CN103772273A - Synthetic method of 2-BOC-amino-3-hydroxyl-5-chloropyridine - Google Patents
Synthetic method of 2-BOC-amino-3-hydroxyl-5-chloropyridine Download PDFInfo
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- CN103772273A CN103772273A CN201410076211.3A CN201410076211A CN103772273A CN 103772273 A CN103772273 A CN 103772273A CN 201410076211 A CN201410076211 A CN 201410076211A CN 103772273 A CN103772273 A CN 103772273A
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- amino
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- chloropyridine
- boc
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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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
Abstract
The invention belongs to the field of organic synthesis, and particularly relates to a synthetic method of 2-BOC-amino-3-hydroxyl-5-chloropyridine. The synthetic method of 2-BOC-amino-3-hydroxyl-5-chloropyridine comprises the following steps: by taking 2-amino-3-hydroxyl-5-chloropyridine and di-tert-butyl dicarbonate ester as raw materials, reacting at the temperature of -10 to 50 DEG C for 2-24 hours under action of alkali in an organic solvent; and preparing the 2-BOC-amino-3-hydroxyl-5-chloropyridine after purifying. By adopting the synthetic method to prepare the 2-BOC-amino-3-hydroxyl-5-chloropyridine, the method is mild in reaction condition, easy to operate, stable in product quality, and high in purity.
Description
Technical field
The invention belongs to organic synthesis field, particularly a kind of synthetic method of 2-BOC-amino-3-hydroxyl-5-chloropyridine.
Background technology
2-amino-3-hydroxyl-5-chloropyridine is an important organic synthesis intermediate, the particularly research in pharmaceutical chemistry and application.Its more function group or potential more function group are its key points that is used to organic synthesis.But 2-amino-3-hydroxyl-5-chloropyridine molecule will prevent from mutually combining between amino, therefore, when synthetic, some amino or carboxy protective must be got up, so that reaction can be undertaken by desired mode
BOC, i.e. BOC acid anhydrides, another name tert-Butyl dicarbonate, DIBOC.BOC is transparent crystallization or liquid, in organic synthesis, be used for introducing tertbutyloxycarbonyl protecting group because of.Apply to especially amino acid whose amido protecting, be widely used in medicine, protein and polypeptide are synthetic, and biological chemistry food, in the multiple products such as makeup synthetic.BOC is introduced to 2-amino-3-hydroxyl-5-chloropyridine, synthesize 2-BOC-amino-3-hydroxyl-5-chloropyridine, can greatly improve the stability of pharmaceutical intermediate.Therefore, develop a kind of raw material cheap and easy to get, easy and simple to handle, reaction conditions gentleness, production cost is low, and productive rate is high, is applicable to scale operation, and the method for storage, production process safety is completely necessary.
Summary of the invention
The present invention is in order to make up the defect of prior art, and a kind of synthetic method that can be applied to laboratory and the synthetic 2-BOC-amino-3-hydroxyl-5-chloropyridine of industrialization is provided.
The present invention is achieved through the following technical solutions:
A synthetic method for 2-BOC-amino-3-hydroxyl-5-chloropyridine, is characterized in that, comprises the following steps:
Take 2-amino-3-hydroxyl-5-chloropyridine and tert-Butyl dicarbonate as raw material, in organic solvent, at-10 ~ 50 ℃ of temperature, under the effect of alkali, react and within 2 ~ 24 hours, generate 2-BOC-amino-3-hydroxyl-5-chloropyridine, through hydrochloric acid neutralization, ethyl acetate extraction, saturated common salt water washing, after anhydrous sodium sulfate drying, rotary evaporation concentrate, obtain the thick product of 2-BOC-amino-3-hydroxyl-5-chloropyridine, thick product obtains sterling through recrystallization.
Described organic solvent is the one in ethyl acetate, ethanol and methylene dichloride.
Described alkali is DIPEA, the one in triethylamine and DMAP.
Described recrystallization solvent is ethyl acetate/normal hexane mixed solvent, and ethyl acetate: normal hexane=1:1 is more than volume ratio.
Described raw material consumption is: 2-amino-3-hydroxyl-5-chloropyridine: tert-Butyl dicarbonate=1:1 ~ 1.5 are more than mol ratio.
Described alkali consumption is: alkali: 2-amino-3-hydroxyl-5-chloropyridine=1:1 ~ 6 are more than mol ratio.
Described solvent load is: every 1mol2-amino-3 hydroxyl-5-chloropyridine solubilizing agent 1/3 ~ 1L.
The invention has the beneficial effects as follows: adopt the present invention to prepare 2-BOC-amino-3-hydroxyl-5-chloropyridine, reaction conditions gentleness, easy handling, and constant product quality, purity is high.
Embodiment
Embodiment 1:
In the single necked round bottom flask of 250 milliliters, add 2-amino-3-hydroxyl-5-chloropyridine (14.4g, 100mmol), tert-Butyl dicarbonate (26.2g, 120mmol), triethylamine (10.1g, 100mmol) and 100mL ethanol.Mixture in reaction flask stirring reaction 0.5 hour at 0 ℃.Be transferred to room temperature reaction 3 hours.After reaction finishes, rotary evaporation, except desolventizing, adds 200mL water and 200mL ethyl acetate, separates organic phase, and water is extracted with ethyl acetate (2 × 200mL), after merging organic phase, uses anhydrous Na
2sO
4dry.Rotary evaporation, except desolventizing obtains brown solid thing, will obtain 14.6g white crystal, productive rate 60% after this brown solid use ethyl acetate solution recrystallization.
