JPS62181257A - Production of fluoropyridine or such - Google Patents
Production of fluoropyridine or suchInfo
- Publication number
- JPS62181257A JPS62181257A JP2114686A JP2114686A JPS62181257A JP S62181257 A JPS62181257 A JP S62181257A JP 2114686 A JP2114686 A JP 2114686A JP 2114686 A JP2114686 A JP 2114686A JP S62181257 A JPS62181257 A JP S62181257A
- Authority
- JP
- Japan
- Prior art keywords
- potassium fluoride
- reaction
- chloro
- bromopyridine
- chloropyridine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 238000004519 manufacturing process Methods 0.000 title claims description 5
- MTAODLNXWYIKSO-UHFFFAOYSA-N 2-fluoropyridine Chemical compound FC1=CC=CC=N1 MTAODLNXWYIKSO-UHFFFAOYSA-N 0.000 title abstract description 4
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 claims abstract description 22
- 239000011698 potassium fluoride Substances 0.000 claims abstract description 15
- 235000003270 potassium fluoride Nutrition 0.000 claims abstract description 11
- 239000010419 fine particle Substances 0.000 claims abstract description 5
- 239000007810 chemical reaction solvent Substances 0.000 claims abstract description 3
- 239000002798 polar solvent Substances 0.000 claims abstract 3
- 238000000034 method Methods 0.000 claims description 11
- 150000005754 fluoropyridines Chemical class 0.000 claims description 10
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 9
- 150000005752 bromopyridines Chemical class 0.000 claims description 4
- 238000006243 chemical reaction Methods 0.000 abstract description 18
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 abstract description 6
- 230000035484 reaction time Effects 0.000 abstract description 5
- IMRWILPUOVGIMU-UHFFFAOYSA-N 2-bromopyridine Chemical compound BrC1=CC=CC=N1 IMRWILPUOVGIMU-UHFFFAOYSA-N 0.000 abstract description 4
- 239000003905 agrochemical Substances 0.000 abstract description 2
- 150000001875 compounds Chemical class 0.000 abstract description 2
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 abstract description 2
- FNRMMDCDHWCQTH-UHFFFAOYSA-N 2-chloropyridine;3-chloropyridine;4-chloropyridine Chemical compound ClC1=CC=NC=C1.ClC1=CC=CN=C1.ClC1=CC=CC=N1 FNRMMDCDHWCQTH-UHFFFAOYSA-N 0.000 abstract 2
- 239000003814 drug Substances 0.000 abstract 1
- 229940079593 drug Drugs 0.000 abstract 1
- 230000015572 biosynthetic process Effects 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 9
- FRRSTGWMCISOKQ-UHFFFAOYSA-N 2-fluoropyridine-3-carbonyl fluoride Chemical compound FC(=O)C1=CC=CN=C1F FRRSTGWMCISOKQ-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- LLLVHTWJGWNRBD-UHFFFAOYSA-N 2-fluoropyridine-3-carboxylic acid Chemical compound OC(=O)C1=CC=CN=C1F LLLVHTWJGWNRBD-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 125000001246 bromo group Chemical group Br* 0.000 description 3
- -1 bromo radical Chemical class 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- ATBIAJXSKNPHEI-UHFFFAOYSA-N pyridine-3-carbonyl chloride Chemical compound ClC(=O)C1=CC=CN=C1 ATBIAJXSKNPHEI-UHFFFAOYSA-N 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- MAKFMOSBBNKPMS-UHFFFAOYSA-N 2,3-dichloropyridine Chemical compound ClC1=CC=CN=C1Cl MAKFMOSBBNKPMS-UHFFFAOYSA-N 0.000 description 2
