CN108503581A - A kind of synthetic method of the fluoro- 2- pyridines ethyl ketones of the bromo- 6- of 3- - Google Patents
A kind of synthetic method of the fluoro- 2- pyridines ethyl ketones of the bromo- 6- of 3- Download PDFInfo
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- CN108503581A CN108503581A CN201810324889.7A CN201810324889A CN108503581A CN 108503581 A CN108503581 A CN 108503581A CN 201810324889 A CN201810324889 A CN 201810324889A CN 108503581 A CN108503581 A CN 108503581A
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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
- C07D213/61—Halogen atoms or nitro radicals
Abstract
The present invention provides a kind of synthetic methods of 3 bromine, 6 fluorine, 2 pyridine ethyl ketone.The synthetic method of the present invention includes the following steps：1）3 bromine, 6 fluorine, 2 pyridine carboxylic acid is dissolved with solvent, potassium permanganate is added, obtains 3 bromine, 6 fluorine, 2 pyridine carboxylic acid；2）Thionyl chloride is added to 3 bromine, 6 fluorine, 2 pyridine carboxylic acid, the mixed liquor reaction of triethylamine, dichloromethane and N, O dimethyl hydroxylamine hydrochloride is added, obtains 3 bromine, 6 fluorine N methoxyl group N picoline amides；3）3 bromine, 6 fluorine N methoxyl group N picolines amide, methyl-magnesium-chloride reaction is added in tetrahydrofuran, obtains 3 bromine, 6 fluorine, 2 pyridine ethyl ketone.The synthetic method of the present invention, synthetic route is succinct, and process choice is reasonable, and cost of material is low, simple and easy to get, and operation and convenient post-treatment are easy to amplify, can carry out the large-scale production of 3 bromine, 6 fluorine, 2 pyridine ethyl ketone.
Description
Technical field
The invention belongs to pharmaceutical intermediate synthesis technical fields, are related to a kind of synthesis side of the fluoro- 2- pyridines ethyl ketones of the bromo- 6- of 3-
Method.
Background technology
The fluoro- 2- pyridines ethyl ketones of the bromo- 6- of 3-, are an important intermediates in organic synthesis and pharmaceutical synthesis, pass through
It can synthesize a series of useful organic molecules and molecule drug candidate；Its 3 bromine atom is the reaction of a high activity
With some segments or intermediate transition metal-catalyzed coupling reaction can occur for site, as Buchwald-Hartwig reaction,
Heck reactions, Sonogashira reactions, Still reactions and Suzuki reactions, extend the mesh such as carbochain, structural modification to reach
's.Studies have shown that using a series of compounds that the molecule is synthesized as parent nucleus, there is the work for inhibiting indoles amine -2,3- dioxygenase
It is that a kind of iron content ferroheme monomeric protein and a kind of flavine rely on enzyme with, indoles amine -2,3- dioxygenase (IDO), it can be with
Make tryptophan catabolism, with immunological rejection, pathogenic infection, central nervous system disease, chorionitis-fascitis-
Consumption symptom in hypereosinophilic syndrome and autoimmunity disease etc. is relevant (US2016075711A1).Except this it
Outside, such molecule also has the function of inducing cell apoptosis, can inhibit the activity of the Bcl-xL albumen of anti-apoptotic
(US201300096120A1)。
Since the fluoro- 2- pyridine carboxaldehydes of the bromo- 6- of 3- have such importance outstanding, in organic synthesis circle especially drug
Region of chemistry causes extensive concern.But the synthesis about the fluoro- 2- pyridine carboxaldehydes of the bromo- 6- of 3- is rarely reported.Therefore, it develops
The synthetic route of one fluoro- 2- pyridines ethyl ketone of the bromo- 6- of 3- has very important significance.
Invention content
In view of the deficiencies of the prior art, one of the objects of the present invention is to provide a kind of fluoro- 2- pyridines ethyl ketones of the bromo- 6- of 3-
Synthetic method, synthetic route is succinct, and process choice is reasonable, and cost of material is low, raw material is simple and easy to get, operation and convenient post-treatment,
It is easy to amplify, the large-scale production of the fluoro- 2- pyridines ethyl ketones of the bromo- 6- of 3- can be carried out.
