JPH03223252A - Production of substituted methylamine compound - Google Patents
Production of substituted methylamine compoundInfo
- Publication number
- JPH03223252A JPH03223252A JP16129490A JP16129490A JPH03223252A JP H03223252 A JPH03223252 A JP H03223252A JP 16129490 A JP16129490 A JP 16129490A JP 16129490 A JP16129490 A JP 16129490A JP H03223252 A JPH03223252 A JP H03223252A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- compound
- aqueous solvent
- expressed
- caustic alkali
- 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
- -1 methylamine compound Chemical class 0.000 title claims abstract description 7
- 238000004519 manufacturing process Methods 0.000 title claims description 7
- BAVYZALUXZFZLV-UHFFFAOYSA-N mono-methylamine Natural products NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 37
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 36
- 239000002253 acid Substances 0.000 claims abstract description 11
- 239000003518 caustics Substances 0.000 claims abstract description 9
- 229910052500 inorganic mineral Inorganic materials 0.000 claims abstract description 9
- 239000011707 mineral Substances 0.000 claims abstract description 9
- 239000003513 alkali Substances 0.000 claims abstract description 8
- 239000003125 aqueous solvent Substances 0.000 claims abstract description 8
- 230000003301 hydrolyzing effect Effects 0.000 claims abstract 3
- 229910052783 alkali metal Inorganic materials 0.000 claims abstract 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 11
- 235000010755 mineral Nutrition 0.000 claims description 7
- 239000000126 substance Substances 0.000 claims 6
- 238000006243 chemical reaction Methods 0.000 abstract description 20
- 238000000034 method Methods 0.000 abstract description 4
- 150000003956 methylamines Chemical class 0.000 abstract description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 abstract description 3
- XPARFBOWIYMLMY-UHFFFAOYSA-N (6-chloropyridin-3-yl)methanamine Chemical compound NCC1=CC=C(Cl)N=C1 XPARFBOWIYMLMY-UHFFFAOYSA-N 0.000 abstract description 2
- 239000003905 agrochemical Substances 0.000 abstract description 2
- 125000001309 chloro group Chemical group Cl* 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract description 2
- CYMRPDYINXWJFU-UHFFFAOYSA-N 2-carbamoylbenzoic acid Chemical class NC(=O)C1=CC=CC=C1C(O)=O CYMRPDYINXWJFU-UHFFFAOYSA-N 0.000 abstract 3
- 125000005842 heteroatom Chemical group 0.000 abstract 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 30
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 18
- 239000000243 solution Substances 0.000 description 13
- 238000003756 stirring Methods 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 8
- 238000005903 acid hydrolysis reaction Methods 0.000 description 8
- 239000013078 crystal Substances 0.000 description 7
- 238000005904 alkaline hydrolysis reaction Methods 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 235000002639 sodium chloride Nutrition 0.000 description 5
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 4
- 235000019341 magnesium sulphate Nutrition 0.000 description 4
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 238000000354 decomposition reaction Methods 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 238000011084 recovery Methods 0.000 description 3