- FILKGCRCWDMBKA-UHFFFAOYSA-N 2,6-dichloropyridine Chemical compound ClC1=CC=CC(Cl)=N1 FILKGCRCWDMBKA-UHFFFAOYSA-N 0.000 description 2
- RXTRRIFWCJEMEL-UHFFFAOYSA-N 2-chloropyridine-3-carbonyl chloride Chemical compound ClC(=O)C1=CC=CN=C1Cl RXTRRIFWCJEMEL-UHFFFAOYSA-N 0.000 description 2
- GRCLBOGXTPXNPL-UHFFFAOYSA-N 2-fluoropyridine-3-carboxamide Chemical compound NC(=O)C1=CC=CN=C1F GRCLBOGXTPXNPL-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- AKVVBYDLMJMJRW-UHFFFAOYSA-N ethyl 2-fluoropyridine-3-carboxylate Chemical compound CCOC(=O)C1=CC=CN=C1F AKVVBYDLMJMJRW-UHFFFAOYSA-N 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- PJNHJXKXBSOLBH-UHFFFAOYSA-N methyl 2-fluoropyridine-3-carboxylate Chemical compound COC(=O)C1=CC=CN=C1F PJNHJXKXBSOLBH-UHFFFAOYSA-N 0.000 description 2
- YNBADRVTZLEFNH-UHFFFAOYSA-N methyl nicotinate Chemical compound COC(=O)C1=CC=CN=C1 YNBADRVTZLEFNH-UHFFFAOYSA-N 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000003586 protic polar solvent Substances 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- DLOOKZXVYJHDIY-UHFFFAOYSA-N 2,3,4,5-tetrachloropyridine Chemical compound ClC1=CN=C(Cl)C(Cl)=C1Cl DLOOKZXVYJHDIY-UHFFFAOYSA-N 0.000 description 1
- OGVLEPMNNPZAPS-UHFFFAOYSA-N 2,3-difluoropyridine Chemical compound FC1=CC=CN=C1F OGVLEPMNNPZAPS-UHFFFAOYSA-N 0.000 description 1
- GCTFDMFLLBCLPF-UHFFFAOYSA-N 2,5-dichloropyridine Chemical compound ClC1=CC=C(Cl)N=C1 GCTFDMFLLBCLPF-UHFFFAOYSA-N 0.000 description 1
- FEYDZHNIIMENOB-UHFFFAOYSA-N 2,6-dibromopyridine Chemical compound BrC1=CC=CC(Br)=N1 FEYDZHNIIMENOB-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- BAZVFQBTJPBRTJ-UHFFFAOYSA-N 2-chloro-5-nitropyridine Chemical compound [O-][N+](=O)C1=CC=C(Cl)N=C1 BAZVFQBTJPBRTJ-UHFFFAOYSA-N 0.000 description 1
- LXOHKRGLGLETIJ-UHFFFAOYSA-N 2-chloro-6-fluoropyridine Chemical compound FC1=CC=CC(Cl)=N1 LXOHKRGLGLETIJ-UHFFFAOYSA-N 0.000 description 1
- OKDGRDCXVWSXDC-UHFFFAOYSA-N 2-chloropyridine Chemical compound ClC1=CC=CC=N1 OKDGRDCXVWSXDC-UHFFFAOYSA-N 0.000 description 1
- PWRBCZZQRRPXAB-UHFFFAOYSA-N 3-chloropyridine Chemical compound ClC1=CC=CN=C1 PWRBCZZQRRPXAB-UHFFFAOYSA-N 0.000 description 1
- PVMNPAUTCMBOMO-UHFFFAOYSA-N 4-chloropyridine Chemical compound ClC1=CC=NC=C1 PVMNPAUTCMBOMO-UHFFFAOYSA-N 0.000 description 1
- ZHIHQFMWBOTCQR-UHFFFAOYSA-N 5-bromo-2-phenoxypyridine Chemical compound N1=CC(Br)=CC=C1OC1=CC=CC=C1 ZHIHQFMWBOTCQR-UHFFFAOYSA-N 0.000 description 1
- AJGLCXBDYCEVIE-UHFFFAOYSA-N 5-chloro-3-hydroxy-1h-pyridin-2-one Chemical compound OC1=CC(Cl)=CN=C1O AJGLCXBDYCEVIE-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- BDAYELRXQIKBPH-UHFFFAOYSA-N C(C1=CC=CC=C1)#N.S1(=O)(=O)CCCC1 Chemical compound C(C1=CC=CC=C1)#N.S1(=O)(=O)CCCC1 BDAYELRXQIKBPH-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- OYTKINVCDFNREN-UHFFFAOYSA-N amifampridine Chemical compound NC1=CC=NC=C1N OYTKINVCDFNREN-UHFFFAOYSA-N 0.000 description 1
- 150000003927 aminopyridines Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000012954 diazonium Substances 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-O diazynium Chemical compound [NH+]#N IJGRMHOSHXDMSA-UHFFFAOYSA-O 0.000 description 1
