CN103420902A - Preparation method of 2-chloro-4-iodo-5-methylpyridine - Google Patents
Preparation method of 2-chloro-4-iodo-5-methylpyridine Download PDFInfo
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- CN103420902A CN103420902A CN2012101538277A CN201210153827A CN103420902A CN 103420902 A CN103420902 A CN 103420902A CN 2012101538277 A CN2012101538277 A CN 2012101538277A CN 201210153827 A CN201210153827 A CN 201210153827A CN 103420902 A CN103420902 A CN 103420902A
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- 0 Cc(cnc(Cl)c1)c1-c1c[n](*)c(C(OC)=O)c1 Chemical compound Cc(cnc(Cl)c1)c1-c1c[n](*)c(C(OC)=O)c1 0.000 description 2
- QGMCCRKFZDLEBP-UHFFFAOYSA-N Cc(c(Br)c1)cnc1Cl Chemical compound Cc(c(Br)c1)cnc1Cl QGMCCRKFZDLEBP-UHFFFAOYSA-N 0.000 description 1
- SBFIDGCVBUYPOH-QGZVFWFLSA-N Cc(cnc(Cl)c1)c1-c1c[nH]c(C(N[C@H](CO)c2cccc(Cl)c2)=O)c1 Chemical compound Cc(cnc(Cl)c1)c1-c1c[nH]c(C(N[C@H](CO)c2cccc(Cl)c2)=O)c1 SBFIDGCVBUYPOH-QGZVFWFLSA-N 0.000 description 1
Abstract
The invention discloses a preparation method of 2-chloro-4-iodo-5-methylpyridine, relates to a preparation method of dihalogen substituted pyridine compound, and specifically relates to a preparation method of 2-chloro-4-iodo-5-methylpyridine. The compound can be used as an intermediate for preparing a protein kinase ERK2 inhibitor (WO2005/100342). The preparation method comprises following steps: taking 2-chloro-5-methylpyridine as the raw material, and then subjecting 2-chloro-5-methylpyridine to 4-nitration reactions, reduction reactions, diazotization reactions, and iodination reactions so as to obtain 2-chloro-4-iodo-5-methylpyridine. The preparation method has the advantages of simple technology, and suitability for industrial mass production.
Description
Technical field
The present invention relates to the preparation method of two halogen substituted pyridine compounds, specifically the preparation method of 2-chlorine-4-iodine-5-picoline; This compound can be as intermediate to prepare Protein kinase ERK 2 inhibitor (WO 2005/100342).
Background technology
Protein kinase (Protein kinase) is responsible for the phosphorylation of body internal protein.The protein dephosphorylation ferment (protein phosphatases) of the dephosphorylation of it and responsible protein has relative function.The phosphorylation of protein determines structure and the activity of protein, affects message transmittance process in cell, so that external stimulation is made to appropriate reaction.At present, the diseases such as common heart trouble, diabetes, senile dementia, inflammation and allergy are all relevant to protein kinase, so kinases inhibitor is most important to treating above-mentioned disease.
Existing patent (WO 2005/100342) has been reported the synthetic method of a proteinoid kinases ERK2 inhibitor, and pyridine derivate is the important structure fragment of such kinases inhibitor, and its structural formula is as follows:
The synthetic of compound 2 can realize according to following synthetic route, referring to WO 2005/100342:
From said synthesis route, can find, the bromo-5-picoline of the chloro-4-of 2-is the important intermediate of synthetic this compounds.But the activity of reactivity ratio's iodo pyridine of pyridine bromide is low, therefore, 2-chlorine-4-iodine-5-picoline (hereinafter to be referred as compound 1) is the better intermediate of synthetic this compounds.
Summary of the invention
The object of the invention is to: the preparation method that a kind of simple and easy, effective 2-chlorine-4-iodine-5-picoline is provided.
For achieving the above object, the present invention adopts following technical scheme to realize:
The present invention prepares the method for 2-chlorine-4-iodine-5-picoline, and its preparation process is:
That is: to take CMP (compound 2) be raw material to the first step, under the acetic acid condition, with hydrogen peroxide, reacts, and generates CMP oxynitride (compound 3); Second step, compound 3 reacts and obtains the chloro-4-nitro of digestion product 2--5-picoline oxynitride (compound 4) under nitric acid and sulfuric acid condition; The 3rd step, compound 4 reduces and generates the chloro-4-amino of 2--5-picoline (compound 5) under iron powder and acetic acid condition; The 4th step, compound 5 first generates diazonium salt under sulfuric acid and Sodium Nitrite condition, then with sodium iodide, reacts and both obtains target product 2-chlorine-4-iodine-5-picoline (compound 1).