For this purpose, the present invention uses following technical scheme：
A kind of synthetic method of the fluoro- 2- pyridines ethyl ketones of the bromo- 6- of 3-, the synthetic method include the following steps：
1) the fluoro- 2- pyridine carboxylic acids of the bromo- 6- of 3- are dissolved with solvent, potassium permanganate is added, is heated to reflux, obtains the bromo- 6- of 3-
Fluoro- 2- pyridine carboxylic acids, wherein the molar ratio of the fluoro- 2- pyridine carboxylic acids of the bromo- 6- of 3- and the potassium permanganate is 1:(2~5)；
2) thionyl chloride is added in the fluoro- 2- pyridine carboxylic acids of the bromo- 6- of 3- that step 1) obtains, is heated to reflux, to reaction
The reaction was continued for the mixed liquor of addition triethylamine, dichloromethane and N, O- dimethyl hydroxylamine hydrochloride in liquid, and it is fluoro- to obtain the bromo- 6- of 3-
N- methoxy-N-methylpyridine amides；
3) cooling in the fluoro- N- methoxy-N-methylpyridines amides of the bromo- 6- of 3- for obtaining tetrahydrofuran addition step 2)
Methyl-magnesium-chloride reaction is added afterwards, obtains the fluoro- 2- pyridines ethyl ketones of the bromo- 6- of 3-.
In step 1), the solvent is water；Wherein, the fluoro- 2- pyridine carboxylic acids of the bromo- 6- of the 3- and the potassium permanganate rub
You are than being 1:(2~5), such as the molar ratio of the fluoro- 2- pyridine carboxylic acids of the bromo- 6- of the 3- and the potassium permanganate is 1:2、1:3、1:
4、1:5。
Preferably, in step 1), potassium permanganate is slowly added in batches；Preferably, the potassium permanganate is every 10
~20min divides 10~12 additions.
In step 1), the temperature of the heating is 100~120 DEG C, for example, the temperature of heating is 100 DEG C, 105 DEG C, 110
℃、115℃、120℃；The time of the reflux is 4~6h, such as the time of reflux is 4h, 4.5h, 5h, 5.5h, 6h.
In step 2), the triethylamine, dichloromethane and N, in the mixed liquor of O- dimethyl hydroxylamine hydrochlorides, three second
The molar ratio of amine and the N, O- dimethyl hydroxylamine hydrochlorides are (10~15):1, for example, the triethylamine and the N, O- diformazans
The molar ratio of base hydroxylamine hydrochloride is 10:1、11:1、12:1、13:1、14:1、15:1.
Preferably, in step 2), the mixed liquor of the triethylamine, dichloromethane and N, O- dimethyl hydroxylamine hydrochlorides are added
Be cooled to -5~-15 DEG C to reaction solution, for example, be cooled to -5 DEG C, -6 DEG C, -7 DEG C, -8 DEG C, -9 DEG C, -10 DEG C, -11 DEG C, -12
℃、-13℃、-14℃、-15℃。
In step 2), the molar ratio of the fluoro- 2- pyridine carboxylic acids of the bromo- 6- of 3- and the triethylamine is 1:(10~25), example
If the molar ratio of the fluoro- 2- pyridine carboxylic acids of the bromo- 6- of the 3- and the triethylamine is 1:10、1:11、1:12、1:13、 1:14、1:
15、1:16、1:17、1:18、1:19、1:20、1:21、1:22、1:23、1:24、1:25。
In step 2), the temperature of the reaction is 20~30 DEG C, for example, the temperature of reaction is 20,21,22,23 DEG C, 24
℃、25℃、26℃、27℃、28℃、29℃、30℃；The time of the reaction be 10~15h, such as the reaction time be 10h,
11h、12h、13h、14h、15h。
In step 3), mole of the bromo- 6- of 3- fluoro- the N- methoxy-N-methylpyridines amide and the methyl-magnesium-chloride
Than being 1:(1~2), for example, the bromo- 6- of the 3- fluoro- N- methoxy-N-methylpyridines amide and the methyl-magnesium-chloride mole
Than being 1:1、1:1.1、1:1.2、1:1.3、1:1.4、1:1.5、1:1.6、1:1.7、1:1.8、 1:1.9、1:2.
