CN101768111B - Method for preparing 2-chloro-5-fluoropyridine-3-benzoic acid - Google Patents
Method for preparing 2-chloro-5-fluoropyridine-3-benzoic acid Download PDFInfo
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- CN101768111B CN101768111B CN 200910044975 CN200910044975A CN101768111B CN 101768111 B CN101768111 B CN 101768111B CN 200910044975 CN200910044975 CN 200910044975 CN 200910044975 A CN200910044975 A CN 200910044975A CN 101768111 B CN101768111 B CN 101768111B
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- palladium
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Abstract
The invention discloses a method for preparing 2-chloro-5-fluoropyridine-3-benzoic acid represented by a formula I, which comprises the step of reacting a compound II and a formate in a solvent in the presence of a palladium catalyst to obtain the compound I. The preparation method of the invention has the advantages that: the formate is used as a reducer, so the equipment corrosion by formic acid adopted in the traditional method is reduced, the production and operation environments are improved and an acid bonding agent is not required; the synthesis process is simple, the cost is low, the yield is as high as 80 to 90 percent, the product purity is high, and industrial production is suitable to be carried out; and the preferred ionic liquid used is environmentally-friendly and simple in post treatment and can be repeatedly used.
Description
Technical field
The present invention relates to a kind of preparation method of pharmaceutical intermediate, the concrete preparation method who relates to a kind of 2-chloro-5-fluorine Nicotinicum Acidum.
Background technology
2-chloro-5-fluorine Nicotinicum Acidum (I) has following structural formula:
This compound is the synthetic field of a medicine midbody commonly used.Feritin vasotonia system (renin-angiotensin system, RAS) medicine important intermediate for example.
So far, bibliographical information 2-chloro-5-fluorine Nicotinicum Acidum synthesizes has two kinds of methods.First method is to use 2, and 6-two chloro-5-fluorine Nicotinicum Acidums are raw material, in N (DMF) solvent, under the palladium catalysis, use excessive formic acid to carry out dechlorination reaction; Second method is that Abbott company uses 2; 6-two chloro-5-fluorine Nicotinicum Acidum methyl esters are raw material; With the sodium methyl mercaptide reaction, at first generate 2-chloro-5-fluoro-6-first mercaptopyridine-3-methyl-formiate, Raney Ni shortening then; Slough the first sulfydryl and generate 2-chloro-5-fluorine Nicotinicum Acidum, but do not see detailed productive rate report.Up to the present synthesizing of this compound do not obtain gratifying result yet.Two kinds of methods are specific as follows:
First method:
X.Wang (J.Org.Chem., 2006,71; P4021) report 2,6-two chloro-5-fluorine Nicotinicum Acidums are raw material, in N and the dimethylacetamide solvent; Under palladium/triphenylphosphine catalysis, use excessive formic acid to be reductive agent, triethylamine is an organic bases; Carry out dechlorination reaction, productive rate is 70%.In this method, use excessive formic acid to be reductive agent, the subsequent waste water generation is big, contains DMF wastewater treatment difficulty, and environmental pollution is heavy.
Second method:
M.Winn (J.Med.Chem., 1993,36; P2676) etc. the people reports and uses 2, and 6-two chloro-5-fluorine Nicotinicum Acidum methyl esters react with sodium methyl mercaptide for setting out raw material; At first generate 2-chloro-5-fluoro-6-first mercaptopyridine-3-methyl-formiate; Raney Ni shortening is sloughed the first sulfydryl and is generated 2-chloro-5-fluorine Nicotinicum Acidum, but do not appear in the newspapers concrete productive rate then.By product thiomethyl alcohol smell is smelly unusually in addition, and the production operation environment is abominable, and it is healthy to influence the employee, and environmental pollution is serious.This method aftertreatment cost is high, is difficult to carry out suitability for industrialized production equally, can not satisfy the heavy demand of medicine industry production to this raw material.