- 238000009837 dry grinding Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012025 fluorinating agent Substances 0.000 description 1
- 238000003682 fluorination reaction Methods 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229960001238 methylnicotinate Drugs 0.000 description 1
- XJUBVXOGCHVDAP-UHFFFAOYSA-N n,n-diethyl-2-fluoropyridine-3-carboxamide Chemical compound CCN(CC)C(=O)C1=CC=CN=C1F XJUBVXOGCHVDAP-UHFFFAOYSA-N 0.000 description 1
- PZYDAVFRVJXFHS-UHFFFAOYSA-N n-cyclohexyl-2-pyrrolidone Chemical compound O=C1CCCN1C1CCCCC1 PZYDAVFRVJXFHS-UHFFFAOYSA-N 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- GNRFLYPJBUPWPB-UHFFFAOYSA-N pyridine-3-carbonyl fluoride Chemical compound FC(=O)C1=CC=CN=C1 GNRFLYPJBUPWPB-UHFFFAOYSA-N 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
Abstract
Description
【発明の詳細な説明】
［産業上の利用分野］
本発明は、フルオロピリジン類の右利な製造法に関する
ものである。DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to an efficient method for producing fluoropyridines.
［従来の技術およびその問題点］
フルオロピリジン類の製法としては、アミノピリジン類
を出発原料として、ジアゾニウムフｒ１１１１：髪；＋
ｌ＋ｆｉｌｌＩ↓し＋：２−１１．ｋＡ−＋１／１１２
’−Ｘ＋−一・・ブー・ノ：Ｉ１．＋ｅ知られている。[Prior art and its problems] As a method for producing fluoropyridines, using aminopyridines as a starting material, diazonium fur r1111: hair; +
l+fillI↓shi+:2-11. kA-+1/112
'-X+-1... Boo No: I1. +e known.
又、ハロゲン交換反応としては、ＫＦ又はＫＨＦ７を用
いる無溶媒で高温、加圧下での反応、及びＫＦ−溶媒系
で長時間反応させる方法等が知られている。しかしなが
ら、これらの従来技術においては、収率が低い、高温・
加圧ドの反応でＬ業的に不利、あるいは長時間の反応を
要する等の問題点を右していた。Further, as the halogen exchange reaction, there are known methods such as a reaction using KF or KHF7 without a solvent at high temperature and under pressure, and a method of reacting for a long time in a KF-solvent system. However, these conventional techniques have low yields and high temperature/
The pressurized reaction is disadvantageous in terms of production, or requires a long reaction time.
［問題点を解決するための゛Ｌ段］
本発明は、前述の問題点を解決すべくなされたものであ
り、クロロ又はブロモピリジン類を１〜５０μの無水フ
ッ化カリウム微粒子を用いて、非プロトン性極性溶媒中
で、フッ素化することにより、比較的温和な反応条件で
、かつ短時間に高収率でフルオロピリジン類を得る方法
を新規に提供するものである。[L Stage for Solving the Problems] The present invention has been made to solve the above-mentioned problems, and it is a method of converting chloro or bromopyridines into non-containing particles using anhydrous potassium fluoride fine particles of 1 to 50μ. The present invention provides a novel method for obtaining fluoropyridines in a high yield in a short period of time under relatively mild reaction conditions by fluorination in a protic polar solvent.
クロロ又はブロモピリジン類としては、ピリジン環の炭
素あるいは核置換基の炭素にクロロ又はブロモ原ｆが少
なくとも１例語合したものである。The chloro or bromopyridines are those in which at least one chloro or bromo radical f is combined with the carbon of the pyridine ring or the carbon of a nuclear substituent.
例えば、２−クロロピリジン、３−グロロピリジン、４
−クロロピリジン、２．３−ジクロロピリジン、２，５
−ジクロロピリジン、２．６−ジクロロピリジン、３．
５−ジクロロピリジン、２−ブロモピリジン、２．６−
ジブロモピリジン、３，５．８−トリクロロ−２−ビリ
ジノール、２−フェノキシ−５〜ブロモピリジン、ニコ
チン酸クロライド、ニコチン酩ブロマイド、２−’）ロ
ロニコチン酸クロライＦ。For example, 2-chloropyridine, 3-chloropyridine, 4
-chloropyridine, 2,3-dichloropyridine, 2,5
-dichloropyridine, 2.6-dichloropyridine, 3.