- KZDJNJBEHMLRES-UHFFFAOYSA-N 2-[(2-chloro-1,3-thiazol-5-yl)methyl]isoindole-1,3-dione Chemical compound S1C(Cl)=NC=C1CN1C(=O)C2=CC=CC=C2C1=O KZDJNJBEHMLRES-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 125000000623 heterocyclic group Chemical class 0.000 description 2
- 239000012456 homogeneous solution Substances 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000005292 vacuum distillation Methods 0.000 description 2
- GVTLFGJNTIRUEG-ZHACJKMWSA-N (e)-n-(3-methoxyphenyl)-3-phenylprop-2-enamide Chemical compound COC1=CC=CC(NC(=O)\C=C\C=2C=CC=CC=2)=C1 GVTLFGJNTIRUEG-ZHACJKMWSA-N 0.000 description 1
- ADZVPBSFWQMJPS-UHFFFAOYSA-N 2-[(2-chloro-1,3-thiazol-5-yl)methylcarbamoyl]benzoic acid Chemical compound OC(=O)C1=CC=CC=C1C(=O)NCC1=CN=C(Cl)S1 ADZVPBSFWQMJPS-UHFFFAOYSA-N 0.000 description 1
- CNGRXEGLSOHJAI-UHFFFAOYSA-N 2-carbamoyl-3-methylbenzoic acid Chemical compound CC1=CC=CC(C(O)=O)=C1C(N)=O CNGRXEGLSOHJAI-UHFFFAOYSA-N 0.000 description 1
- SKCNYHLTRZIINA-UHFFFAOYSA-N 2-chloro-5-(chloromethyl)pyridine Chemical compound ClCC1=CC=C(Cl)N=C1 SKCNYHLTRZIINA-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- FYRHIOVKTDQVFC-UHFFFAOYSA-M potassium phthalimide Chemical compound [K+].C1=CC=C2C(=O)[N-]C(=O)C2=C1 FYRHIOVKTDQVFC-UHFFFAOYSA-M 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000003021 water soluble solvent Substances 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、クロロ置換へテロ環で置換されたメチルアミ
ン類の新規な製造方法に関するものであり、該製造方法
により得られる化合物類は医薬及び農薬の中間体として
有用な化合物である。Detailed Description of the Invention [Field of Industrial Application] The present invention relates to a novel method for producing methylamines substituted with a chloro-substituted heterocycle, and the compounds obtained by this method are useful as pharmaceuticals. It is also a compound useful as an intermediate for agricultural chemicals.
を示す。 shows.
）で表わされるＮ
置換フタルイミ
ドを
ヒドラジンで分解し、一般式Ａ−ＣＨ２ＮＨ＋で表わさ
れる置換メチルアミン類を得る方法については、西独公
開特許３７２７１２６号に記載されており、ヘテロ環の
クロロ置換基がヒドラジンにより来談置換されずに、目
的物が得られるという特徴を有している事が記されてい
る。) is decomposed with hydrazine to obtain substituted methylamines represented by the general formula A-CH2NH+. It is noted that it has the characteristic that the desired object can be obtained without being replaced.
しかし、こうした従来の方法では、ヒドラジン分解後、
濃縮操作や濾過操作等の煩雑な後処理操作を必要とし、
又収率もあまり高いものではなく、操作的にも経済的に
も好ましい工業的製法とはいえない。However, in these conventional methods, after hydrazine decomposition,
Requires complicated post-processing operations such as concentration and filtration operations,
Furthermore, the yield is not very high, and it cannot be said to be an industrial production method that is operationally or economically preferable.
本発明者は、これらの欠点を改良する目的で、鋭意検討
を重ねた結果、一般式
（式中、Ａは前記と同し意味を示す。）で表わされる化
合物を、水溶媒中苛性アルカリで加水分解し、ついて鉱
酸て加水分解する事により、ヘテロ環のクロロ置換基が
影響を受ける事なく、穏和な反応条件下に容易にかつ好
収率で、−数式％式％（）
で表わされる置換メチルアミン類が得られる事を知るに
至り、本発明を完成した。In order to improve these shortcomings, the present inventors have conducted intensive studies and found that a compound represented by the general formula (wherein A has the same meaning as above) was prepared using a caustic alkali in an aqueous solvent. By hydrolysis and subsequent hydrolysis with mineral acids, the chloro substituent on the heterocycle is not affected, and under mild reaction conditions, it can be easily and in good yield expressed by the formula % (). The present invention was completed after discovering that substituted methylamines can be obtained.
本発明を反応式で示せば下記のとおりである。The reaction formula of the present invention is as follows.