Summary of the invention
Technical problem to be solved by this invention is the defective that can produce corrosion and need to use the acid binding agent triethylamine of expensive equipment for reductive agent formic acid used in the method that overcomes existing preparation 2-chloro-5-fluorine Nicotinicum Acidum, and a kind of preparation method of 2-chloro-5-fluorine Nicotinicum Acidum is provided.Preparing method of the present invention uses formate to be reductive agent, can reduce in the existing method formic acid to corrosion on Equipment, thereby improve the production operation environment, and can avoid the use of acid binding agent; Synthesis technique is simple, and cost is lower, and yield is higher, can reach 80%～90%, and product purity is also higher, is suitable for carrying out suitability for industrialized production; And when using preferred lyate ion liquid, environmentally friendly, aftertreatment is simple, and can reuse.
The present invention relates to a kind of preparation method suc as formula the 2-chloro-5-fluorine Nicotinicum Acidum shown in the I, it comprises the following step: in the solvent, under the effect of palladium catalyst, compound I I and formate react, and can make compound I.
Wherein, described formate is preferable is in ammonium formiate, sodium formiate, potassium formiate, lithium formate, cesium formate, magnesium formiate and the calcium formiate etc. one or more, the preferable formic acid ammonium; The consumption of described formate is preferable is 1.5～5 times of compound I I molar weight, and better is 1.5～3.0 times;
Described solvent can be for the conventional solvent of this type of reaction of this area, like N, and dinethylformamide and/or N; The N-N,N-DIMETHYLACETAMIDE, the preferred especially N of the present invention, dinethylformamide, N; In N-N,N-DIMETHYLACETAMIDE and the ionic liquid one or more, best is ionic liquid.The consumption of solvent is this area conventional amount used, when solvent is ionic liquid, the volume mass of ionic liquid and compound I I than preferable be 3～10ml/g, that better is 4.7～5.7ml/g; Described ionic liquid can be existing all ionic liquid, and that preferable is 1-methyl-3-ethyl imidazol(e) a tetrafluoro borate ([EMI] BF
4), 1-methyl-3-NSC 158165 a tetrafluoro borate ([BMI] BF
4), 1-methyl-3-benzyl imidazole a tetrafluoro borate ([BnMI] BF
4), 1-methyl-3-ethyl imidazol(e) hexafluorophosphate ([EMI] PF
6), 1-methyl-3-NSC 158165 hexafluorophosphate ([BMI] PF
6) and 1-methyl-3-benzyl imidazole hexafluorophosphate ([BnMI] PF
6) in waiting one or more.
That described palladium catalyst is preferable is Palladous chloride, palladium bromide, palladium iodide, palladous sulfate, Palladous nitrate, palladium, trifluoracetic acid palladium, propionic acid palladium, levulinic acid palladium [Pd (acac)
2], two (triphenylphosphine) Palladous chloride [Pd (PPh
3)
2Cl
2], two (triphenylphosphine) palladium bromide [Pd (PPh
3)
2Br
2], two (triphenylphosphine) palladium [Pd (PPh
3)
2(OAc)
2] and tetrakis triphenylphosphine palladium [Pd (PPh
3)
4] in waiting one or more, can also be the mixture of palladium and triphenylphosphine; The consumption of described palladium catalyst is preferable is 0.01～0.1 times of compound I I molar weight, and better is 0.04～0.06 times;
What the temperature of described reaction was preferable is 50～120 ℃, and better is 60～100 ℃; The time of described reaction preferable with detection reaction fully till, preferred 5～15 hours, better was 8～12 hours;
Among the preparation method of the present invention, after reaction is accomplished, only need carry out simple aftertreatment and can obtain pure compound I as filtering.
Except that specified otherwise, raw material that the present invention relates to and reagent are all commercially available to be got.
Positive progressive effect of the present invention is:
(1) among the preparation method of the present invention, reductive agent is a formate, not only can reduce in the existing method and use formic acid to corrosion on Equipment, improves the production operation environment, and can save the more expensive acid binding agent triethylamine of price that uses in the existing method.
(2) preparing method's cost of the present invention is lower, and technology is simple, easy handling, and yield is higher, can reach 80%～90%, and product purity is also higher, not only is fit to the laboratory and prepares on a small scale, and be fit to upward scale operation of industry.