5-dichloropyridine, 2-bromopyridine, 2.6-
Dibromopyridine, 3,5.8-trichloro-2-pyridinol, 2-phenoxy-5-bromopyridine, nicotinic acid chloride, nicotinic acid chloride, 2-') loronicotinic acid chloride F.
２−フロモニコチン酸フロマイト、３−フロモー４，５
−ジアミノピリジン、２−クロロ−５−二トロピリジン
、２−クロロ−８−トリクロロメチルピリジン、５−ク
ロロ−２，３−ピリジンジオール、 ２，３，４゜５．
６−ペンタクロロピリジン、２，３，４．５−テトラク
ロロピリジン、２，３，５．８−テトラクロロピリジン
、３．５−ジブロモ−４−ピリジンチオール、 ２，３
゜５−トリクロロピリジン、２，３．６−１−ジクロロ
ピリジン、２，４．８−）ジクロロピリジン、笠を挙げ
ることができる。2-furomonicotinic acid furomite, 3-furomor 4,5
-diaminopyridine, 2-chloro-5-nitropyridine, 2-chloro-8-trichloromethylpyridine, 5-chloro-2,3-pyridinediol, 2,3,4°5.
6-pentachloropyridine, 2,3,4.5-tetrachloropyridine, 2,3,5.8-tetrachloropyridine, 3.5-dibromo-4-pyridinethiol, 2,3
Examples include 5-trichloropyridine, 2,3,6-1-dichloropyridine, 2,4,8-)dichloropyridine, and Kasa.
未発１１方法において、ピリジン環の炭素に直接結合し
たクロロ又はブロモ原子がフッ化カリウムによりフッ素
原子に置換するものであるが、クロロ又はブロモ原ｆ以
外の核置換ノ、（にクロロやブロモ原ｒ−が結合したも
の、例えばニコチン酸クロライドやブロマイド、２−ク
ロロニコチン酸クロライド、２−ブロモニコチン酸ブロ
マイド笠のように核置換基の炭素に結合したクロロやブ
ロモ原子も比較的容易にフッ素原ｒ−に変換することが
でき、対応するフルオロピリジン類、すなわち、ニコチ
ン酸フルオライド、２−フル十ロニコチン酸フルオライ
ドを得ることができる。In method 11, the chloro or bromo atom directly bonded to the carbon of the pyridine ring is replaced by a fluorine atom with potassium fluoride. Those with r- bonded to them, such as nicotinic acid chloride, bromide, 2-chloronicotinic acid chloride, and 2-bromonicotinic acid bromide caps, also have chloro and bromo atoms bonded to the carbon atoms of the nuclear substituents relatively easily. r- to give the corresponding fluoropyridines, ie, nicotinic acid fluoride, 2-fluoronicotinic acid fluoride.
本発明の反応溶媒は、アセトニトリル、ジメチルホルム
アミド、ジメチルスルホキサイド、ジメチルアセトアミ
ド、ベンゾニトリルスルホラン、Ｎ−メチル−２−ピロ
リドン、Ｎ−シクロへキシル−２−ピロリドン、ヘキサ
メチルホスホルトリアミド、１．３−ジメチル−２−イ
ミダゾリジノン等の−Ｉ＋プロトン性極性溶媒を用いる
ことがＥ？であり、特にスルホランやジメチルスルホキ
サイドが好ましい、溶媒の使用１．１は特に限定される
ものではないが、出発原料のクロロ又はブロモピリジン
類に対して、重量部基準で１〜１００倍量、好ましくは
３〜ｌＯ倍量の範囲から選定するとよい。The reaction solvent of the present invention includes acetonitrile, dimethylformamide, dimethylsulfoxide, dimethylacetamide, benzonitrile sulfolane, N-methyl-2-pyrrolidone, N-cyclohexyl-2-pyrrolidone, hexamethylphosphortriamide, 1. Is it possible to use -I+ protic polar solvents such as 3-dimethyl-2-imidazolidinone? In particular, sulfolane and dimethyl sulfoxide are preferable.Use of solvent 1.1 is not particularly limited, but is 1 to 100 times the amount by weight based on the chloro or bromopyridine as the starting material. , preferably from a range of 3 to 10 times the amount.
