CN109776401A - A method of preparing the chloro- 5- trifluoromethyl -2-aminopyridine of 6- - Google Patents
A method of preparing the chloro- 5- trifluoromethyl -2-aminopyridine of 6- Download PDFInfo
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- CN109776401A CN109776401A CN201711125477.2A CN201711125477A CN109776401A CN 109776401 A CN109776401 A CN 109776401A CN 201711125477 A CN201711125477 A CN 201711125477A CN 109776401 A CN109776401 A CN 109776401A
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Abstract
A method of the chloro- 5- trifluoromethyl -2-aminopyridine of 6-, which is prepared, using the iodo- 2-aminopyridine of the chloro- 5- of 6- as raw material obtains product by reaction steps such as amido protecting, trifluoromethylation and deprotections.
Description
Technical field
Field of medicine and chemical technology.
Background technique
Existing method is with 3- trifluoromethyl -2,6- dichloropyridine for raw material, prepares the chloro- 5- trifluoro of 6- using ammonolysis reaction
Methyl-2-amino pyridine.The method has raw material to be not easy to obtain, and domain of the existence is selectively bad, and product is difficult to purify not
Foot.
Summary of the invention
In view of the drawbacks of the prior art, the invention discloses a kind of chloro- 5- fluoroforms of more economic, easily operated 6-
Base -2-aminopyridine preparation method.Using the iodo- 2-aminopyridine of the chloro- 5- of valence 6- as raw material, pass through amido protecting, trifluoromethyl
Change and the reaction steps such as deprotection obtain product.Entire reaction process is selectively good, is not difficult to isolated isomers, thus easily
In isolating and purifying.Reaction condition is mild, easy to operate, is suitable for producing in batches.
Preparing the chloro- 5- trifluoromethyl of 6- -2-aminopyridine (formula IV) starting material is the iodo- 2-aminopyridine of the chloro- 5- of 6-
(Formulas I) can occur iodide reaction with the chloro- 2-aminopyridine of 6- and N- N-iodosuccinimide etc. and be prepared, be referred to
Document European Journal of Medicinal Chemistry, 2014, p.404-416.
Prepare the chloro- 5- trifluoromethyl of 6- -2-aminopyridine (formula IV) the following steps are included:
A) it is reacted by amido protecting for raw material with the iodo- 2-aminopyridine of the chloro- 5- of 6- (Formulas I), obtains formula (II) compound,
Wherein, R1 H, R2 be acetyl group (Ac), tertbutyloxycarbonyl (Boc), mesyl (Ms), p-toluenesulfonyl (Ts),
Or R1 and R2 is simultaneously tertbutyloxycarbonyl (Boc)；
B) Formula II compound is reacted by trifluoromethylation, and compound formula III is prepared, wherein the definition of R1 and R2 is with before
It states identical；
C) formula III compound takes off amino protecting group, and the chloro- 5- trifluoromethyl of 6- -2-aminopyridine (formula IV) is prepared.
Wherein, in step a), upper amino protecting group agents useful for same be chloroacetic chloride, di-tert-butyl dicarbonate, methane sulfonyl chloride,
One of paratoluensulfonyl chloride.In step b), it is trifluoromethyl trimethylsilane and 1,10- that trifluoromethylation, which reacts agents useful for same,
Phenanthroline.In step c), being deprotected acid used is concentrated hydrochloric acid, trifluoroacetic acid, hydrobromic acid.
Specific embodiment
The preparation of the iodo- 2-aminopyridine of the chloro- 5- of 1 6- of embodiment (Formulas I)
Compound of formula I can refer to document European Journal of Medicinal Chemistry, and 2014, p.404-416
Preparation.The chloro- 2-aminopyridine of 100g 6- is dissolved in 400mL n,N-Dimethylformamide, 195g N- iodo fourth two is added
Acid imide.It stirs to fully reacting, reaction solution is poured into 400g water, is extracted with ethyl acetate, extract liquor anhydrous sodium sulfate
It is dry.Filtering, is concentrated to give fine work, and crude product ethyl alcohol obtains product 126.7g, yield 64%, HPLC testing product purity after must crystallizing
98.6%。
HRMS:m/e+H=254.9180, theoretical value: 254.9183.
The preparation of the iodo- 2-aminopyridine of the chloro- 5- of 2 6- of embodiment (Formulas I)
The chloro- 2-aminopyridine of 60g 6- is dissolved in 400mL glacial acetic acid, 75.5g lodine chloride is added.It stirs to fully reacting,
Reaction solution is poured into 200g water, is extracted with ethyl acetate, extract liquor is dry with anhydrous sodium sulfate.Filtering, is concentrated to give fine work,
Crude product ethyl alcohol obtains product 126.7g, yield 71%, HPLC testing product purity 99.5% after must crystallizing.
