CN110041252A - A kind of preparation method of the chloro- 4- hydrazino pyridine of 2- - Google Patents
A kind of preparation method of the chloro- 4- hydrazino pyridine of 2- Download PDFInfo
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- CN110041252A CN110041252A CN201910428762.4A CN201910428762A CN110041252A CN 110041252 A CN110041252 A CN 110041252A CN 201910428762 A CN201910428762 A CN 201910428762A CN 110041252 A CN110041252 A CN 110041252A
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- China
- Prior art keywords
- chloro
- hydrazino pyridine
- pyridine
- bromo
- hydrazino
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Classifications
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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
- C07D213/76—Nitrogen atoms to which a second hetero atom is attached
- C07D213/77—Hydrazine radicals
Abstract
The invention discloses a kind of synthetic methods of the chloro- 4- hydrazino pyridine of 2-, characterized in that the following steps are included: dispersing the bromo- 2- chloropyridine of 4- in hydrazine hydrate, after reacting 12 ~ 48h at 20 ~ 60 DEG C, adjusts pH to alkalinity, obtains the chloro- 4- hydrazino pyridine of 2-.A kind of synthetic method of the chloro- 4- hydrazino pyridine of 2- of the invention, operating procedure is simple, reaction process is mild, solid waste pollution is small；Meanwhile the bromo- 2- chloropyridine raw material of 4- is cheap and easy to get, atom availability is better than corresponding iodo object, and simple process, high income, and product is chromatographed without column, significantly reduces production cost, is suitable for the chloro- 4- hydrazino pyridine of large scale preparation 2-.
Description
Technical field
The present invention relates to a kind of preparation methods of the chloro- 4- hydrazino pyridine of 2-, belong to fine chemistry industry and medicine intermediate synthesis
Technical field.
Background technique
The chloro- 4- hydrazino pyridine of 2- is important medicinal intermediate, is widely used in one major class CFTR regulator of synthesis, PI3K
Inhibitor.Have in the Therapy study of tumour, rheumatoid arthritis, psoriasis, disease in the blood system or cardiovascular disease
Important application.
US2013165464A1 reports the synthetic method of I a kind of, and from compound II, and hydration hydrazine reaction can be with
Compound I is obtained in high yield:
Reagent and condition: NH2-NH2, EtOH, reflux, 97%.
In the preparation process, raw material 2- chlorine-4-iodine pyridine (II) price is higher, high process cost when largely preparing I.
Patent WO200446120 is reported from the chloro- 4-aminopyridine of 2- (III) by diazotising and reduction preparation I:
Reagent and condition: a) NaNO2,H2SO4; b)SnCl2。
In the preparation method, intermediate is diazonium salt, there is potential risk of explosion.And SnCl2Reduction can generate a large amount of stanniferous
Solid waste, final product are also required to by column chromatographic purifying.
Therefore, above two technique is unsuitable for the chloro- 4- hydrazino pyridine of large scale preparation 2-.
Summary of the invention
The technical problem to be solved by the present invention is to overcome the deficiencies of existing technologies, a kind of chloro- 4- hydrazino pyridine of 2- is provided
Synthetic method, the chloro- 4- hydrazino pyridine of 2- is prepared by a kind of new synthetic method, reaction process is mild, solid waste pollution
It is small.
Above-mentioned technical purpose of the invention has the technical scheme that
A kind of synthetic method of the chloro- 4- hydrazino pyridine of 2-, comprising the following steps: it disperses the bromo- 2- chloropyridine of 4- in hydrazine hydrate,
After reacting 12 ~ 48h at 20 ~ 60 DEG C, pH is adjusted to alkalinity, obtains the chloro- 4- hydrazino pyridine of 2-；
Reaction process are as follows:
。
Preferably, the molar ratio of the bromo- 2- chloropyridine of the 4- and hydrazine hydrate is 1.0: 0.2 ~ 1.0: 30.0.
Preferably, the molar ratio of the bromo- 2- chloropyridine of the 4- and hydrazine hydrate is 1.0: 6.0 ~ 1.0: 12.0.