In step 3), the temperature of the reaction is -1~1 DEG C, such as the temperature of reaction is -1 DEG C, 0 DEG C, 1 DEG C；It is described anti-
The time answered is 1~3h, such as the time of reaction is 1h, 1.5h, 2h, 2.5h, 3h.
As the preferred embodiment of the present invention, a kind of synthetic method of the fluoro- 2- pyridines ethyl ketones of the bromo- 6- of 3- includes the following steps：
1) by the fluoro- 2- pyridine carboxylic acids water dissolutions of the bromo- 6- of 3-, divide 10~12 addition potassium permanganate every 10~20min,
100~120 DEG C of 4~6h of reflux are heated to, obtain the fluoro- 2- pyridine carboxylic acids of the bromo- 6- of 3-, wherein the fluoro- 2- pyridines of the bromo- 6- of 3-
The molar ratio of formic acid and the potassium permanganate is 1:(2~5)；
2) thionyl chloride is added in the fluoro- 2- pyridine carboxylic acids of the bromo- 6- of 3- that step 1) obtains, is heated to reflux, to reaction
It is added at a temperature of 20~30 DEG C of the mixed liquor of triethylamine, dichloromethane and N, O- dimethyl hydroxylamine hydrochloride that the reaction was continued in liquid 10
~15h obtains the fluoro- N- methoxy-N-methylpyridines amides of the bromo- 6- of 3-, wherein the triethylamine and the N, O- dimethyl hydroxyls
The molar ratio of amine hydrochlorate is (10~15):1, the molar ratio of the fluoro- 2- pyridine carboxylic acids of the bromo- 6- of 3- and the triethylamine is
1:(10~25)；
3) in the fluoro- N- methoxy-N-methylpyridines amides of the bromo- 6- of 3- for obtaining tetrahydrofuran addition step 2), protection
After being cooled to -1~1 DEG C in atmosphere, it is slowly added to methyl-magnesium-chloride reaction, wherein the fluoro- N- methoxyl groups-N- of the bromo- 6- of 3-
The molar ratio of picoline amide and the methyl-magnesium-chloride is 1:(1~2) obtains the fluoro- 2- pyridines ethyl ketones of the bromo- 6- of 3-.
In the present invention, the synthesis technology of the fluoro- 2- pyridines ethyl ketones of the bromo- 6- of 3- is the fluoro- 2- picolines of the bromo- 6- of 3- by Gao Meng
Sour potassium is oxidized to the fluoro- 2- pyridine carboxylic acids of the bromo- 6- of 3- and the fluoro- N- methoxyl groups-N- of the bromo- 6- of 3- are obtained by the reaction in Trifluoromethanesulfonic anhydride
The fluoro- 2- pyridines ethyl ketones of the bromo- 6- of 3- are finally obtained by the reaction in picoline amide with grignard reagent；The fluoro- 2- of the bromo- 6- of 3- of the present invention
The reaction equation of the synthetic method of pyridine ethyl ketone is as follows：
The second object of the present invention is to provide a kind of fluoro- 2- of bromo- 6- of the 3- that synthetic method as described above is prepared
Pyridine ethyl ketone.
Compared with prior art, beneficial effects of the present invention are：
The synthetic method of the fluoro- 2- pyridines ethyl ketones of the bromo- 6- of 3- of the present invention, using the fluoro- 2- picolines of the bromo- 6- of 3- as raw material,
Synthetic route is succinct, and process choice is reasonable, and cost of material is low, raw material is simple and easy to get, and operation and convenient post-treatment are easy to amplify,
It can carry out the large-scale production of the fluoro- 2- pyridines ethyl ketones of the bromo- 6- of 3-.
Specific implementation mode
The technical solution further illustrated the present invention below by specific implementation mode.
Unless specific instructions, various raw materials of the invention are commercially available buys, or is prepared according to the conventional method of this field
It obtains.