(3) among the preparation method of the present invention, when solvent is preferably ionic liquid, can avoid the use of any poisonous and hazardous organic solvent; Environmentally friendly, and aftertreatment is simple, has saved the distillation reclaimer to the poisonous and harmful solvent; Used ionic liquid not only is easy to reclaim, and can reuse.
Embodiment
Further specify the present invention with embodiment below, but the present invention is not limited.
Embodiment 1
To add Palladous chloride (0.001mol), ammonium formiate (0.12mol), 2,6-two chloro-5-fluorine Nicotinicum Acidums (0.1mol) are to N (60ml).Heat to 60 ℃ then, stirred 7 hours, HPLC follows the tracks of the raw material completely dissolve.Cool to room temperature, filtering and obtaining target compound is light yellow solid, productive rate is 90%, purity 99.6% (HPLC), appraising datum and document X.Wang (J.Org.Chem., 2006,71, p4021) report is consistent.
Embodiment 2
With palladium bromide (0.004mol), sodium formiate (0.15mol), 6-two chloro-5-fluorine Nicotinicum Acidums (0.1mol) join in the N (100ml).Heat to 80 ℃ then, stirred 6 hours, HPLC follows the tracks of the raw material completely dissolve.Cool to room temperature, filtering and obtaining target compound is light yellow solid, productive rate is 88%, purity 99.4% (HPLC).
Embodiment 3
To add palladium iodide (0.006mol), potassium formiate (0.2mol), 2,6-two chloro-5-fluorine Nicotinicum Acidums (0.1mol) are in N,N-DIMETHYLACETAMIDE (120ml).Heat to 50 ℃ then, stirred 15 hours, HPLC follows the tracks of the raw material completely dissolve.Cool to room temperature, filtering and obtaining target compound is light yellow solid, productive rate is 84%, purity 98.8% (HPLC).
Embodiment 4
To add palladium (0.01mol), lithium formate (0.3mol), 2,6-two chloro-5-fluorine Nicotinicum Acidums (0.1mol) are to N,N-DIMETHYLACETAMIDE (180ml), in the reaction flask.Heat to 100 ℃ then, stirred 6 hours, HPLC follows the tracks of the raw material completely dissolve.Cool to room temperature, filtering and obtaining target compound is light yellow solid, productive rate is 90%, purity 99.0% (HPLC).
Embodiment 5
With levulinic acid palladium [Pd (acac)
2] (0.002mol), magnesium formiate (0.5mol), N,N-DIMETHYLACETAMIDE (130ml), 2,6-two chloro-5-fluorine Nicotinicum Acidums (0.1mol) add in the reaction flask.Heat to 110 ℃ then, stirred 5 hours, HPLC follows the tracks of the raw material completely dissolve.Cool to room temperature, filtering and obtaining target compound is light yellow solid, productive rate is 87%, purity 99.3% (HPLC).
Embodiment 6
With two (triphenylphosphine) Palladous chloride [Pd (PPh
3)
2Cl
2] (0.0035mol), cesium formate (0.3mol), N,N-DIMETHYLACETAMIDE (210ml), 2,6-two chloro-5-fluorine Nicotinicum Acidums (0.1mol) add in the reaction flask.Heat to 120 ℃ then, stirred 5 hours, HPLC follows the tracks of the raw material completely dissolve.Cool to room temperature, filtering and obtaining target compound is light yellow solid, productive rate is 92%, purity 99.1% (HPLC).
Embodiment 7
With palladous sulfate (0.005mol), calcium formiate (0.2mol), 2, (MW:210,0.1mol 21g) add ionic liquid 1-methyl-3-ethyl imidazol(e) a tetrafluoro borate ([EMI] BF to 6-two chloro-5-fluorine Nicotinicum Acidums
4) (63ml) in.Heat to 60 ℃ then, stirred 7 hours, HPLC follows the tracks of the raw material completely dissolve.Cool to room temperature, filtering and obtaining target compound is light yellow solid, productive rate is 80%, purity 98.6% (HPLC), appraising datum and document X.Wang (J.Org.Chem., 2006,71, p4021) report is identical.