By using above-mentioned technical proposal, reacted using the bromo- 2- chloropyridine of the 4- of certain mol proportion and hydrazine hydrate, one
Aspect is conducive to progress and the last handling process of reaction, is on the other hand conducive to improve yield.
Preferably, the reaction temperature is 40 DEG C ~ 50 DEG C.
It by using above-mentioned technical proposal, is reacted within a reasonable temperature range, reaction rate not only can be improved
It can also promote the progress of reaction.
Preferably, the reaction time is 24 ~ 30h.
By using above-mentioned technical proposal, is reacted in range at a reasonable time, yield not only can be improved, moreover it is possible to
Save reaction cost.
Preferably, the pH is 9 ~ 12.
By using above-mentioned technical proposal, available yield is higher in a certain range of pH, the higher 2- of purity is chloro-
4- hydrazino pyridine.
In conclusion the invention has the following advantages:
(1) synthetic method of the chloro- 4- hydrazino pyridine of a kind of 2- of the invention, operating procedure is simple, reaction process is mild, solid waste is dirty
It contaminates small；
(2) synthetic method of the chloro- 4- hydrazino pyridine of a kind of 2- of the invention, the bromo- 2- chloropyridine raw material of 4- is cheap and easy to get, atom benefit
Expenditure is better than corresponding iodo object, and simple process, high income, and product is chromatographed without column, significantly reduces production cost, fits
In the chloro- 4- hydrazino pyridine of large scale preparation 2-.
Detailed description of the invention
Fig. 1 is the chloro- 4- hydrazino pyridine of 2- of the invention1HNMR figure.
Specific embodiment
The invention will be further described below.Following embodiment is only used for clearly illustrating technical side of the invention
Case, and not intended to limit the protection scope of the present invention.
A kind of synthetic method of the chloro- 4- hydrazino pyridine of 2-, comprising the following steps: disperse hydration for the bromo- 2- chloropyridine of 4-
In hydrazine, after reacting 12 ~ 48h at 20 ~ 60 DEG C, pH is adjusted to alkalinity, obtains the chloro- 4- hydrazino pyridine of 2-；
Reaction process are as follows:
。
The chloro- 4- hydrazino pyridine of 2- of the invention1HNMR figure is as shown in Figure 1.
Embodiment 1
The synthesis of the chloro- 4- hydrazino pyridine of 2-:
150 ml, 80% hydrazine hydrate (2.397 is dispersed by the bromo- 2- chloropyridine V(50 g of 4-, 260 mmol, 1.0 equiv.)
Mol, 9.2 equiv.), 40 DEG C of oil bath are reacted 24 hours, and TLC display reaction terminates, and 2NSodium hydrate aqueous solution tune pH is extremely
11, EA/THF(2: 1) extracting, organic phase is concentrated to give 30.6 g faint yellow solids, the chloro- 4- hydrazino pyridine I of as 2-, and yield is
82%。
1H NMR (400 MHz, DMSO-D6):δPpm 7.97(s, 1H) 7.77(d,J =5.80 Hz, 1H) 6.65
(s, 1H), 6.55(d,J =5.72 Hz, 1H) 4.32(s, 2H).
Embodiment 2
The synthesis of the chloro- 4- hydrazino pyridine of 2-:
96 ml, 80% hydrazine hydrate (1.563 is dispersed by the bromo- 2- chloropyridine V(50 g of 4-, 260 mmol, 1.0 equiv.)
Mol, 6 equiv.), 20 DEG C of oil bath are reacted 12 hours, and TLC display reaction terminates, and 2NSodium hydrate aqueous solution tune pH to 9,
EA/THF(2: 1) extracting, and organic phase is concentrated to give 24.3g faint yellow solid, the chloro- 4- hydrazino pyridine I of as 2-, yield 65%.
1H NMR (400 MHz, DMSO-D6):δPpm 7.97(s, 1H) 7.77(d,J =5.80 Hz, 1H) 6.65
(s, 1H), 6.55(s,J =5.72 Hz, 1H), 4.32(s, 2H).