In the described the first step, oxygenant is hydrogen peroxide, permonosulphuric acid, carbamide peroxide or peroxide 0-chloro-benzoic acid, wherein preferred hydrogen peroxide; Solvent in the described the first step is selected from acetic acid, water, methylene dichloride, and 1,2-ethylene dichloride is wherein that acetic acid is preferred with hydrogen peroxide oxidation.In the described the first step, the mole dosage of oxygenant with the ratio of the molar weight of 2-chloro-5-methypyridine is: 2.5-1; Temperature of reaction is 80 ℃; Reaction times is 1-10 hour, usually at 5-7 hour, has reacted.
In described second step, nitrating agent is sulfuric acid and nitrate mixture; The mole dosage of sulfuric acid used and nitric acid with the ratio of the molar weight of CMP oxynitride is: 10-6-1; Temperature of reaction is 100-160 ℃, wherein take 100 ℃ as excellent; Reaction times is 5-15 hour, usually at 7-10 hour, has reacted.
In described three-step reaction, going back original reagent is iron powder/acetic acid, iron powder/hydrochloric acid, glass putty/hydrochloric acid, tindichloride/hydrochloric acid and hydrogen/palladium carbon, wherein take iron powder/acetic acid as excellent; In described the 3rd step, the mole dosage of reductive agent with the ratio of the molar weight of the chloro-4-nitro of 2--5-picoline oxynitride is: 7-1; Temperature of reaction is 80-120 ℃; Reaction times is 1-5 hour, usually at 2-3 hour, has reacted.
In described four-step reaction, generating diazonium salt acid used is sulfuric acid, hydrochloric acid, Tetrafluoroboric acid and Hydrogen bromide, and the reaction that wherein generates the iodo thing be take sulfuric acid as excellent; Nitrite used is Sodium Nitrite and potassium nitrite; Iodide used are potassiumiodide and sodium iodide; Solvent used is water and water/acetone; The mole dosage of described four-step reaction nitrite and the mole dosage of potassiumiodide are 1.3-1.2-1 with the ratio of the molar weight of the chloro-4-amido of 2--5-picoline; In described four-step reaction, diazotizing temperature of reaction is-10 ℃, and the iodide reaction temperature is 0 ℃; Reaction times is 2-6 hour, usually at 3-4 hour, has reacted.Solvent load described in six-step process is in mL, and the quality of described compound is counted with g.
The invention has the advantages that: the synthetic bibliographical information that there is no at present of compound 1, the present invention is by a brand-new synthetic route, take CMP cheap and easy to get as raw material, generate pyridine nitric oxide through peroxidation, make next step nitration reaction be positioned four of pyridine ring, nitratedly obtain after the nitro product reducing again nitro and oxynitride simultaneously and make amine, finally by diazotization, iodo, obtain desired compound 1.The present invention can, at the industrial compound 1 of producing easily requirement, can further prepare Protein kinase ERK 2 inhibitor with this.
Embodiment
Embodiment below by concrete, be described in detail the present invention, but the invention is not restricted to these examples itself.
One, the preparation of compound 3:
CMP (5.1g, 0.04mol) is placed in to the 100mL reaction flask, adds acetic acid (19.4mL), and slow dropping hydrogen peroxide under stirring at room (35%, 9mL).Drip and finish, be warmed up to 80 ℃, reaction 7h.After cool to room temperature, solvent evaporated, obtain deep yellow liquid 5.6g.Yield 99%.
1H?NMR(400MHz，CDCl
3)δ8.29(s，1H)，7.39(d，J＝8.3Hz，1H)，7.11(dd，J＝8.3，1.4Hz，1H)，2.31(s，3H)；LRMS(ESI
+)calcd?for?C
6H
6ClNO[M+H，
35Cl]
+144.0；found?144.1；[M+H，?
37Cl]146.0；found?146.1。
Two, the preparation of compound 4:
CMP oxynitride (5.50g, 0.04mol) is placed in to the 100mL reaction flask, slowly drips the vitriol oil (20.4mL) and concentrated nitric acid (16.1mL) mixture under stirring at room, be warmed up to 100 ℃ of stirring reaction 7h.Be cooled to room temperature after reacting completely, reaction mixture is poured in 200g ice, will use Na
2CO
3Regulate pH=2～3, filter, filter cake washs with frozen water.Filter cake is dissolved in hot chloroform, filters out not dissolved salt, filter cake washs with chloroform.Filtrate is used Na
2SO
4Drying, solvent evaporated after filtering, obtain yellow solid 6.85g, productive rate 85%.