Embodiment 8
With Palladous nitrate (0.005mol), sodium formiate (0.2mol), 2,6-two chloro-5-fluorine Nicotinicum Acidums (0.1mol) join ionic liquid 1-methyl-3-NSC 158165 a tetrafluoro borate ([EMI] BF
4) (80ml) in.Heat to 80 ℃ then, stirred 5 hours, HPLC follows the tracks of the raw material completely dissolve.Cool to room temperature, filtering and obtaining target compound is light yellow solid, productive rate is 85%, purity 99.0% (HPLC).
Embodiment 9
With trifluoracetic acid palladium (0.005mol), potassium formiate (0.2mol), 2,6-two chloro-5-fluorine Nicotinicum Acidums (0.1mol) join ionic liquid 1-methyl-3-benzyl imidazole a tetrafluoro borate ([BnMI] BF
4) (98.7ml) in.Heat to 100 ℃ then, stirred 5 hours, HPLC follows the tracks of the raw material completely dissolve.Cool to room temperature, filtering and obtaining target compound is light yellow solid, productive rate is 87%, purity 99.4% (HPLC)
Embodiment 10
With propionic acid palladium (0.005mol), lithium formate (0.2mol), 2,6-two chloro-5-fluorine Nicotinicum Acidums (0.1mol) join ionic liquid 1-methyl-3-ethyl imidazol(e) hexafluoro phosphonate ([EMI] PF
6) (120ml), add in the reaction flask.Heat to 60 ℃ then, stirred 7 hours, HPLC follows the tracks of the raw material completely dissolve.Cool to room temperature, filtering and obtaining target compound is light yellow solid, productive rate is 89%, purity 99.1% (HPLC).
Embodiment 11
With two (triphenylphosphine) palladium bromide (0.005mol), magnesium formiate (0.2mol), 2,6-two chloro-5-fluorine Nicotinicum Acidum (0.1mol) ionic liquid 1-methyl-3-NSC 158165 hexafluoro phosphonate ([EMI] PF
6) (180ml) add in the reaction flask.Heat to 80 ℃ then, stirred 9 hours, HPLC follows the tracks of the raw material completely dissolve.Cool to room temperature, filtering and obtaining target compound is light yellow solid, productive rate is 90%, purity 99.2% (HPLC).
Embodiment 12
With two (triphenylphosphine) palladium (0.005mol), cesium formate (0.2mol), 2,6-two chloro-5-fluorine Nicotinicum Acidum (0.1mol) ionic liquid 1-methyl-3-benzyl imidazole hexafluoro phosphonate ([BnMI] PF
6) (210ml) add in the reaction flask.Heat to 100 ℃ then, stirred 9 hours, HPLC follows the tracks of the raw material completely dissolve.Cool to room temperature, filtering and obtaining target compound is light yellow solid, productive rate is 92%, purity 99.0% (HPLC).
Embodiment 13
With tetrakis triphenylphosphine palladium (0.005mol), cesium formate (0.2mol), 2,6-two chloro-5-fluorine Nicotinicum Acidum (0.1mol) ionic liquid 1-methyl-3-benzyl imidazole hexafluoro phosphonate ([BnMI] PF
6) (210ml) add in the reaction flask.Heat to 100 ℃ then, stirred 9 hours, HPLC follows the tracks of the raw material completely dissolve.Cool to room temperature, filtering and obtaining target compound is light yellow solid, productive rate is 92%, purity 99.0% (HPLC).
Embodiment 14
With palladium (0.005mol), triphenylphosphine (0.01mol), ammonium formiate (0.2mol), 2,6-two chloro-5-fluorine Nicotinicum Acidum (0.1mol) ionic liquid 1-methyl-3-benzyl imidazole hexafluoro phosphonate ([BnMI] PF
6) (210ml) add in the reaction flask.Heat to 100 ℃ then, stirred 9 hours, HPLC follows the tracks of the raw material completely dissolve.Cool to room temperature, filtering and obtaining target compound is light yellow solid, productive rate is 92%, purity 99.0% (HPLC).