Embodiment 3
The synthesis of the chloro- 4- hydrazino pyridine of 2-:
96 ml, 80% hydrazine hydrate (4.794 is dispersed by the bromo- 2- chloropyridine V(50 g of 4-, 260 mmol, 1.0 equiv.)
Mol, 12 equiv.), 60 DEG C of oil bath are reacted 48 hours, and TLC display reaction terminates, and 2NSodium hydrate aqueous solution tune pH is extremely
12, EA/THF(2: 1) extracting, organic phase is concentrated to give 31.3g faint yellow solid, the chloro- 4- hydrazino pyridine I of as 2-, and yield is
84%。
1H NMR (400 MHz, DMSO-D6):δPpm 7.97(s, 1H) 7.77(d,J =5.80 Hz, 1H) 6.65
(s, 1H), 6.55(d,J =5.72 Hz, 1H) 4.32(s, 2H).
The above is only a preferred embodiment of the present invention, protection scope of the present invention is not limited merely to above-mentioned implementation
Example, all technical solutions belonged under thinking of the present invention all belong to the scope of protection of the present invention.It should be pointed out that for the art
Those of ordinary skill for, several improvements and modifications without departing from the principles of the present invention, these improvements and modifications
It should be regarded as protection scope of the present invention.
Claims (6)
1. a kind of synthetic method of the chloro- 4- hydrazino pyridine of 2-, characterized in that the following steps are included: the bromo- 2- chloropyridine of 4- is dispersed
In hydrazine hydrate, after reacting 12 ~ 48h at 20 ~ 60 DEG C, pH is adjusted to alkalinity, obtains the chloro- 4- hydrazino pyridine of 2-；
Reaction process are as follows:
。
2. a kind of synthetic method of the chloro- 4- hydrazino pyridine of 2- according to claim 1, characterized in that the bromo- 2- chlorine of 4-
The molar ratio of pyridine and hydrazine hydrate is 1.0: 0.2 ~ 1.0: 30.0.
3. a kind of synthetic method of the chloro- 4- hydrazino pyridine of 2- according to claim 2, characterized in that the bromo- 2- chlorine of 4-
The molar ratio of pyridine and hydrazine hydrate is 1.0: 6.0 ~ 1.0: 12.0.
4. a kind of synthetic method of the chloro- 4- hydrazino pyridine of 2- according to claim 1, characterized in that the reaction temperature
It is 40 DEG C ~ 50 DEG C.
5. a kind of synthetic method of the chloro- 4- hydrazino pyridine of 2- according to claim 1, characterized in that the reaction time
For 24 ~ 30h.
6. a kind of synthetic method of the chloro- 4- hydrazino pyridine of 2- according to claim 1, characterized in that the pH is 9 ~ 12.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201910428762.4A CN110041252A (en) | 2019-05-22 | 2019-05-22 | A kind of preparation method of the chloro- 4- hydrazino pyridine of 2- |
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| CN201910428762.4A CN110041252A (en) | 2019-05-22 | 2019-05-22 | A kind of preparation method of the chloro- 4- hydrazino pyridine of 2- |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013096630A1 (en) * | 2011-12-23 | 2013-06-27 | Millennium Pharmaceuticals, Inc. | Heteroaryls and uses thereof |
| CN106588758A (en) * | 2016-11-08 | 2017-04-26 | 江苏富比亚化学品有限公司 | Synthetic process for 2-hydrazinylpyridine derivative |
-
2019
- 2019-05-22 CN CN201910428762.4A patent/CN110041252A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013096630A1 (en) * | 2011-12-23 | 2013-06-27 | Millennium Pharmaceuticals, Inc. | Heteroaryls and uses thereof |
| CN106588758A (en) * | 2016-11-08 | 2017-04-26 | 江苏富比亚化学品有限公司 | Synthetic process for 2-hydrazinylpyridine derivative |
Non-Patent Citations (1)
| Title |
|---|
| MICHAEL G. C. KAHN等: "Microwave-enhanced nucleophilic fluorination in the synthesis of fluoropyridyl derivatives of [3,2-c]pyrazolo-corticosteroids,potential glucocorticoid receptor-mediated imaging agents", 《BIOORG. MED. CHEM. LETT.》 * |
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