Embodiment
The first step：The synthesis of the fluoro- 2- pyridine carboxylic acids of the bromo- 6- of 3-
Water (1600mL) is added in the fluoro- 2- picolines (60g, 0.32mol) of the bromo- 6- of 3-, mechanical agitation simultaneously heats
To reflux, potassium permanganate (220g, 1.4mol) is divided 11 times and is added in flask, per minor tick 15min, continued back after adding
Flow 5h.Reaction solution is cooled to room temperature, filter, filtrate with dilute hydrochloric acid adjust pH to 5 or so, then filtrate is spin-dried for, then to
Absolute ethyl alcohol (500ml) is wherein added, heating stirring reflux 30min is filtered while hot, is the bromo- 6- of 3- fluoro- after filtrate is spin-dried for
2- pyridine carboxylic acids (31g, 45%).
Second step：The synthesis of the fluoro- N- methoxy-N-methylpyridines amides of the bromo- 6- of 3-
Thionyl chloride (200ml) is slowly added in the fluoro- 2- pyridine carboxylic acids (20g, 0.09mol) of the bromo- 6- of 3-, is heated to reflux
5h.Reaction solution is spin-dried for for use.By triethylamine (180g, 1.8mol), dichloromethane (200ml), N, O dimethyl hydroxylamine hydrochloric acid
Salt (13g, 0.135mol) mixed liquor is cooled to -10 DEG C, and reaction is slowly added drop-wise to after ready-made acyl chlorides is dissolved with dichloromethane
In liquid, reacted at room temperature overnight after adding.It after being spin-dried for solvent, is extracted with ethyl acetate, is the fluoro- N- methoxies of the bromo- 6- of 3- after concentration
Base-N- picolines amide (15g, 63%).
Third walks：The synthesis of the fluoro- 2- pyridines ethyl ketones of the bromo- 6- of 3-
Anhydrous tetrahydro furan (200ml) is added in the fluoro- N- methoxy-N-methylpyridines amides of the bromo- 6- of 3-
(15.0g, 0.057mol), nitrogen protection are cooled to 0 DEG C, be slowly added into thereto methyl-magnesium-chloride (6.40g,
0.086mol), 2h is reacted after adding.Add a small amount of water quenching to go out, after being spin-dried for tetrahydrofuran, is extracted with ethyl acetate, organic phase rotation
Silica gel column chromatography after dry, obtains the fluoro- 2- pyridines ethyl ketones of the bromo- 6- of 3- (6g, 50%).
1HNMR(400MHz,CDCl3)：2.68 (s, 3H), 7.00 (dd, J=8.6,3.6Hz, 1H), 8.09 (dd, J=
8.6,6.8Hz, 1H).
Comparative example 1
This comparative example compared with Example 1, the difference is that, in step 1), the fluoro- 2- pyridine carboxylic acids of the bromo- 6- of 3- with it is high
The molar ratio of potassium manganate is 1:1, other conditions are same as Example 1, this comparative example obtains the receipts of the bromo- 7- oxyquinolines of 3-
Rate is 36%.
Comparative example 2
This comparative example compared with Example 1, the difference is that, in step 1), the fluoro- 2- pyridine carboxylic acids of the bromo- 6- of 3- with it is high
The molar ratio of potassium manganate is 1:8, other conditions are same as Example 1, this comparative example obtains the receipts of the bromo- 7- oxyquinolines of 3-
Rate is 42%.
Comparative example 3
This comparative example compared with Example 1, the difference is that, in step 1), potassium permanganate is once added, other
Condition is same as Example 1, and the yield that this comparative example obtains the bromo- 7- oxyquinolines of 3- is 32%.
Comparative example 4
This comparative example compared with Example 1, the difference is that, in step 2), the triethylamine and the N, O- diformazans
The molar ratio of base hydroxylamine hydrochloride is 2:1, other conditions are same as Example 1, this comparative example obtains the bromo- 7- oxyquinolines of 3-
Yield be 40%.
Comparative example 5
This comparative example compared with Example 1, the difference is that, in step 2), triethylamine and N, O- dimethyl hydroxylamine salt
The molar ratio of hydrochlorate is 20:1, other conditions are same as Example 1, this comparative example obtains the yield of the bromo- 7- oxyquinolines of 3-
It is 41%.