Claims (7)
1. preparation method suc as formula the 2-chloro-5-fluorine Nicotinicum Acidum shown in the I, it is characterized in that comprising the following step: in the solvent, under the effect of palladium catalyst, compound I I and formate react, and can make compound I; Wherein, Described solvent is an ionic liquid, and described ionic liquid is one or more in 1-methyl-3-ethyl imidazol(e) a tetrafluoro borate, 1-methyl-3-NSC 158165 a tetrafluoro borate, 1-methyl-3-benzyl imidazole a tetrafluoro borate, 1-methyl-3-ethyl imidazol(e) hexafluorophosphate, 1-methyl-3-NSC 158165 hexafluorophosphate and the 1-methyl-3-benzyl imidazole hexafluorophosphate; Described palladium catalyst is one or more in Palladous chloride, palladium bromide, palladium iodide, palladous sulfate, Palladous nitrate, palladium, trifluoracetic acid palladium, propionic acid palladium, levulinic acid palladium, two (triphenylphosphine) Palladous chloride, two (triphenylphosphine) palladium bromide, two (triphenylphosphine) palladium and the tetrakis triphenylphosphine palladium, the perhaps mixture of palladium and triphenylphosphine;
2. preparation method as claimed in claim 1 is characterized in that: described formate is one or more in ammonium formiate, sodium formiate, potassium formiate, lithium formate, cesium formate, magnesium formiate and the calcium formiate.
3. preparation method as claimed in claim 1 is characterized in that: the consumption of described formate is 1.5～5 times of compound I I molar weight.
4. preparation method as claimed in claim 3 is characterized in that: the consumption of described formate is 1.5～3.0 times of compound I I molar weight.
5. preparation method as claimed in claim 1 is characterized in that: described ionic liquid is 3～10ml/g with the volume mass ratio of compound I I.
6. preparation method as claimed in claim 1 is characterized in that: the consumption of described palladium catalyst is 0.01～0.1 times of compound I I molar weight.
7. preparation method as claimed in claim 1 is characterized in that: the temperature of described reaction is 50～120 ℃; The time of described reaction with detection reaction fully till.
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| CN103724257B (en) * | 2012-10-11 | 2015-06-10 | 中国中化股份有限公司 | Method for preparing 2,3-pyridinedicarboxylate compounds |
| CN108003092B (en) * | 2017-12-21 | 2021-04-02 | 重庆中邦科技有限公司 | Synthetic method of 2, 3-dichloropyridine |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004099149A1 (en) * | 2003-05-09 | 2004-11-18 | Asahi Glass Company, Limited | Processes for producing 3-substituted 2-chloro-5fluoropyridine or salt thereof |
| CN1626519A (en) * | 2003-12-09 | 2005-06-15 | 无锡药明康德新药开发有限公司 | Industrialized method for preparing 2-chlorine-5-fluorin-nicotinic aicd |
| WO2008077086A1 (en) * | 2006-12-19 | 2008-06-26 | Vertex Pharmaceuticals Incorporated | Aminopyrimidines useful as inhibitors of protein kinases |
-
2009
- 2009-01-07 CN CN 200910044975 patent/CN101768111B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004099149A1 (en) * | 2003-05-09 | 2004-11-18 | Asahi Glass Company, Limited | Processes for producing 3-substituted 2-chloro-5fluoropyridine or salt thereof |
| CN1626519A (en) * | 2003-12-09 | 2005-06-15 | 无锡药明康德新药开发有限公司 | Industrialized method for preparing 2-chlorine-5-fluorin-nicotinic aicd |
| WO2008077086A1 (en) * | 2006-12-19 | 2008-06-26 | Vertex Pharmaceuticals Incorporated | Aminopyrimidines useful as inhibitors of protein kinases |
Non-Patent Citations (1)
| Title |
|---|
| Xin Wang et al..A Practical Synthesis of 2-((1H-Pyrrolo[2,3-b]pyridine-4-yl)methylamino)-5-fluoronicotinic Acid.《J. Org. Chem.》.2006,第71卷(第10期),4021-4023. * |
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