1H?NMR(400MHz，CDCl
3)δ8.28(d，J＝4.1Hz，1H)，8.22(d，J＝8.5Hz，1H)，2.31(s，3H)；LRMS(ESI
+)calcd?for?C
6H
5ClN
2O
3[M+H，
35Cl]
+189.0；found?189.1；[M+H，
37Cl]191.0；found?191.1。
Three, the preparation of compound 5:
The chloro-4-nitro of 2--5-picoline oxynitride (1.5g, 8.0mmol) is placed in to the 50mL reaction flask, adds Glacial acetic acid (30mL), add reduced iron powder (3.0g, 54mmol) under stirring at room, be warming up to 100 ℃ of stirring reaction 1h.Reaction mixture is poured in NaOH (5M), regulated pH=9～10, be extracted with ethyl acetate (3 * 30mL), saturated common salt water washing separatory for organic phase, organic phase Na
2SO
4Dry.Filter, obtain yellow powdery, column chromatography for separation refined product 0.92g, productive rate 81% after evaporate to dryness.
1H-NMR(400MHz，CDCl
3)δ7.87(s，1H)，6.53(s，1H)，4.22(s，2H)，2.07(s，3H)；LRMS(ESI
+)calcd?for?C
6H
7ClN
2[M+H，
35Cl]
+143.0；found?143.1；[M+H，
37Cl]145.0；found?145.1。
Four, the preparation of compound 1:
The chloro-4-amido of 2--5-picoline (0.25g, 1.75mmol) is placed in to the 50mL reaction flask, adds water (4.17mL), be cooled to 0 ℃.Under stirring, add the vitriol oil (98%, 0.11mL) be cooled to-10 ℃, add by NaNO
2The water of (0.16g, 2.32mmol) (1.39mL) solution ,-10 ℃ of stirring reaction 1h.Add acetone (6mL), then under agitation drip water (1.39mL) solution of KI (0.35g, 2.11mmol), 0 ℃ of lower stirring reaction 4h.After reacting completely, with 35%NaOH solution, be neutralized to pH=7, by extracted with diethyl ether (3 * 10mL), separatory, use Na
2SO
4Drying, filter, the evaporate to dryness organic solvent, and the column chromatography for separation refined product, obtain yellow powdery 0.25g, productive rate 56.4%.
1H-NMR(400MHz，CDCl
3)δ8.14(s，1H)，7.79(s，1H)，2.38(s，3H)；LRMS(ESI
+)calcd?for?C
6H
5ClIN[M+H，?
35Cl]
+253.9；found?253.9；[M+H，
37Cl]255.9；found?255.9。
Claims (7)
1. the preparation method of 2-chlorine-4-iodine-5-picoline, take CMP as raw material, comprises the steps:
(a), CMP and oxidant reaction generate oxynitride;
(b), oxynitride issues the caliche reaction at sulfuric acid and nitric acid effect, obtains 4-nitro substitution compound;
(c), metal catalytic hydrogenation obtains the 4-aminocompound;
(d), intermediate diazotization under acid and nitrite condition, then iodo generation target compound 2-chlorine-4-iodine-5-picoline.
2. the preparation method of a kind of 2-chlorine-4-iodine according to claim 1-5-picoline, it is characterized in that: the oxidizing reaction in step (a) is carried out in acetic acid or methylene dichloride, oxidising agent is hydrogen peroxide or metachloroperbenzoic acid, described oxidizing reaction temperature is 70-90 ℃, and described oxidation time is 7-10 hour.
3. the preparation method of a kind of 2-chlorine-4-iodine according to claim 1-5-picoline, it is characterized in that: the nitration reaction in step (b) is carried out in sulfuric acid, nitrating agent used is nitric acid, described nitration reaction temperature is 100-160 ℃, and the described nitration reaction time is 5-15 hour.
4. the preparation method of a kind of 2-chlorine-4-iodine according to claim 1-5-picoline, it is characterized in that: the catalytic hydrogenation in step (c) is carried out in methyl alcohol or ethanol, described catalytic hydrogenation temperature is 15～100 ℃, the pressure of described catalytic hydrogenation system is 0.2～3.0MPa, and the described catalytic hydrogenation time is 3～12 hours.
