of new preparation method of Netupitant is provided, to overcome drawbacks described above.
The content of the invention
It is an object of the invention to provide a kind of preparation method of Netupitant.
A kind of preparation method of Netupitant, comprises the following steps：
Wherein, X, Y are halogen；
(1) chemical compounds I passes through in organic solvent with formic acid is condensed to yield compound ii；
(2) in a solvent, compound III is obtained with reducing agent reducing compound II；
Wherein, described reducing agent is Lithium Aluminium Hydride or sodium borohydride, Red-Al, DIBAH, compound ii and reducing agent
Mol ratio is 1:1.5~3, reaction temperature is 0~80 DEG C, and the reaction time is 4~8h；
(3) compound III under weak base and solvent condition with (Boc)2The amido protecting thing of O reaction generation compound IIIs,
Halo obtains compound IV after pulling out hydrogen with highly basic again；
(4) in the presence of alkali and catalyst, compound IV is coupled with o-methyl-benzene boric acid, obtains compound V；
(5) compound V is taken off into Boc and obtains de- Boc products, in the presence of alkali, condensing agent and solvent, compound V takes off Boc productions
Thing obtains amidated products VI with compound a in 0~110 DEG C of reaction；
Wherein, described condensing agent is HOBT, HATU, TBTU, PYBOP or T3P；Described alkali is triethylamine, potassium carbonate
Or DIEA；Compound V：Compound a：Condensing agent：The mol ratio of alkali is 1:(1~2):(2~3):(2~3)；
(6) compound VI reacts with N methyl piperazine in the presence of solvent and alkali, produces Netupitant VII.
Further, the solvent described in step (2) is tetrahydrofuran, ether or its mixed solvent；And/or step (5)
Described in solvent be N,N-dimethylformamide, dichloromethane or its mixed solvent.Further, in the step (1), instead
It is 0~120 DEG C to answer temperature, and the reaction time is 1~3h；And/or described organic solvent is selected from formic acid, dichloromethane, N, N- bis-
NMF；And/or the molar ratio of compound 1 and formic acid is 1:5~7.
Further, the reaction temperature is 100 DEG C, reaction time 2h, and organic solvent is formic acid, compound 1 and first
The mol ratio of acid is 1:5.7.
Further, in step (2), the reducing agent is Lithium Aluminium Hydride, and solvent is tetrahydrofuran, reaction temperature 25
DEG C, the mol ratio of reaction time 6h, compound II and reducing agent is 1:2.
Further, in step (3), compound III and (Boc)2O reaction temperature be 0~40 DEG C, the reaction time be 2~
6h；And/or described weak base is triethylamine or DIEA；And/or the solvent is dichloromethane, methanol, N, N- dimethyl methyls
Acid amides；And/or compound III and alkali, (Boc)2O mol ratio is 1：(1.2~3)：(1.2~2).
Further, the reaction temperature is 25 DEG C, and reaction time 3h, the weak base is triethylamine, and solvent is dichloro
Methane, compound III and alkali, (Boc)2O mol ratio is 1:2:1.5.
Further, in step (3), described halo is iodo, and halo is compound III's after described highly basic pulls out hydrogen
Amido protecting thing in the presence of solvent and alkali with I24h~24h is reacted at -78~60 DEG C；And/or described highly basic is normal-butyl
Lithium, HMDSLi or LDA；And/or compound III amido protecting thing：Highly basic：I2Mol ratio be 1:(2.5~4)：(1~
2)；And/or the solvent is mixed solvents one or more kinds of in ether, tetrahydrofuran, methyl tertiary butyl ether(MTBE).
Further, the reaction temperature that the highly basic pulls out halo after hydrogen is -78~25 DEG C, reaction time 16h, described strong
Alkali is n-BuLi, compound III amido protecting things：Alkali：I2Mol ratio be 1：2.5：1.5, the solvent is tetrahydrofuran.