（Ｉ）
（ＩＩ）
Ａ Ｃ８２ＮＨ２（ｎｌ）
（ａ＋工程で得られる化合物（？）は新規化合物であり
、容易に単離することができるがアルカリ加水分解後の
反応液に、引き続き鉱酸を加えて酸加水分解する事によ
り、化合物（ＩＩ）を単離した場合と同等の収率で化合
物（ＩＩＩ）を得る事かできｔａ＋工程のアルカリ加水
分解において、使用する苛性アルカリとしては苛性ソー
ダあるいは苛性カリが挙げられ、化合物（Ｉ）の１当量
に対して１．０〜１．３当量を使用すればよい。反応温
度は５０°Ｃ〜１００℃が好ましく、これより低いと反
応速度が遅くなり、これより高いと化合物（Ｉｌｒ）が
分解するおそれがある。(I) (II) A C82NH2(nl) (The compound (?) obtained in step a+ is a new compound and can be easily isolated, but mineral acid is subsequently added to the reaction solution after alkaline hydrolysis. Compound (III) can be obtained in the same yield as when compound (II) is isolated by acid hydrolysis.In the alkaline hydrolysis in the ta+ step, caustic soda or caustic potassium is used as the caustic alkali. 1.0 to 1.3 equivalents may be used per equivalent of compound (I).The reaction temperature is preferably 50°C to 100°C, and if it is lower than this, the reaction rate will be slow. If it is higher, the compound (Ilr) may be decomposed.
ｆｂｌ工程の酸加水分解において、使用する鉱酸として
は塩酸あるいは硫酸等が挙げられ、化合物（ＩＩ）の１
当量に対して１．０５〜１．３当量を使用すればよい。In the acid hydrolysis of the fbl step, examples of mineral acids used include hydrochloric acid and sulfuric acid.
What is necessary is just to use 1.05-1.3 equivalent with respect to an equivalent.
反応温度は７０°Ｃ−１００°Ｃが好ましく、これより
反応温度が低いと、反応速度が遅くなる。又、酸加水分
解において、一部逆反応が進行し、化合物（ｎ）により
化合物（１）か副生ずるが、副生じた化合物ＣＩ）はト
ルエン等の溶媒で容易に抽出除去回収でき、再使用する
ことができる。The reaction temperature is preferably 70°C to 100°C; if the reaction temperature is lower than this, the reaction rate will be slow. In addition, in acid hydrolysis, a partial reverse reaction proceeds, and compound (1) is produced as a by-product from compound (n), but the by-produced compound CI) can be easily extracted and recovered with a solvent such as toluene, and can be reused. can do.
反応終了後、得られた化合物（ＩＩＩ）の鉱酸塩を含む
水溶液を苛性アルカリでアルカリ性とし、水難溶性溶媒
、例えばクロロホルム等で抽出し、濃縮する等、通常の
処理をする事により、化合物（ＩＩＩ）を得る事ができ
る。After completion of the reaction, the resulting aqueous solution containing the mineral acid salt of compound (III) is made alkaline with caustic alkali, extracted with a poorly water-soluble solvent such as chloroform, and concentrated. III) can be obtained.
以下に示す実施例は、本発明を説明するものであって、
何らこれに限定されるものではない。The examples given below illustrate the invention:
It is not limited to this in any way.
実施例１
２−クロロ−５−（アミノメチル）ピリジン化合物（Ｉ
ＩＩ−ａ） ：
Ｎ−Ｃ（２−クロロピリジン−５−イル）メチル〕フタ
ルイミド〔化合物（Ｉ−ａ）〕２７２．６ｇ （１，０
ｍｏｌ）を水１１に懸濁させた中に、２５％苛性ソーダ
水溶液１９２．０ ｇ （１，２ｍｏｌ）を加え、攪拌
下に７０℃で１時間アルカリ加水分解した。Example 1 2-chloro-5-(aminomethyl)pyridine compound (I
II-a): N-C(2-chloropyridin-5-yl)methyl]phthalimide [compound (I-a)] 272.6 g (1,0
192.0 g (1.2 mol) of a 25% aqueous sodium hydroxide solution was added to a suspension of 11 mol of sodium hydroxide in water, and alkaline hydrolysis was carried out at 70° C. for 1 hour with stirring.