フッ素化剤としてフッ化カリウムは、スプレー乾燥法、
瞬間蒸発加熱管方式、又は乾式粉砕等により、１〜１０
０μ、好ましくは１〜５０μにほぼ均一・な微粒りに粉
砕された無水フッ化カリウムを使用することが重要であ
る。 ＫＦの他、ＲｂＦ ’ｅ９ｃｓＦ等の微粒子−で
もよいが、性能及び価格面からＫＦが好ましい。Potassium fluoride as a fluorinating agent can be used by spray drying method,
1 to 10 by instant evaporation heating tube method or dry grinding, etc.
It is important to use anhydrous potassium fluoride that has been ground to a substantially uniform fine particle size of 0μ, preferably 1 to 50μ. In addition to KF, fine particles such as RbF'e9csF may be used, but KF is preferable from the viewpoint of performance and cost.
ＫＦの使用！逢は、クロロ又はブロモピリジン類中のフ
ッ素置換すべきクロロやブロモ原ｆ−がフッ素に置換す
るために必要な反応理論Ｈ，Ｈの１−１０倍、好ましく
は１〜３倍から選定するとよい。Use of KF! It is preferable to select from 1 to 10 times, preferably 1 to 3 times, the reaction theory H, H necessary for replacing chloro or bromo base f- in chloro or bromopyridines with fluorine. .
本発明における１反応温度 １１ｊＦ間又は圧力等の反
応条件は、適宜最適な条件を選定すればよいが、およそ
５０〜３００ ’０、好ましくは １００〜２５０℃の
反応温度、０．５〜２０時間、 １１１’ましくは１〜
５時間の反応時間、ｌ〜２０Ｋｇ／ｃｍ７の反応圧力を
採用すればよい、これらの反応条件は、出発原料の種類
によっては、極めて重要な要素となる場合があり、例え
ば、以Ｆのように反応温度と反応時間を操作することに
より１選択的にモノ置換体である。２−クロロ−６−フ
ルオロピリジンを得ることができる。０内は収率［％］
。1 Reaction conditions in the present invention such as reaction temperature 11jF or pressure may be appropriately selected, but the reaction temperature is approximately 50 to 300°C, preferably 100 to 250°C, and 0.5 to 20 hours. , 111' or 1~
A reaction time of 5 hours and a reaction pressure of 1 to 20 Kg/cm7 may be used. These reaction conditions may be extremely important depending on the type of starting materials. For example, as shown in F below. By manipulating the reaction temperature and reaction time, one can be selectively monosubstituted. 2-chloro-6-fluoropyridine can be obtained. Values within 0 are yield [%]
.
未発明方υ：により得られるフン素化生成物は、 Ｖ＋
１過溶媒留去、抽出、基留等の通常の分離操作を経て、
医農薬中間体として有用なフルオロピリジン類を高純度
で収−（に良く得ることができる。未発明方Ｖ：に従っ
て得られるフルオロピリジン類は、参考例に示すごとく
、エステル化、加水分解、アミド化等通常の反応操作を
経て、その他の有用なフルオロピリジン、Ａ ４ 体へ
と導くことかできる。The fluorinated product obtained by the uninvented method υ: is V+
1. After normal separation operations such as supersolvent distillation, extraction, and base distillation,
Fluoropyridines useful as pharmaceutical and agrochemical intermediates can be obtained with high purity. Fluoropyridines obtained according to uninvented method V: can be esterified, hydrolyzed, and amide as shown in the reference example. Other useful fluoropyridines and A 4 forms can be obtained through conventional reaction operations such as chemical reaction.
実施例１ ２−フルオロニコチン酸フルオリ！・の合Ｌ＆。Example 1 2-Fluoronicotinic acid fluori!・The combination of L&.