Further, in step (4), the temperature of described coupling is 60 DEG C~120 DEG C, and the reaction time is 2h~12h；
And/or the alkali is selected from potassium carbonate, sodium carbonate, cesium carbonate or potassium phosphate；And/or the catalyst is selected from four triphenylphosphines
Palladium, Pd (dppf) Cl2, palladium or two triphenylphosphine palladiums；And/or compound IV：O-methyl-benzene boric acid：Catalyst：
Alkali mol ratio is 1:(1~2):(0.05~0.15):(3~4)；And/or reaction dissolvent is DMF/water, two
Six rings of oxygen/water, tetrahydrofuran/water.
Further, the temperature is 80 DEG C, reaction time 5h, and the alkali is potassium carbonate, and the catalyst is four or three
Phenylphosphine palladium, reaction dissolvent are dioxane/water, compound IV：O-methyl-benzene boric acid：Catalyst：Alkali mol ratio is 1:1.2:
0.103:3。
Further, in step (5), it is 0~40 DEG C of 2~4h of reaction under acid and solvent condition that compound V, which takes off Boc,；
And/or described acid is hydrochloric acid, trifluoroacetic acid or p-methyl benzenesulfonic acid；The solvent is methanol, dioxane, dichloromethane；Change
Compound V：Sour mol ratio is 1:(0.1~1).
Further, the reaction temperature is 25 DEG C, and in reaction time 2h, the acid is trifluoroacetic acid, and the solvent is
Dichloromethane, compound V：Sour mol ratio is 1:0.1.
Further, in step (5), the de- Boc products of compound V and the time of compound a reaction are 3~12h.
Further, the reaction temperature is 100 DEG C, and reaction time 4h, the condensing agent is T3P, and alkali is triethylamine,
Solvent is DMF, and compound V and compound a, condensing agent, alkali mol ratio are 1:1.2:2:2.
Further, in step (6), described alkali is potassium carbonate, sodium carbonate, triethylamine or DIEA；Compound VI：N- first
Base piperazine：The mol ratio of alkali is 1:(1~2):(1~4)；Reaction dissolvent is in N,N-dimethylformamide, acetonitrile, dichloromethane
One or more kinds of mixed solvents；Reaction temperature is 0~100 DEG C, and the reaction time is 2~8h.
Further, the alkali is potassium carbonate, and compound VI and N methyl piperazine, the mol ratio of alkali are 1：1.5：3, reaction
Solvent is DMF, and reaction temperature is 80 DEG C, reaction time 3h.
The invention provides a kind of preparation method of Netupitant, has advantages below：
1st, the present invention is improved to the synthesis technique of Netupitant, restores to obtain methyl after amino is protected,
The generation of double methylates is avoided, improves reaction yield.In addition, improving condensation condition, acid amides is directly carried out with acid
Change, without previously prepared acyl chlorides, greatly improve environmental friendliness.
2nd, it is higher often to walk yield for this preparation method, and post processing is simpler, and environmental pollution is small, is that one kind is suitable for industrial life
Production, there is the preparation method of larger application value.Product purity is obtained up to 99.81% using this route, maximum list is miscellaneous to be only
0.07%.The relatively simple process such as extraction, recrystallization are taken in purifying.Existing patent route is needed through being excessively reported as column chromatography
Purifying, complex operation are difficult.
Obviously, according to the above of the present invention, according to the ordinary technical knowledge and customary means of this area, do not departing from
Under the premise of the above-mentioned basic fundamental thought of the present invention, the modification, replacement or change of other diversified forms can also be made.
The embodiment of form by the following examples, the above of the present invention is remake further specifically
It is bright.But the scope that this should not be interpreted as to the above-mentioned theme of the present invention is only limitted to following example.It is all to be based on the above of the present invention
The technology realized belongs to the scope of the present invention.
Embodiment
The raw material that is used in the specific embodiment of the invention, equipment are known product, are obtained by buying commercially available prod.