ついで、この反応液を７０〜７５℃に保った１０％塩酸
水溶液８７５．０ ｇ （２，４ｍｏｌ）中に攪拌下に
滴下し、滴下終了後、９０〜９５°Ｃにて１時間１時間
酸加水分解した。反応終了後、トルエン５００−を徐々
に加えて洗浄し、熱時分液して得た水層を室温迄冷却し
た。ついで、食塩２６０．０ ｇを加えた後、５０％苛
性ソーダ水溶液２６０．０ ｇ（３，２ｍｏｌ）を加え
てアルカリ性として、クロロホルム８００−で２回抽出
した。得られたクロロホルム層を硫酸マグネシウムで乾
燥後、濃縮して１２７、４ ｇのｏｉｌ （冷却する
と固化した）を得た。Next, this reaction solution was added dropwise to 875.0 g (2.4 mol) of a 10% aqueous hydrochloric acid solution kept at 70 to 75°C with stirring, and after the dropwise addition was completed, the acid was heated at 90 to 95°C for 1 hour. Hydrolyzed. After the reaction was completed, 500 g of toluene was gradually added for washing, and the aqueous layer obtained by thermal separation was cooled to room temperature. Next, 260.0 g of common salt was added, and then 260.0 g (3.2 mol) of a 50% aqueous sodium hydroxide solution was added to make the mixture alkaline, and the mixture was extracted twice with 800 g of chloroform. The obtained chloroform layer was dried over magnesium sulfate and concentrated to obtain 127.4 g of oil (which solidified upon cooling).
このｏｉｌを減圧蒸留に付しｌｍｍＨｇ９２〜９４°Ｃ
の留分１２４．８ｇ（冷却すると固化。ｍ、 ｐ、
２５〜２６６Ｃ）を得た。This oil was subjected to vacuum distillation at lmmHg92-94°C.
124.8g of fraction (solidifies when cooled. m, p,
25-266C) was obtained.
収率８７．５％
ＮＮＲスペクトル（ＣＤ（１３）δｐｐｍ；１．４９
（２ＨＸｓ ｂｒｏａｄ）３．９０ （２Ｈ，ｓ）７
、２９〜８．３４ （３Ｈ，ｍ）
又、酸加水分解後の洗浄トルエン層を濃縮乾固すること
により、１４．４ ｇの化合物（１−ａ）が回収された
。回収率５．３％
実施例２
Ｎ−〔（２−クロロピリジン−５−イル）メチル〕フタ
ルアミド酸〔化合物（ＩＩ−ａ））：化合物（Ｉ−ａ）
５．４５ ｇ （２０ｍｒｎｏｌ）を水２〇−に懸濁さ
せた中に、２５％苛性ソーダ水溶液３゜８４ ｇ （２
４ｍｍｏｌ）を加え、攪拌下に７０℃で１時間アルカリ
加水分解し、均一な溶液を得た。この溶液に水３０ｄを
加えて室温迄冷却し、攪拌下に３５％塩酸を滴下したｐ
Ｈを１．０とした。析出した結晶を濾過水洗し、乾燥し
て融点１６９〜１７１０Ｃ（分解）の白色結晶５．７６
ｇを得た。収率９９．１％ＮＭＲスペクトル（Ｄｒｖ
ｔＳＯ−ｄｓ ）δ＋：１ｍ：４．４５ （２ＨＸｄ）
７．４５〜８．４３ （７Ｈ，ｍ）８．８９ （ＩＨ
，ｔ）１３．００ （ＩＨ，５ｂｒｏａｄ）
実施例３
２−クロロ−５−（アミノメチル）ピリジン〔化合物（
Ｉ［Ｉ−ａ））
化合物（ＩＩ−ａ） ５．８１ ｇ （２０ｍｍｏｌ）
を４゜５％塩酸水溶液］ ９．４７ ｇ （２４ｍｍｏ
ｌ）に懸濁させ、攪拌下に９０〜９５℃にて１時間酸加
水分解した。反応後、熱時にトルエン１０−で洗浄し、
分液して得た水層を室温迄冷却し、食塩６．６ｇを加え
た後、５０％苛性ソーダ水溶液５．２０ｇ（６４ｍｍｏ
ｌ）を加えてアルカリ性とし、クロロホルムで抽出した
。得られたクロロホルム層を硫酸マグネシウムで乾燥後
濃縮し、２．５６ ｇの目的物ｏｉ１ （冷却すると固
化した。）を得た。収率８９．８％
ＮＭＲスペクトル（ＣＤＣｊ７３） δｐｐｍ；１．４
９ （２Ｈ，ｓ ｂｒｏａｄ）３．９０ （２Ｈ，ｓ
）７．２９〜８．３４ （３Ｈ，ｍ）
又、酸加水分解後の洗浄トルエン層を濃縮乾固すること
により、０．３０ ｇの化合物（Ｉ−ａ）が回収された
。回収率５．５％。Yield 87.5% NNR spectrum (CD(13)δppm; 1.49
(2HXs broad)3.90 (2H,s)7
, 29-8.34 (3H, m) In addition, 14.4 g of compound (1-a) was recovered by concentrating and drying the washed toluene layer after acid hydrolysis. Recovery rate 5.3% Example 2 N-[(2-chloropyridin-5-yl)methyl]phthalamic acid [Compound (II-a)): Compound (I-a)
In a suspension of 5.45 g (20 mrnol) in 20 mn of water, 3°84 g (2 mrnol) of a 25% aqueous solution of caustic soda was added.