２Ｑ三つロフラスコの中によく乾燥したスプレードライ
・フン化カリウム（森［１１化学製）２２０ｇ（３，７
８ｓｏｌ）、 無水スルフオラン１． ｌｆ２をいれ１
００℃、１時１川、メカニカルスターラーにより激しく
攪拌した。そこに２−クロロニコチン酸クロリド２２０
ｇ（１，２ｆｉａ＋ｏ ｌ）を加え １８０°０２時間
反応させた。これを２ ｍｍＨｇでフラッシュ蒸留し、
留出物を１１蒸留しｂｐ８０〜８１’Ｃ／ １８ｍｍＨ
Ｈの２−フルオロニコチン酸フルオリド １８８ｇ（収
−（に９２％）ヲ得た。220 g (3,7
8sol), anhydrous sulforane 1. Insert lf2 1
The mixture was stirred vigorously using a mechanical stirrer at 00°C for 1 hour. There 2-chloronicotinic acid chloride 220
g (1,2fia+ol) was added and reacted at 180° for 2 hours. This was flash distilled at 2 mmHg,
The distillate was distilled 11 times and the bp was 80-81'C/18mmH.
188 g (yield: 92%) of 2-fluoronicotinic acid fluoride was obtained.
実施例２
２−フルオロピリジンの合成
２ＱＥつ目フラスコの中によく乾燥したスプレードライ
・フン化カリウム（森Ｉｌ＋化学製）２２０ｇ（３，７
８ｍｏ ｌ） 、 無水スルフオラン１．１（２をい
れ１００°０．１時用１．メカニカルスターラーにより
激しく攪拌した。そこに２−クロロピリジン１４２ｇ＜
１．２８ｓｏｌ）を加え２４０℃１２時間反応ネせた。Example 2 Synthesis of 2-fluoropyridine 220 g (3,7
8 mol), anhydrous sulforane (2) were added and stirred vigorously using a mechanical stirrer at 100°.
1.28 sol) was added thereto, and the reaction was continued at 240°C for 12 hours.
これを２ ｍｍＨｇでフランシュ蒸留し、留出物を再蒸
留しｂｐ５Ｂ〜５９℃／８０＋ｓｄｇの２−フルオロピ
リジン１３３ｇ （収率９２％）を得た。This was subjected to Franche distillation at 2 mmHg, and the distillate was redistilled to obtain 133 g (92% yield) of 2-fluoropyridine with a bp of 5B to 59°C/80+sdg.
実施例３
２．６−ジフルオロピリジンの合成
２Ｑ ：、つ「１フラスコの中によく乾燥したスプレー
トライ・フン化カリウム（森［口化学製）２２０ｇ（３
，７８＋ｓｏ ｌ）、無水スルフオラン １．ＩＱをい
れ１００℃、１時間、メカニカルスターラーにより激し
く攪拌した。そこに２，６−ジクロロピリジン１８５ｇ
（１，２８ｓｏｌ）を加え２４０℃２時間反応させた。Example 3 Synthesis of 2.6-difluoropyridine 2Q: In one flask, put 220 g (3
, 78+sol), anhydrous sulforane 1. IQ was added and stirred vigorously using a mechanical stirrer at 100°C for 1 hour. 185g of 2,6-dichloropyridine
(1,28 sol) was added and reacted at 240°C for 2 hours.
これを２ ｍｍＨｇでフラッシュ蒸留し、留出物を１番
ｆ蒸留しｂｐｅｏ〜８２℃／ ７０ｍｍＨｇノ２．８−
ジフルオロピリジン１５４ｇ （収率９２％）を得た。This was flash-distilled at 2 mmHg, and the distillate was distilled at No. 1F to bpeo~82℃/70mmHg~2.8-
154 g (yield 92%) of difluoropyridine was obtained.
８ＪＳ例１
２−フルオロニコチン酸ジエチルアミドの合成ジエチル
アミン２０ｔｓＱ（０，１９ｓｏｌ） （１） Ｔ Ｈ
Ｆ （テトラ上１ζロフラン） （５ｈ（２）の溶液を
氷冷ド攪拌しながら実施例１で得た２−フルオロニコチ
ン酸フルオリドｌＯｇ（０，０７＋＊ａｌ）を滴ドし、
氷冷ド３時間攪拌した。これを飽和重炭酸カリウム水溶
液により中和、酢酸エチルにより抽出（２Ｘ ５０＋Ｉ
Ｑ）、ついで飽和食塩水により洗浄したのち硫酸マグネ
シウムにより乾燥、ろ別したのち蒸留しｈｐ、 １１３
〜１１５℃７２ｍｍ＋Ｈｇの２−フルオロニコチン酸ジ
エチルアミド１０．７ｇを得た（収率７８％）。8JS Example 1 Synthesis of 2-fluoronicotinic acid diethylamide Diethylamine 20tsQ (0,19sol) (1) T H
2-fluoronicotinic acid fluoride 1Og (0,07+*al) obtained in Example 1 was added dropwise to the solution of F (1ζlofuran on tetra) (5h) while stirring the solution under ice-cooling.