3 II a(R1 of embodiment=H, R2=Ac) preparation
By 2g chemical compounds I, triethylamine, methylene chloride is added in flask, cooling with ice salt bath under nitrogen protection.Second is added dropwise
The dichloromethane solution of acyl chlorides, after being added dropwise, temperature reaction to raw material disappears.Reaction solution 1M hydrochloric acid, saturated sodium bicarbonate,
Water successively washs, and crude product is obtained after concentration.With after ethyl alcohol recrystallization solid 0.85g, product purity 95.1%.
4 II b(R1 of embodiment=H, R2=Boc) preparation
By 2g compound I, THF is added in flask, under nitrogen protection, is bathed and is cooled down with dry ice-propanone, two silicon of hexamethyl is added dropwise
Base lithium amide (LHMDS) solution, is stirred to react 1h, di-tert-butyl dicarbonate is then added, and after being added dropwise, insulation reaction is extremely
Raw material disappears.Reaction solution is quenched with 10% citric acid, separates organic phase, and water phase is quenched with the tertiary ether of first to be taken, merges organic phase, anhydrous sulphur
Sour sodium dries, filters, and product, yield 75.3% are obtained after concentration.
1H-NMR (CDCl3, 400MHz): δ ppm 8.01(d, J=8.6Hz, 1H), 7.64(d, J=8.6Hz,
1H), 7.26(brs, 1H), 1.51(s, 9H).
13C-NMR (CDCl3, 100MHz): δ ppm 151.78, 151.69, 151.47, 150.14, 111.94,
84.46, 81.78, 28.10.
5 IIc(R1 of embodiment=H, R2=Ms) preparation
By 2g compound I, triethylamine, methylene chloride is added in flask, cooling with ice salt bath under nitrogen protection.First is added dropwise
The dichloromethane solution of alkanesulphonyl chlorides, after being added dropwise, temperature reaction to raw material disappears.Reaction solution 1M hydrochloric acid, saturated carbon
Sour hydrogen sodium, water successively wash, and crude product is obtained after concentration, obtains solid, yield 83.7%, product purity after crude product ethyl alcohol recrystallization
97.2%。
6 IId(R1 of embodiment=H, R2=Ts) preparation
By 2g compound I, triethylamine, methylene chloride is added in flask, cooling with ice salt bath under nitrogen protection.Dropwise addition pair
The dichloromethane solution of toluene sulfochloride, after being added dropwise, temperature reaction to raw material disappears.Reaction solution 1M hydrochloric acid, saturated carbon
Sour hydrogen sodium, water successively wash, and crude product is obtained after concentration.With after ethyl alcohol recrystallization solid 1.15g, product purity 95.1%.
7 IIe(R1 of embodiment=R2=Boc) preparation
By 2g compound I, THF is added in flask, cooling with ice salt bath under nitrogen protection, and 60% sodium hydride, stirring is added
2h is reacted, di-tert-butyl dicarbonate is then added, after being added dropwise, temperature reaction to raw material disappears.Reaction solution is slowly poured into
10% citric acid is quenched, and separates organic phase, and water phase is quenched with the tertiary ether of first to be taken, merges organic phase, and anhydrous sodium sulfate dries, filters, concentration
Product, yield 72.0% are obtained afterwards.
1H-NMR (CDCl3, 400MHz): δ ppm 8.12 (d, J=8.6Hz, 1H), 7.04(d, J=8.6Hz,
1H), 1.51(s, 18H).
13C-NMR (CDCl3, 100MHz): δ ppm 152.62, 151.43, 150.42, 149.95, 119.95,
90.84, 83.91, 27.80.
8 II a(R1 of I of embodiment=H, R2=Ac) preparation
Compound IIa, cuprous iodide, potassium fluoride, 1,10- phenanthroline, DMF, fluoroform are added into reaction flask for nitrogen protection
Base trimethylsilane, stirring to fully reacting.Reaction solution is poured into 2M hydrochloric acid, ethyl acetate extraction, organic phase anhydrous slufuric acid
Sodium dries, filters, and filtrate obtains solid after being concentrated to give.
9 II Ib(R1 of embodiment=H, R2=Boc) preparation
Compound IIb, stannous chloride, potassium fluoride, 1,10- phenanthroline, NMP, fluoroform are added into reaction flask for nitrogen protection
Base trimethylsilane, stirring to fully reacting.Reaction solution is poured into 2M hydrochloric acid, ethyl acetate extraction, organic phase anhydrous slufuric acid
Sodium dries, filters, and filtrate obtains solid after being concentrated to give.