4 mmol) was added thereto, and alkaline hydrolysis was carried out at 70° C. for 1 hour while stirring to obtain a homogeneous solution. 30 d of water was added to this solution, cooled to room temperature, and 35% hydrochloric acid was added dropwise with stirring.
H was set to 1.0. The precipitated crystals were filtered, washed with water, and dried to give white crystals with a melting point of 169-1710C (decomposition) of 5.76
I got g. Yield 99.1% NMR spectrum (Drv
tSO-ds) δ+:1m:4.45 (2HXd)
7.45-8.43 (7H, m) 8.89 (IH
, t) 13.00 (IH, 5broad) Example 3 2-chloro-5-(aminomethyl)pyridine [Compound (
I[I-a)) Compound (II-a) 5.81 g (20 mmol)
9.47 g (24 mmo
1) and acid hydrolyzed at 90 to 95° C. for 1 hour while stirring. After the reaction, wash with toluene 10- while hot,
The aqueous layer obtained by liquid separation was cooled to room temperature, 6.6 g of common salt was added, and 5.20 g of 50% caustic soda aqueous solution (64 mm
1) was added to make the mixture alkaline, and the mixture was extracted with chloroform. The obtained chloroform layer was dried over magnesium sulfate and concentrated to obtain 2.56 g of the target product oi1 (solidified upon cooling). Yield 89.8% NMR spectrum (CDCj73) δppm; 1.4
9 (2H,s broad)3.90 (2H,s
)7.29-8.34 (3H, m) Furthermore, 0.30 g of compound (I-a) was recovered by concentrating and drying the washed toluene layer after acid hydrolysis. Recovery rate 5.5%.
実施例４
２−知ロー５−アミノチアシーツ収化合物（■−ｂ）〕
Ｎ（２−クロロ−５−チアゾリルメチル）フタルイミド
１３２．６ｇ （０，４８ｍｏｌ） Ｃ化合物（Ｉ−ｂ
）］を水１１５１に懸濁させた中に２５％苛性ソーダ水
溶液９１．３ ｇ （０，５７ｍｏｌ）を加え、攪拌下
に５０℃で１．５時間アルカリ加水分解した。Example 4 2-Chiro 5-aminothia sheet compound (■-b)] N(2-chloro-5-thiazolylmethyl)phthalimide 132.6 g (0.48 mol) C compound (I-b)
)] was suspended in 1151 water, 91.3 g (0.57 mol) of a 25% aqueous sodium hydroxide solution was added, and alkaline hydrolysis was carried out at 50° C. for 1.5 hours while stirring.