The preparation method of 1 Netupitant of the present invention of embodiment
1st, compound II preparation
The chloro- 5- aminopyridines (chemical compounds I) (45.0g, 350mmol) of 2- are added in formic acid (75mL, 1980mmol), are returned
Stirring reaction 2h is flowed, decompression boils off formic acid, and saturated sodium bicarbonate solution 300ml is added into residue, then uses ethyl acetate
600ml is extracted twice every time, merges organic layer, with anhydrous sodium sulfate drying, filtering, is spin-dried for, is obtained oily compound II
(52.1g, 95%).
2nd, compound III preparation
Compound II (52.0g, 332mmol) is dissolved in THF (300ml), is slowly added to Lithium Aluminium Hydride in batches at room temperature
(25.2g, 664mmol), stirring reaction 6h, Disodium sulfate decahydrate is added into reaction solution to after precipitating completely, is filtered, filtrate is dense
It is reduced to dry, obtains oily compound III (41.0g, 87%).
3rd, compound IV preparation
Compound III (41.0g, 288mmol) is dissolved in dichloromethane, added (Boc)2O (94.3g, 432mmol),
Triethylamine (58.3g, 576mmol), stirring at normal temperature reaction 3h, is extracted 2 times with water, adds anhydrous sodium sulfate drying organic layer, mistake
Filter is concentrated to give amido protecting thing, then adds in THF (250ml), is cooled to -78 DEG C under nitrogen protection, then instills positive fourth
Base lithium (288ml, 720mmol), -30 DEG C, stirring reaction 30min are warming up to after being added dropwise, are then cooled to -78 DEG C, be added dropwise
THF (400ml) solution of iodine (109.6g, 432mmol), after being added dropwise, is warmed to room temperature, stirring reaction is overnight, question response knot
Shu Hou, 250ml 20% aqueous solution of sodium bisulfite is added, be extracted with ethyl acetate three times, merge organic phase, dry, mistake
Filter, is spin-dried for obtaining oily compound IV (60.3g, 78%).4th, compound V preparation
Isosorbide-5-Nitrae-dioxane and water (300ml, 3:1) in the mixed solvent, addition compound IV (60.3g,
225mmol), o-methyl-benzene boric acid (36.7g, 270mmol), tetra-triphenylphosphine palladium (26.6g, 23mmol) and potassium carbonate
(93.2g, 675mmol), under nitrogen protection, 80 DEG C are heated to, stirring reaction 5h, is filtered after terminating with diatomite, filtrate adds
Water, it is extracted with ethyl acetate three times, merges organic phase, through anhydrous sodium sulfate drying, filtering, is spin-dried for, column chromatography obtains after purification
Solid chemical compound V (44.5g, 85%).
5th, compound VI preparation
Compound V (44.5g, 191mmol) is dissolved in dichloromethane (300ml), addition trifluoroacetic acid (2.2g,
19.1mmol), reaction 2h is stirred at room temperature, adds water washing twice, with anhydrous sodium sulfate drying organic layer, is spin-dried for being then dissolved in
In DMF (300ml), add 2- (3,5- bis trifluormethyl-phenyl) -2 Methylpropionic acid (68.7,229mmol), T3P (121.5g,
382mmol) with triethylamine (38.7g, 382mmol), 100 DEG C are heated to, reacts 4h, water is added, is extracted with ethyl acetate three times,
Merge organic phase, dry, solid chemical compound VI (73.8g, 75%) is obtained after being spin-dried for.
6th, compound VII preparation
Compound VI (73.8g, 143mmol) is dissolved in DMF (300ml), addition N methyl piperazine (21.5g,
215mmol), potassium carbonate (59.2g, 429mmol), 80 DEG C of reaction 3h is heated to, after reaction terminates, water is added, uses ethyl acetate
Extraction, dry, concentration, with ethyl alcohol recrystallization, filtering, dry obtain after filter cake pulverulent solids Netupitant (66.2g,
80%).
It is filler (such as Agilent Eclipse XDB-C18,250 × 4.6mm, 5 with octadecylsilane chemically bonded silica
μm)；With water (ammoniacal liquor adjusts PH to 7.0)-acetonitrile-methanol (20:50:30) it is mobile phase；Detection wavelength is 254nm, and flow velocity is
1.0ml per minute, 35 DEG C of column temperature.Precision measures the μ l of need testing solution 10, injects liquid chromatograph, purity 99.81%.