1H-NMR (CDCl3, 400MHz): δ ppm7.93-8.02(m, 2H), 7.64(m 1H), 1.51(s,
9H).
10 IIIc(R1 of embodiment=H, R2=Ms) preparation
Compound IIc, stannous chloride, potassium fluoride, 1,10- phenanthroline, DMSO, trifluoro are added into reaction flask for nitrogen protection
Methyl trimethoxy silane, stirring to fully reacting.Reaction solution is poured into 2M hydrochloric acid, ethyl acetate extraction, the anhydrous sulphur of organic phase
Sour sodium dries, filters, and filtrate obtains solid after being concentrated to give.
11 IIId(R1 of embodiment=H, R2=Ts) preparation
Compound IId, cuprous iodide, potassium fluoride, 1,10- phenanthroline, DMF, fluoroform are added into reaction flask for nitrogen protection
Base trimethylsilane, stirring to fully reacting.Reaction solution is poured into 2M hydrochloric acid, ethyl acetate extraction, organic phase anhydrous slufuric acid
Sodium dries, filters, and filtrate obtains solid after being concentrated to give.
12 IIIe(R1 of embodiment=R2=Boc) preparation
Nitrogen protection, the addition compound ii e into reaction flask, cuprous iodide, tetrabutyl ammonium fluoride, 1,10- phenanthroline, DMF,
Trifluoromethyl trimethylsilane, stirring to fully reacting.Reaction solution is poured into 2M hydrochloric acid, ethyl acetate extraction, organic phase nothing
Aqueous sodium persulfate dries, filters, and filtrate obtains solid after being concentrated to give.
1H-NMR (CDCl3, 400MHz): δ ppm 8.12 (d, J=8.4Hz, 1H), 7.04(d, J=8.4Hz,
1H), 1.55(s, 18H).
13C-NMR (CDCl3, 100MHz): δ ppm 153.80, 150.34, 147.31, 138.37, 122.36,
121.92, 115.92. 27.89.
19F-NMR (CDCl3, 376Hz): 62.89.
The preparation of 13 formula IV compound of embodiment
Nitrogen protection, compound IIIa, ethyl alcohol are added into reaction flask, and concentrated hydrochloric acid is heated until fully reacting.By reaction solution
It is concentrated, methylene chloride and sodium bicarbonate solution is added in residue, after stirring, layering obtains crude product, ethyl alcohol weight after organic phase concentration
Crystallize to obtain product.
1H-NMR (CDCl3, 400MHz): δ ppm 7.65 (d, J=8.5Hz, 1H), 6.39(d, J=8.5Hz,
1H), 5.31( brs, 2H).
13C-NMR (CDCl3, 100MHz): δ ppm 159.87, 147.86, 137.87, 123.0, 113.8,
105.55.
The preparation of 13 formula IV compound of embodiment
Nitrogen protection, compound III b, ethyl alcohol are added into reaction flask, and concentrated hydrochloric acid is heated until fully reacting.Reaction solution is dense
It contracts, methylene chloride and sodium bicarbonate solution is added in residue, after stirring, layering obtains crude product after organic phase concentration, and ethyl alcohol is tied again
It is brilliant to obtain product.
The preparation of 14 formula IV compound of embodiment
Nitrogen protection, compound III e is added into reaction flask, and trifluoroacetic acid is heated until fully reacting.Reaction solution is concentrated,
Methylene chloride and sodium bicarbonate solution are added in residue, after stirring, layering obtains crude product, ethyl alcohol recrystallization after organic phase concentration
Obtain product.
The preparation of 15 formula IV compound of embodiment
Protection, compound III c is added into reaction flask, and hydrobromic acid solution is heated until fully reacting.Reaction solution is concentrated, it is residual
Methylene chloride and sodium bicarbonate solution are added in excess, after stirring, layering obtains crude product after organic phase concentration, and ethyl alcohol recrystallization obtains
Product.
Claims (10)
1. a kind of prepare the chloro- 5- trifluoromethyl of 6- -2-aminopyridine (formula IV) method, which comprises the following steps:
It a) is that raw material obtains formula (II) compound by the reaction of amido protecting with the iodo- 2-aminopyridine of the chloro- 5- of 6- (Formulas I),
Wherein, R1 H, R2 be acetyl group (Ac), tertbutyloxycarbonyl (Boc), mesyl (Ms), p-toluenesulfonyl (Ts),
Or R1 and R2 is simultaneously tertbutyloxycarbonyl (Boc)；
B) Formula II compound is reacted by trifluoromethylation, and compound formula III is prepared,
Wherein, the definition of R1 and R2 is same a)；
C) formula III compound takes off amino protecting group, and the chloro- 5- trifluoromethyl of 6- -2-aminopyridine (formula IV) is prepared.