この反応液を室温まで冷却後、８０〜８５℃に保った２
０％塩酸水溶液２０８．４ ｇ （１，１４ｍｏｌ）中
に滴下し、滴下終了後、９５〜１００℃にて２時間酸加
水分解を行った。反応終了後、トルエン４００−を徐々
に加え、熱時トルエン抽出・分液した。得られた水層は
室温まで冷却し食塩１１０ｇを加えた後、２５％苛性ソ
ーダ水溶液３７４．０ ｇ（２，３４ｍｏｌ）でアルカ
リ性としたのち、クロロホルム５００−で３回抽出した
。得られたクロロホルム層を硫酸マグネシウムで乾燥後
、濃縮し６４゜Ｏｇのオイルを得た。このオイルを減圧
蒸留に付し１ＩＨｇ７８．５〜８０．０℃の留分５７．
４ ｇを得た。After cooling the reaction solution to room temperature, it was kept at 80-85°C.
It was dropped into 208.4 g (1.14 mol) of a 0% aqueous hydrochloric acid solution, and after the dropwise addition was completed, acid hydrolysis was performed at 95 to 100°C for 2 hours. After the reaction was completed, 400 g of toluene was gradually added, and hot toluene extraction and liquid separation were carried out. The obtained aqueous layer was cooled to room temperature, 110 g of common salt was added, and then made alkaline with 374.0 g (2.34 mol) of a 25% aqueous solution of caustic soda, and then extracted three times with 500 ml of chloroform. The obtained chloroform layer was dried with magnesium sulfate and concentrated to obtain a 64°Og oil. This oil was subjected to vacuum distillation and a fraction of 1IHg 78.5-80.0°C was obtained.
4 g was obtained.
収率８０．５％
ＮＭＲスペクトル（ＣＤＣｊ’＋）δｐｐｍ：２．１８
（２Ｈ，Ｓ ｂｒｏａｄ） 、４．０３ （２８゜
ｓ） 、７．３６ （ＩＨ，ｓ）
実施例５
Ｎ−［（２−クロロチアゾール−５−イル）〕メチルフ
タルアミド酸（化合物（ＩＩ−ｂ））：Ｎ−（２−クロ
ロ−５−チアゾリルメチル）フタルイミド１３．９ ｇ
（０，０５ｍｏｌ）を水５０１ｒ！に懸濁させた中に
、２５％苛性ソーダ水溶液９，６ｇ（０，０６ｍｏｌ）
を加え、攪拌下に７０℃で２．５時間アルカリ加水分解
し均一な溶液を得た。この溶液に水２０−を加えて室温
まで冷却し、攪拌下に３５％塩酸を滴下してｐＨを１．
０とした。析出した結晶を濾過水洗し白色結晶１４．１
ｇを得た。（収率９５，１％）
この結晶をアセトンより再結晶し融点１６７５〜１６８
．５°Ｃ（分解）の白色針状晶を得た。Yield 80.5% NMR spectrum (CDCj'+) δppm: 2.18
(2H,S broad), 4.03 (28°s), 7.36 (IH,s) Example 5 N-[(2-chlorothiazol-5-yl)]methylphthalamic acid (compound (II- b)): 13.9 g of N-(2-chloro-5-thiazolylmethyl)phthalimide
(0.05 mol) in 501 r of water! 9.6 g (0.06 mol) of 25% caustic soda aqueous solution was suspended in
was added, and alkaline hydrolysis was performed at 70° C. for 2.5 hours with stirring to obtain a homogeneous solution. Add 20% of water to this solution, cool it to room temperature, and add 35% hydrochloric acid dropwise while stirring to adjust the pH to 1.
It was set to 0. The precipitated crystals were filtered and washed with water to give white crystals 14.1.
I got g. (Yield 95.1%) This crystal was recrystallized from acetone with a melting point of 1675-168.
．． White needles were obtained at 5°C (decomposition).
ＮＭＲスペクトル（ＤＭＳＯ−ｄａ ）δｐｐｍ＋７．
４１〜７．６１ （４Ｈ，ｍ） 、７．８０ （ＬＨ
。NMR spectrum (DMSO-da) δppm+7.
41-7.61 (4H, m), 7.80 (LH
.