1H NMR(400MHz,CDCl3)δ8.00(s,1H),7.75(s,1H),7.66(s,2H),7.27(s,4H),6.51
(s,1H),3.58(s,4H),2.35-2.13(m,13H),1.49(s,3H),1.33(s,3H)。
In summary, the present invention is improved to the synthesis technique of Netupitant, is restored after amino is protected
To methyl, the generation of double methylates is avoided, improves reaction yield.In addition, improving condensation condition, directly entered with acid
Row amidatioon, without previously prepared acyl chlorides, greatly improve environmental friendliness.
Claims (17)
- A kind of 1. preparation method of Netupitant, it is characterised in that：Comprise the following steps：Wherein, X, Y are halogen；(1) chemical compounds I passes through in organic solvent with formic acid is condensed to yield compound ii；(2) in a solvent, compound III is obtained with reducing agent reducing compound II；Wherein, described reducing agent is Lithium Aluminium Hydride or sodium borohydride, Red-Al, DIBAH, compound ii and reducing agent mole Than for 1:1.5~3, reaction temperature is 0~80 DEG C, and the reaction time is 4~8h；(3) compound III under weak base and solvent condition with (Boc)2The amido protecting thing of O reaction generation compound IIIs, then with by force Halo obtains compound IV after alkali pulls out hydrogen；(4) in the presence of alkali and catalyst, compound IV is coupled with o-methyl-benzene boric acid, obtains compound V；(5) compound V is taken off into Boc and obtains de- Boc products, in the presence of alkali, condensing agent and solvent, compound V take off Boc products with Compound a obtains amidated products VI in 0~110 DEG C of reaction；Wherein, described condensing agent is HOBT, HATU, TBTU, PYBOP or T3P；Described alkali be triethylamine, potassium carbonate or DIEA；Compound V：Compound a：Condensing agent：The mol ratio of alkali is 1:(1~2):(2~3):(2~3)；(6) compound VI reacts with N methyl piperazine in the presence of solvent and alkali, produces Netupitant VII.
- 2. preparation method according to claim 1, it is characterised in that：Solvent described in step (2) is tetrahydrofuran, second Ether or its mixed solvent；And/or the solvent described in step (5) is that DMF, dichloromethane or its mixing are molten Agent.
- 3. preparation method according to claim 1, it is characterised in that：In the step (1), reaction temperature is 0~120 DEG C, the reaction time is 1~3h；And/or described organic solvent is selected from formic acid, dichloromethane, DMF；With/ Or, the molar ratio of compound 1 and formic acid is 1:(5~7).
- 4. preparation method according to claim 3, it is characterised in that：The reaction temperature is 100 DEG C, and the reaction time is 2h, organic solvent are formic acid, and the mol ratio of compound 1 and formic acid is 1:5.7.
- 5. preparation method according to claim 1, it is characterised in that：In step (2), the reducing agent is Lithium Aluminium Hydride, Solvent is tetrahydrofuran, and reaction temperature is 25 DEG C, reaction time 6h, compound II and the mol ratio of reducing agent is 1:2.
- 6. preparation method according to claim 1, it is characterised in that：In step (3), compound III and (Boc)2O reactions Temperature is 0~40 DEG C, and the reaction time is 2~6h；And/or described weak base is triethylamine or DIEA；And/or the solvent is Dichloromethane, methanol, N,N-dimethylformamide；And/or compound III and alkali, (Boc)2O mol ratio is 1：(1.2~ 3)：(1.2~2).
- 7. preparation method according to claim 6, it is characterised in that：The reaction temperature is 25 DEG C, reaction time 3h, The weak base is triethylamine, and solvent is dichloromethane, compound III and alkali, (Boc)2O mol ratio is 1:2:1.5.