Comparative example 6
This comparative example compared with Example 1, the difference is that, in step 2), the temperature of reaction solution is 20 DEG C, other
Condition is same as Example 1, and the yield that this comparative example obtains the bromo- 7- oxyquinolines of 3- is 29%.
Comparative example 7
This comparative example compared with Example 1, the difference is that, in step 3), the fluoro- N- methoxy-. N-methyls of the bromo- 6- of 3-
The molar ratio of picolinamide and methyl-magnesium-chloride is 1:0.1, other conditions are same as Example 1, and it is bromo- that this comparative example obtains 3-
The yield of 7- oxyquinolines is 33%.
Comparative example 8
This comparative example compared with Example 1, the difference is that, in step 3), the fluoro- N- methoxy-. N-methyls of the bromo- 6- of 3-
The molar ratio of picolinamide and methyl-magnesium-chloride is 1:5, other conditions are same as Example 1, this comparative example obtains the bromo- 7- of 3-
The yield of oxyquinoline is 37%.
Comparative example 9
This comparative example compared with Example 1, the difference is that, in step 3), the temperature of reaction is 10 DEG C, other conditions
Same as Example 1, the yield that this comparative example obtains the bromo- 7- oxyquinolines of 3- is 35%.
Raw material proportioning is too low or excessively high it can be seen from embodiment and comparative example 1,2,4,5,7,8, final 3- obtained
The yield of bromo- 7- oxyquinolines can all reduce, and in synthetic method it can be seen from embodiment and comparative example 3,6, change reaction
Time and temperature equally affect the yield of the bromo- 7- oxyquinolines of 3-.
The synthetic method of the fluoro- 2- pyridines ethyl ketones of the bromo- 6- of 3- of the present invention, using the fluoro- 2- picolines of the bromo- 6- of 3- as raw material,
Synthetic route is succinct, and process choice is reasonable, and cost of material is low, raw material is simple and easy to get, and operation and convenient post-treatment are easy to amplify,
It can carry out the large-scale production of the fluoro- 2- pyridines ethyl ketones of the bromo- 6- of 3-.
The present invention illustrates detailed process equipment and the technological process of the present invention by above-described embodiment, but the present invention is not
It is confined to above-mentioned detailed process equipment and technological process, that is, does not mean that the present invention has to rely on above-mentioned detailed process equipment and work
Skill flow could be implemented.Person of ordinary skill in the field is it will be clearly understood that any improvement in the present invention, to product of the present invention
The equivalence replacement of each raw material and the addition of auxiliary element, the selection of concrete mode etc., all fall within protection scope of the present invention and public affairs
Within the scope of opening.
Claims (10)
1. a kind of synthetic method of the fluoro- 2- pyridines ethyl ketones of the bromo- 6- of 3-, which is characterized in that the synthetic method includes the following steps：
1）The fluoro- 2- pyridine carboxylic acids of the bromo- 6- of 3- are dissolved with solvent, potassium permanganate is added, is heated to reflux, obtains the fluoro- 2- of the bromo- 6- of 3-
Pyridine carboxylic acid, wherein the molar ratio of the fluoro- 2- pyridine carboxylic acids of the bromo- 6- of 3- and the potassium permanganate is 1:(2~5)；
2）Thionyl chloride is added to step 1）In the obtained fluoro- 2- pyridine carboxylic acids of the bromo- 6- of 3-, it is heated to reflux, into reaction solution
The reaction was continued for the mixed liquor of addition triethylamine, dichloromethane and N, O- dimethyl hydroxylamine hydrochloride, obtains the fluoro- N- first of the bromo- 6- of 3-
Oxygroup-N- picoline amides；
3）Step 2 is added in tetrahydrofuran）In the obtained fluoro- N- methoxy-N-methylpyridines amides of the bromo- 6- of 3-, add after cooling
Enter methyl-magnesium-chloride reaction, obtains the fluoro- 2- pyridines ethyl ketones of the bromo- 6- of 3-.
2. synthetic method according to claim 1, which is characterized in that step 1）In, the solvent is water；
Preferably, step 1）In, potassium permanganate is slowly added in batches；
Preferably, the potassium permanganate is every 10 ~ 20min points of 10 ~ 12 additions.