Embodiment 2:
In the single necked round bottom flask of 2500 milliliters, add 2-amino-3-hydroxyl-5-chloropyridine (144g, 1mol), tert-Butyl dicarbonate (305.2g, 1.4mol), DIPEA (129g, 1mol) and 1000mL ethyl acetate.Mixture in reaction flask stirring reaction 10 hours at 25 ℃.After reaction finishes, add 2000mL water, separate organic phase, water is extracted with ethyl acetate (2 × 2000mL), after merging organic phase, uses anhydrous Na
2sO
4dry.Rotary evaporation, except desolventizing obtains brown solid, for brown solid obtains this 90.5g pale yellow crystals, productive rate 37% after ethyl acetate/normal hexane=1:1 mixed solvent recrystallization.
Embodiment 3:
In the single necked round bottom flask of 500 milliliters, add 2-amino-3-hydroxyl-5-chloropyridine (43.4g, 300mmol), tert-Butyl dicarbonate (78.5g, 360mmol), DMAP (6.1g, 50mmol) and 100mL methylene dichloride.Mixture in reaction flask stirring reaction 12 hours at-10 ℃.After reaction finishes, add 200mL water and 200mL ethyl acetate, separate organic phase, water is extracted with ethyl acetate (2 × 200mL), after merging organic phase, uses anhydrous Na
2sO
4dry.Rotary evaporation, except desolventizing obtains brown solid, will obtain 30.8g white crystal, productive rate 42% after this brown solid use n-hexane/ethyl acetate solution weight crystallization.
Embodiment 4:
In the single necked round bottom flask of 250 milliliters, add 2-amino-3-hydroxyl-5-chloropyridine (43.4g, 300mmol), tert-Butyl dicarbonate (78.5g, 360mmol), triethylamine (30.3g, 300mmol) and 100mL methylene dichloride.Mixture in reaction flask stirring reaction 2 hours at 50 ℃.After reaction finishes, add 200mL water and 200mL ethyl acetate, water is extracted with ethyl acetate (2 × 200mL), after merging organic phase, uses anhydrous Na
2sO
4dry.Rotary evaporation, except desolventizing obtains brown solid, for brown solid obtains this light brown crystal of 44g after ethyl acetate/normal hexane=1:1 mixed solvent recrystallization.Productive rate 60%.
Claims (7)
1. a synthetic method for 2-BOC-amino-3-hydroxyl-5-chloropyridine, is characterized in that, comprises the following steps:
Take 2-amino-3-hydroxyl-5-chloropyridine and tert-Butyl dicarbonate as raw material, in organic solvent, at-10 ~ 50 ℃ of temperature, under the effect of alkali, react and within 2 ~ 24 hours, generate 2-BOC-amino-3-hydroxyl-5-chloropyridine, through hydrochloric acid neutralization, ethyl acetate extraction, saturated common salt water washing, after anhydrous sodium sulfate drying, rotary evaporation concentrate, obtain the thick product of 2-BOC-amino-3-hydroxyl-5-chloropyridine, thick product obtains sterling through recrystallization.
2. the synthetic method of 2-BOC-amino-3-hydroxyl-5-chloropyridine according to claim 1, is characterized in that: described organic solvent is the one in ethyl acetate, ethanol and methylene dichloride.
3. the synthetic method of 2-BOC-amino-3-hydroxyl-5-chloropyridine according to claim 1, is characterized in that: described alkali is DIPEA the one in triethylamine and DMAP.
4. the synthetic method of 2-BOC-amino-3-hydroxyl-5-chloropyridine according to claim 1, is characterized in that: described recrystallization solvent is ethyl acetate/normal hexane mixed solvent, ethyl acetate: normal hexane=1:1, is more than volume ratio.
5. the synthetic method of 2-BOC-amino-3-hydroxyl-5-chloropyridine according to claim 1, is characterized in that: described raw material consumption is: 2-amino-3-hydroxyl-5-chloropyridine: tert-Butyl dicarbonate=1:1 ~ 1.5 are more than mol ratio.
6. the synthetic method of 2-BOC-amino-3-hydroxyl-5-chloropyridine according to claim 1, is characterized in that: described alkali consumption is: alkali: 2-amino-3-hydroxyl-5-chloropyridine=1:1 ~ 6 are more than mol ratio.
7. the synthetic method of 2-BOC-amino-3-hydroxyl-5-chloropyridine according to claim 1, is characterized in that: described solvent load is: every 1mol2-amino-3 hydroxyl-5-chloropyridine solubilizing agent 1/3 ~ 1L.
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| CN201410076211.3A CN103772273A (en) | 2014-03-04 | 2014-03-04 | Synthetic method of 2-BOC-amino-3-hydroxyl-5-chloropyridine |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998015278A1 (en) * | 1996-10-07 | 1998-04-16 | Smithkline Beecham Corporation | Method for stimulating bone formation |
| WO2009032651A1 (en) * | 2007-08-31 | 2009-03-12 | Smithkline Beecham Corporation | Inhibitors of akt activity |
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2014
- 2014-03-04 CN CN201410076211.3A patent/CN103772273A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998015278A1 (en) * | 1996-10-07 | 1998-04-16 | Smithkline Beecham Corporation | Method for stimulating bone formation |
| WO2009032651A1 (en) * | 2007-08-31 | 2009-03-12 | Smithkline Beecham Corporation | Inhibitors of akt activity |
Non-Patent Citations (1)
| Title |
|---|
| JIAN-QIANG QIAN等: "A novel approach for the synthesis of Crizotinib through the key chiral alcohol intermediate by asymmetric hydrogenation using highly active Ir-Spiro-PAP catalyst", 《TETRAHEDRON LETTERS》 * |
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Application publication date: 20140507 |