- 8. preparation method according to claim 1, it is characterised in that：In step (3), described halo is iodo, described Highly basic pull out amido protecting thing that halo after hydrogen is compound III in the presence of solvent and alkali with I24h is reacted at -78~60 DEG C ~24h；And/or described highly basic is n-BuLi, HMDSLi or LDA；And/or compound III amido protecting thing：By force Alkali：I2Mol ratio be 1:(2.5~4)：(1~2)；And/or the solvent is in ether, tetrahydrofuran, methyl tertiary butyl ether(MTBE) One or more kinds of mixed solvents.
- 9. preparation method according to claim 8, it is characterised in that：The halo is that reaction temperature is -78~25 DEG C of ranks Ladder heating, the highly basic is n-BuLi, compound III amido protecting things：Highly basic：I2Mol ratio be 1：2.5：1.5, it is described Solvent is tetrahydrofuran.
- 10. preparation method according to claim 1, it is characterised in that：In step (4), the temperature of described coupling is 60 DEG C~120 DEG C, the coupling reaction time is 2h~12h；And/or the alkali is selected from potassium carbonate, sodium carbonate, cesium carbonate or potassium phosphate； And/or the catalyst is selected from tetra-triphenylphosphine palladium, Pd (dppf) Cl2, palladium or two triphenylphosphine palladiums；With/ Or, compound IV：O-methyl-benzene boric acid：Catalyst：Alkali mol ratio is 1:(1~2):(0.05~0.15):(3~4)；And/or Reaction dissolvent is N,N-dimethylformamide/water, dioxane/water, tetrahydrofuran/water.
- 11. preparation method according to claim 10, it is characterised in that：The temperature is 80 DEG C, reaction time 5h, institute It is potassium carbonate to state alkali, and the catalyst is tetra-triphenylphosphine palladium, and reaction dissolvent is that volume ratio is 3:1 dioxane and water, change Compound IV：O-methyl-benzene boric acid：Catalyst：Alkali mol ratio is 1:1.2:0.103:3.
- 12. preparation method according to claim 1, it is characterised in that：In step (5), compound V take off Boc be acid and Under solvent condition, 0~40 DEG C of 2~4h of reaction；And/or described acid is hydrochloric acid, trifluoroacetic acid or p-methyl benzenesulfonic acid；It is described molten Agent is methanol, dioxane, dichloromethane；Compound V：Sour mol ratio is 1:(0.1~1).
- 13. preparation method according to claim 12, it is characterised in that：The reaction temperature is 25 DEG C, and the reaction time is 2h, the acid are trifluoroacetic acid, and the solvent is dichloromethane, compound V：Sour mol ratio is 1:0.1.
- 14. preparation method according to claim 1, it is characterised in that：In step (5), the de- Boc products of compound V with The time of compound a reaction is 3~12h.
- 15. according to the preparation method of claim 1,2 or 14, it is characterised in that：The reaction temperature is 100 DEG C, during reaction Between be 4h, the condensing agent is T3P, and alkali is triethylamine, and solvent is DMF, compound V and compound a, contracting Mixture, the mol ratio of alkali are 1:1.2:2:2.
- 16. preparation method according to claim 1, it is characterised in that：In step (6), described alkali is potassium carbonate, carbonic acid Sodium, triethylamine or DIEA；Compound VI：N methyl piperazine：The mol ratio of alkali is 1:(1~2):(1~4)；Reaction dissolvent is N, One or more kinds of mixed solvent in dinethylformamide, acetonitrile, dichloromethane；Described reaction is entered at 0~100 DEG C 2~8h of row.
- 17. preparation method according to claim 16, it is characterised in that：The alkali is potassium carbonate, compound VI and N- first Base piperazine, the mol ratio of alkali are 1：1.5：3, reaction dissolvent is DMF, and the reaction carries out 3h at 80 DEG C.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2020184670A1 (en) | 2019-03-13 | 2020-09-17 | 大塚製薬株式会社 | Method for introducing deuterated lower alkyl into amine moiety of compound containing secondary amine |
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| CN101646669A (en) * | 2007-03-28 | 2010-02-10 | 神经研究公司 | Purinyl derivatives and their use as potassium channel modulators |
| 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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