3. synthetic method according to claim 1 or 2, which is characterized in that step 1）In, the temperature of the heating is 100 ~
120 DEG C, the time of the reflux is 4 ~ 6h.
4. according to the synthetic method described in one of claim 1-3, which is characterized in that step 2）In, the triethylamine, dichloromethane
Alkane and N, in the mixed liquor of O- dimethyl hydroxylamine hydrochlorides, the triethylamine and the N, mole of O- dimethyl hydroxylamine hydrochlorides
Than for (10 ~ 15):1；
Preferably, step 2）In, the mixed liquor of the triethylamine, dichloromethane and N, O- dimethyl hydroxylamine hydrochlorides are added to instead
Liquid is answered to be cooled to -5 ~ -15 DEG C.
5. according to the synthetic method described in one of claim 1-4, which is characterized in that step 2）In, the fluoro- 2- of the bromo- 6- of 3-
The molar ratio of pyridine carboxylic acid and the triethylamine is 1:(10~25).
6. according to the synthetic method described in one of claim 1-5, which is characterized in that step 2）In, the temperature of the reaction is
20 ~ 30 DEG C, the time of the reaction is 10 ~ 15h.
7. according to the synthetic method described in one of claim 1-6, which is characterized in that step 3）In, the fluoro- N- of the bromo- 6- of 3-
The molar ratio of methoxy-N-methylpyridine amide and the methyl-magnesium-chloride is 1:(1~2).
8. according to the synthetic method described in one of claim 1-7, which is characterized in that step 3）In, the temperature of the reaction is-
1 ~ 1 DEG C, the time of the reaction is 1 ~ 3h.
9. according to the synthetic method described in one of claim 1-8, which is characterized in that the synthetic method includes the following steps：
1）The fluoro- 2- pyridine carboxylic acids water dissolutions of the bromo- 6- of 3- are heated to every 10 ~ 20min points of 10 ~ 12 addition potassium permanganate
100 ~ 120 DEG C of 4 ~ 6h of reflux, obtain the fluoro- 2- pyridine carboxylic acids of the bromo- 6- of 3-, wherein the fluoro- 2- pyridine carboxylic acids of the bromo- 6- of 3- and institute
The molar ratio for stating potassium permanganate is 1:(2~5)；
2）Thionyl chloride is added to step 1）In the obtained fluoro- 2- pyridine carboxylic acids of the bromo- 6- of 3-, it is heated to reflux, into reaction solution
10 ~ the 15h that is added at a temperature of 20 ~ 30 DEG C of the mixed liquor of triethylamine, dichloromethane and N, O- dimethyl hydroxylamine hydrochloride that the reaction was continued,
Obtain the fluoro- N- methoxy-N-methylpyridines amides of the bromo- 6- of 3-, wherein the triethylamine and the N, O- dimethyl hydroxylamine hydrochloric acid
The molar ratio of salt is (10 ~ 15):1, the molar ratio of the fluoro- 2- pyridine carboxylic acids of the bromo- 6- of 3- and the triethylamine is 1:(10~
25)；
3）Step 2 is added in tetrahydrofuran）In the obtained fluoro- N- methoxy-N-methylpyridines amides of the bromo- 6- of 3-, protective atmosphere
In be cooled to -1 ~ 1 DEG C after, be slowly added to methyl-magnesium-chloride reaction, wherein the fluoro- N- methoxy-. N-methyls pyrroles of the bromo- 6- of 3-
The molar ratio of pyridine amide and the methyl-magnesium-chloride is 1:(1 ~ 2) obtains the fluoro- 2- pyridines ethyl ketones of the bromo- 6- of 3-.
10. a kind of fluoro- 2- pyridines ethyl ketones of the bromo- 6- of 3- being prepared such as claim 1-9 any one of them synthetic methods.
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| ARK PHARM, INC.提供的产品目录: "STN检索报告1", 《数据库REGISTRY（在线）》 * |
| 樊能廷: "《有机合成事典》", 31 January 1992, 北京理工大学出版社 * |
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