2. according to the method described in claim 1, upper amino protecting group agents useful for same is chloroacetic chloride, two carbonic acid two in step a)
One of the tert-butyl ester, methane sulfonyl chloride, paratoluensulfonyl chloride.
3. according to the method described in claim 1, it is trifluoromethyl front three silicon that trifluoromethylation, which reacts agents useful for same, in step b)
Alkane and 1,10- phenanthroline.
4. according to the method described in claim 1, being deprotected acid used is concentrated hydrochloric acid, trifluoroacetic acid, hydrogen bromine in step c)
Acid.
5. according to the method described in claim 2, by compound I, triethylamine, methylene chloride is added to flask in step a)
In, it is cooling with ice salt bath under nitrogen protection, the dichloromethane solution of chloroacetic chloride is added dropwise, after reaction, prepares after post treatment
Obtain compound II(R1=H, R2=Ac).
6. according to the method described in claim 2, compound I, THF are added in flask in step a), under nitrogen protection,
It is bathed and is cooled down with dry ice-propanone, lithium hexamethyldisilazide (LHMDS) solution is added dropwise, is stirred to react, two carbonic acid two is then added
Compound II(R1=H, R2=Boc is prepared after reaction in the tert-butyl ester after post treatment).
7. according to the method described in claim 2, compound I, THF are added in flask in step a), under nitrogen protection,
It is cooling with ice salt bath, 60% sodium hydride is added, di-tert-butyl dicarbonate is then added, after reaction, is prepared into after post treatment
To compound II(R1=Boc, R2=Boc).
8. according to the method described in claim 3, compound II(R1=H, R2=Ac are added into reaction flask in step b)), iodine
Change cuprous, potassium fluoride, 1,10- phenanthroline, DMF, trifluoromethyl trimethylsilane, stirring to fully reacting, after post treatment, preparation
Obtain chemical combination III(R1=H, R2=Ac).
9. according to the method described in claim 3, compound II(R1=H, R2=Boc are added into reaction flask in step b)), chlorine
Change cuprous, potassium fluoride, 1,10- phenanthroline, N-Methyl pyrrolidone (NMP), trifluoromethyl trimethylsilane, stirring is to having reacted
Entirely, after post treatment, chemical combination III(R1=H, R2=Boc is prepared).
10. according to the method described in claim 3, in step b), it is added compound II(R1=Boc into reaction flask, R2=
Boc), cuprous iodide, tetrabutyl ammonium fluoride, 1,10- phenanthroline, DMF, trifluoromethyl trimethylsilane, stirring to fully reacting, warp
Later it handles, chemical combination III(R1=Boc, R2=Boc is prepared).
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2010222304A (en) * | 2009-03-24 | 2010-10-07 | Kyushu Univ | Method for producing trifluoromethyl arenes |
| CN102137859A (en) * | 2008-06-13 | 2011-07-27 | Astex治疗学有限公司 | Imidazopyridine derivatives as inhibitors of receptor tyrosine kinases |
| CN105228620A (en) * | 2013-03-15 | 2016-01-06 | 德西费拉制药有限责任公司 | Represent N-acyl group-N '-(pyridine-2-base) urea and the analog of anticancer and antiproliferative activity |
| WO2016168098A1 (en) * | 2015-04-16 | 2016-10-20 | Merck Sharp & Dohme Corp. | FACTOR XIa INHIBITORS |
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- 2017-11-14 CN CN201711125477.2A patent/CN109776401A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102137859A (en) * | 2008-06-13 | 2011-07-27 | Astex治疗学有限公司 | Imidazopyridine derivatives as inhibitors of receptor tyrosine kinases |
| JP2010222304A (en) * | 2009-03-24 | 2010-10-07 | Kyushu Univ | Method for producing trifluoromethyl arenes |
| CN105228620A (en) * | 2013-03-15 | 2016-01-06 | 德西费拉制药有限责任公司 | Represent N-acyl group-N '-(pyridine-2-base) urea and the analog of anticancer and antiproliferative activity |
| WO2016168098A1 (en) * | 2015-04-16 | 2016-10-20 | Merck Sharp & Dohme Corp. | FACTOR XIa INHIBITORS |
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