The mixture was stirred on ice for 3 hours. This was neutralized with saturated aqueous potassium bicarbonate solution and extracted with ethyl acetate (2X 50+I
Q), then washed with saturated saline, dried with magnesium sulfate, filtered, and distilled to HP, 113
10.7 g of 2-fluoronicotinic acid diethylamide was obtained at ~115° C. 72 mm+Hg (yield 78%).
参考例２
２−フルオロニコチン酸アミドの合成
２００ｍ（２耐圧反応管にＴ ＨＦ ４０ｍＱ、実施例
１で（ＩＪ タ２− フルオロニコチン酸フルオ’）
トｌＯｇ（０，０７ｓｏｌ）を入れ、アンモニアガス
５．１ｇ（０，３ｍｏｌ）を仕込み常温で・昼夜攪拌し
た。未反応のアンモニア、ＴＨＦを除去し残った固体を
アセトンで抽出した（２Ｘ ２００ｍ１２）。アセトン
を除去し固体を析出させ、これを水より＋ｌｆ結晶し、
ｍｐ、 １１８〜１２０℃の２−フルオロニコチン酸ア
ミドを得た。Reference Example 2 Synthesis of 2-fluoronicotinic acid amide 200 m (40 mQ of THF in 2 pressure-resistant reaction tubes, (IJ 2-fluoronicotinic acid fluoro') in Example 1)
Add 10g (0.07sol) and ammonia gas
5.1 g (0.3 mol) was added and stirred day and night at room temperature. Unreacted ammonia and THF were removed and the remaining solid was extracted with acetone (2X 200ml). Acetone is removed to precipitate a solid, which is +lf crystallized from water,
mp, 2-fluoronicotinic acid amide with a temperature of 118-120°C was obtained.
参考例３
２−フルオロニコチン酸の合成
’ｉｎ！＝４１ＡＬで得た２−フルオロニコチン酸フル
オリド１０ｇ（０，０７ＩＩｏｌ）を水２０＋ｓ１２に
滴ド、常温で３０分攪拌することにより白い固体が析出
し、これをろ別復水でｉｌ結晶し２−フルオロニコチン
酸を得た。Reference Example 3 Synthesis of 2-fluoronicotinic acid 'in! =41 10 g (0.07 IIol) of 2-fluoronicotinic acid fluoride obtained in AL was dropped into 20 + s12 of water and stirred at room temperature for 30 minutes to precipitate a white solid, which was filtered and crystallized with condensed water to give 2- Fluoronicotinic acid was obtained.
参考例４
２−フルオロニコチン酸メチルの合成
乾燥エタノール４０ＩＩＱに実施例１で得た２−フルオ
ロニコチン酸フルオリドｌＯｇ（０，０７鳳ｏ１）を滴
ド、常温で１時間攪拌し、飽和上炭酸カリウム水溶液で
中和、酢酸エチルで抽出（２Ｘ２０■Ｑ）、水洗後硫酸
マグネシウムにより乾燥、ろ別したのち蒸留し、 ｂｐ
、１１３〜ｂ
２−フルオロニコチン酸エチル９．２７ｇを得た（収＝
４＜ ７８％）。Reference Example 4 Synthesis of methyl 2-fluoronicotinate 10 g (0.07 o 1) of the 2-fluoronicotinic acid fluoride obtained in Example 1 was added dropwise to 40 IIQ of dry ethanol, stirred at room temperature for 1 hour, and saturated with potassium carbonate. Neutralized with aqueous solution, extracted with ethyl acetate (2X20■Q), washed with water, dried with magnesium sulfate, filtered, and distilled.
, 113-b 9.27 g of ethyl 2-fluoronicotinate was obtained (yield =
4 < 78%).