ｄ） 、９．０４ （ＩＨＸｓ ｂｒｏａｄ） 、１
３．０（ＩＨ，ｓ ｂｒｏａｄ）
実施例６
Ｎ−（（２−クロロチアゾール−５−イル）〕メチルフ
タルアミド酸８．９０ ｇ （３０ｍｍｏｌ）を、４．
５％塩酸水溶液３６．５ ｇ （４５ｍｍｏｌ）に懸濁
させ、攪拌下に９０〜９５℃にて２時間酸加水分解を行
った。反応終了後、トルエン４００−を徐々に加え、熱
時トルエン抽出・分液した。得られた水層は室温まで冷
却し食塩５ｇを加えた後、２５％苛性ソーダ水溶液８．
６４ ｇ （５４ｍｍｏｌ）でアルカリ性としたのち、
クロロホルムで抽出した。得られたクロロホルム層を硫
酸マグネシウムで乾燥後、濃縮し３、８８ ｇの目的物
オイルを得た。収率８７．２％又、酸加水分解後の洗浄
トルエン層を濃縮乾固することにより、０．４２ ｇの
化合物（１−ｂ）が回収された。回収率５．０％
参考例１
化合物（Ｉ−ａ）：
２−クロロ−５−（クロロメチル）ピリジン１２９、６
ｇ （０，８ｍｏｌ）をジメチルホルムアミド４００
−に溶解し、ついでフタルイミドカリウム１５１゜１
ｇ （０，８１６ｍｏｌ）を加えて、攪拌下７０℃にて
３時間反応させた。反応終了後、反応液を冷水２！に攪
拌しながら投入し、析出した白色結晶を濾過水洗し、乾
燥して、目的物結晶２１４．７ｇを得た。融点２３９〜
２４０°Ｃ収率９８．５％〔発明の効果〕
上記実施例からも明らかなように本発明の製造方法は新
規化合物（ＩＩ）を経由することにより、従来法に比し
、容易な操作、穏和な反応条件で好収率で目的物が得ら
れ、工業的に優れた製造方法である。d), 9.04 (IHXs broad), 1
3.0 (IH, s broad) Example 6 8.90 g (30 mmol) of N-((2-chlorothiazol-5-yl)]methylphthalamic acid was added to 4.0 (IH, s broad).
It was suspended in 36.5 g (45 mmol) of a 5% aqueous hydrochloric acid solution, and acid hydrolysis was performed at 90 to 95° C. for 2 hours while stirring. After the reaction was completed, 400 g of toluene was gradually added, and hot toluene extraction and liquid separation were carried out. The obtained aqueous layer was cooled to room temperature, 5 g of common salt was added, and 8.5 g of 25% aqueous sodium hydroxide solution was added.
After making it alkaline with 64 g (54 mmol),
Extracted with chloroform. The obtained chloroform layer was dried with magnesium sulfate and then concentrated to obtain 3.88 g of target oil. Yield: 87.2% 0.42 g of compound (1-b) was recovered by concentrating and drying the washed toluene layer after acid hydrolysis. Recovery rate 5.0% Reference Example 1 Compound (I-a): 2-chloro-5-(chloromethyl)pyridine 129,6
g (0.8 mol) in dimethylformamide 400
- dissolved in potassium phthalimide 151゜1
g (0,816 mol) was added thereto, and the mixture was reacted at 70° C. for 3 hours with stirring. After the reaction is complete, pour the reaction solution into cold water for 2 hours! The precipitated white crystals were filtered, washed with water, and dried to obtain 214.7 g of target crystals. Melting point 239~
Yield at 240°C: 98.5% [Effects of the Invention] As is clear from the above examples, the production method of the present invention uses the novel compound (II), so compared to the conventional method, the production method is easier to operate, The desired product can be obtained in good yield under mild reaction conditions, making it an industrially excellent production method.