5. the preparation method of a kind of 2-chlorine-4-iodine according to claim 4-5-picoline, it is characterized in that: described catalytic hydrogenation also includes the metallic reducing catalyzer, described metallic reducing catalyzer is iron powder, palladium charcoal, a kind of in tin, tin protochloride.
6. the preparation method of a kind of 2-chlorine-4-iodine according to claim 5-5-picoline is characterized in that: the consumption of described metallic reducing catalyzer is 0.1～5 times of quality of the chloro-4-nitro of 2--5-picoline.
7. the preparation method of a kind of 2-chlorine-4-iodine according to claim 1-5-picoline, it is characterized in that: the diazotization reaction in step (d) is carried out under the sulfuric acid condition, and nitrite used is Sodium Nitrite or potassium nitrite; Iodo reagent is sodium iodide or potassiumiodide; Described diazotization reaction temperature is-5～5 ℃; The described diazotization reaction time is 3-5 hour.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106467488A (en) * | 2016-09-28 | 2017-03-01 | 贵州大学 | A kind of preparation technology of 2 iodine, 3 bromine 5 chloropyridine |
| CN106748721A (en) * | 2016-11-17 | 2017-05-31 | 山东铂源药业有限公司 | A kind of preparation method of the iodo-benzoic acid of 2 chlorine 5 |
| CN106928130A (en) * | 2017-04-20 | 2017-07-07 | 无锡捷化医药科技有限公司 | A kind of preparation method of the picoline of 2 chlorine, 6 methoxyl group 3 |
| CN114380738A (en) * | 2021-09-28 | 2022-04-22 | 都创(重庆)医药科技有限公司 | Synthetic method of 3-bromo-4-chloro-2-methylpyridine |
| CN114751855A (en) * | 2022-05-23 | 2022-07-15 | 上海皓鸿生物医药科技有限公司 | Preparation method of 2-bromo-4-amino-5-methylpyridine |
| CN115340492A (en) * | 2022-09-26 | 2022-11-15 | 武汉海特生物创新医药研究有限公司 | Preparation method of 2-hydroxy-4-amino-5-methylpyridine |
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| US20040029857A1 (en) * | 2002-04-26 | 2004-02-12 | Hale Michael Robin | Heterocyclic inhibitors of ERK2 and uses thereof |
| US20060019953A1 (en) * | 2004-03-26 | 2006-01-26 | Michael Hale | Pyridine inhibitors of ERK2 and uses thereof |
| CN102105150A (en) * | 2008-05-21 | 2011-06-22 | 阿里亚德医药股份有限公司 | Phosphorous derivatives as kinase inhibitors |
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2012
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| US20040029857A1 (en) * | 2002-04-26 | 2004-02-12 | Hale Michael Robin | Heterocyclic inhibitors of ERK2 and uses thereof |
| US20060019953A1 (en) * | 2004-03-26 | 2006-01-26 | Michael Hale | Pyridine inhibitors of ERK2 and uses thereof |
| CN102105150A (en) * | 2008-05-21 | 2011-06-22 | 阿里亚德医药股份有限公司 | Phosphorous derivatives as kinase inhibitors |
Non-Patent Citations (2)
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106467488A (en) * | 2016-09-28 | 2017-03-01 | 贵州大学 | A kind of preparation technology of 2 iodine, 3 bromine 5 chloropyridine |
| CN106748721A (en) * | 2016-11-17 | 2017-05-31 | 山东铂源药业有限公司 | A kind of preparation method of the iodo-benzoic acid of 2 chlorine 5 |
| CN106748721B (en) * | 2016-11-17 | 2019-06-21 | 山东铂源药业有限公司 | A kind of preparation method of the chloro- 5- iodo-benzoic acid of 2- |
| CN106928130A (en) * | 2017-04-20 | 2017-07-07 | 无锡捷化医药科技有限公司 | A kind of preparation method of the picoline of 2 chlorine, 6 methoxyl group 3 |
| CN114380738A (en) * | 2021-09-28 | 2022-04-22 | 都创(重庆)医药科技有限公司 | Synthetic method of 3-bromo-4-chloro-2-methylpyridine |
| CN114751855A (en) * | 2022-05-23 | 2022-07-15 | 上海皓鸿生物医药科技有限公司 | Preparation method of 2-bromo-4-amino-5-methylpyridine |
| CN115340492A (en) * | 2022-09-26 | 2022-11-15 | 武汉海特生物创新医药研究有限公司 | Preparation method of 2-hydroxy-4-amino-5-methylpyridine |
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