参考例５
２−フルオロニコチン酸エチルの合成
２−フルオロニコチン酸メチルの合成と同様にして行な
い、実施例１で得た２−フルオロニコチン酸フルオリド
１０ｇ（０，００７ｍｏ ｌ）を用い、２−フルオロニ
コチン酸メチル７．０ｇ （収率６５％）を得た。Reference Example 5 Synthesis of ethyl 2-fluoronicotinate Synthesis was carried out in the same manner as the synthesis of methyl 2-fluoronicotinate, using 10 g (0,007 mol) of 2-fluoronicotinic acid fluoride obtained in Example 1. 7.0 g (yield 65%) of methyl nicotinate was obtained.
［発明の効果］
本発明方法に従えば、比較的温和な反応条件で、かつ短
時間の品数−（ぺで、医農薬中間体として有用なフルオ
ロピリジン類を得ることができる。又、［１重化合物に
よっては１反応温度及び反応時間を操作することにより
、選択率を大幅に数片することができる。[Effects of the Invention] According to the method of the present invention, fluoropyridines useful as pharmaceutical and agricultural intermediates can be obtained under relatively mild reaction conditions and in a short time. Depending on the polymer compound, the selectivity can be greatly varied by manipulating the reaction temperature and reaction time.
Claims (1)
りフッ素化し、フルオロピリジン類を得る方法において
、反応溶媒として、非プロトン性極性溶媒を用い、フッ
化カリウムとして１〜５０μの無水フッ化カリウム微粒
子を用いることを特徴とするフルオロピリジン類の製造
法。1. In the method of obtaining fluoropyridines by fluorinating chloro or bromopyridines with potassium fluoride, an aprotic polar solvent is used as the reaction solvent, and anhydrous potassium fluoride fine particles of 1 to 50μ are used as potassium fluoride. A method for producing fluoropyridines, characterized by:
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2114686A JPS62181257A (en) | 1986-02-04 | 1986-02-04 | Production of fluoropyridine or such |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2114686A JPS62181257A (en) | 1986-02-04 | 1986-02-04 | Production of fluoropyridine or such |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPS62181257A true JPS62181257A (en) | 1987-08-08 |
Family
ID=12046761
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2114686A Pending JPS62181257A (en) | 1986-02-04 | 1986-02-04 | Production of fluoropyridine or such |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS62181257A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH04504405A (en) * | 1988-01-04 | 1992-08-06 | イー・アイ・デユポン・デ・ニモアス・アンド・カンパニー | Cyanodienes, halopyridines, intermediates and their production methods |
| US20140031558A1 (en) * | 2012-07-24 | 2014-01-30 | Dow Agrosciences Llc | Fluoropicolinoyl fluorides and processes for their preparation |
| CN106380447A (en) * | 2016-08-29 | 2017-02-08 | 联化科技(盐城)有限公司 | 3-difluoromethyl-1-methyl-1H-pyrazol-4-formic acid and preparation method of intermediate and intermediate |
-
1986
- 1986-02-04 JP JP2114686A patent/JPS62181257A/en active Pending
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH04504405A (en) * | 1988-01-04 | 1992-08-06 | イー・アイ・デユポン・デ・ニモアス・アンド・カンパニー | Cyanodienes, halopyridines, intermediates and their production methods |
| US20140031558A1 (en) * | 2012-07-24 | 2014-01-30 | Dow Agrosciences Llc | Fluoropicolinoyl fluorides and processes for their preparation |
| US9045427B2 (en) * | 2012-07-24 | 2015-06-02 | Dow Agrosciences Llc | Fluoropicolinoyl fluorides and processes for their preparation |
| JP2015524806A (en) * | 2012-07-24 | 2015-08-27 | ダウ アグロサイエンシィズ エルエルシー | Fluoropicolinoyl fluoride and methods for their preparation |
| US9376388B2 (en) | 2012-07-24 | 2016-06-28 | Dow Agrosciences Llc | Fluoropicolinoyl fluorides and processes for their preparation |
| CN106380447A (en) * | 2016-08-29 | 2017-02-08 | 联化科技(盐城)有限公司 | 3-difluoromethyl-1-methyl-1H-pyrazol-4-formic acid and preparation method of intermediate and intermediate |
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