Claims (4)
数式、化学式、表等があります▼を示す。）で表わされ
るＮ−置換フタルイミドを、水溶媒中苛性アルカリで加
水分解して、 一般式 ▲数式、化学式、表等があります▼（II） （式中、Ａは前記と同じ意味を示す。）で表わされる化
合物のアルカリ金属塩を得、ついで化合物（II）を水溶
媒中鉱酸で加水分解する事を特徴とする、一般式 Ａ−ＣＨ＿２ＮＨ＿２（III） （式中、Ａは前記と同じ意味を示す。）で表わされる化
合物の製造方法。(1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (I) (In the formula, A is ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or ▲
There are mathematical formulas, chemical formulas, tables, etc. Showing ▼. ) is hydrolyzed with caustic alkali in an aqueous solvent to form the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (II) (In the formula, A has the same meaning as above.) The alkali metal salt of the compound represented by is obtained, and then the compound (II) is hydrolyzed with a mineral acid in an aqueous solvent. ).
ある特許請求の範囲第１項に記載の製造方法。(2) The manufacturing method according to claim 1, wherein the caustic alkali is caustic soda and the mineral acid is hydrochloric acid.
合物。(3) A compound represented by the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (II) (In the formula, A has the same meaning as above.)
合物を水溶媒中、鉱酸で加水分解する事を特徴とする一
般式 Ａ−ＣＨ＿２ＮＨ＿２（III） （式中、Ａは前記と同じ意味を示す。）で表わされる化
合物の製造方法。(4) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (II) Characterized by hydrolyzing the compound represented by the formula (in the formula, A has the same meaning as above) with a mineral acid in an aqueous solvent. A method for producing a compound represented by the general formula A-CH_2NH_2(III) (wherein A has the same meaning as above).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP16129490A JPH03223252A (en) | 1989-12-27 | 1990-06-21 | Production of substituted methylamine compound |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1-336232 | 1989-12-27 | ||
| JP33623289 | 1989-12-27 | ||
| JP16129490A JPH03223252A (en) | 1989-12-27 | 1990-06-21 | Production of substituted methylamine compound |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH03223252A true JPH03223252A (en) | 1991-10-02 |
Family
ID=26487475
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP16129490A Pending JPH03223252A (en) | 1989-12-27 | 1990-06-21 | Production of substituted methylamine compound |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH03223252A (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0722933A1 (en) * | 1994-12-23 | 1996-07-24 | Bayer Ag | Process for the preparation of chloromethylpyridine derivatives and acylaminomethyl pyridines as intermediates |
| WO1998028285A1 (en) * | 1996-12-20 | 1998-07-02 | Bayer Aktiengesellschaft | Method for producing 2-chloro-5-aminomethylthiazole from 2-chloro-5-methylthiazole via 2-chloro-5-chloromethylthiazole |
| JP2005112807A (en) * | 2003-10-09 | 2005-04-28 | Toray Fine Chemicals Co Ltd | Method for producing aminoalkoxycarbostyryl derivative |
| WO2011065590A1 (en) * | 2009-11-30 | 2011-06-03 | 住友化学株式会社 | Method for producing 5-(aminomethyl)-2-chlorothiazole |
-
1990
- 1990-06-21 JP JP16129490A patent/JPH03223252A/en active Pending
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0722933A1 (en) * | 1994-12-23 | 1996-07-24 | Bayer Ag | Process for the preparation of chloromethylpyridine derivatives and acylaminomethyl pyridines as intermediates |
| KR100424198B1 (en) * | 1994-12-23 | 2004-06-16 | 바이엘 악티엔게젤샤프트 | Process for the preparation of chloromethylpyridines |
| WO1998028285A1 (en) * | 1996-12-20 | 1998-07-02 | Bayer Aktiengesellschaft | Method for producing 2-chloro-5-aminomethylthiazole from 2-chloro-5-methylthiazole via 2-chloro-5-chloromethylthiazole |
| JP2005112807A (en) * | 2003-10-09 | 2005-04-28 | Toray Fine Chemicals Co Ltd | Method for producing aminoalkoxycarbostyryl derivative |
| WO2011065590A1 (en) * | 2009-11-30 | 2011-06-03 | 住友化学株式会社 | Method for producing 5-(aminomethyl)-2-chlorothiazole |
| US8754235B2 (en) | 2009-11-30 | 2014-06-17 | Sumitomo Chemical Company, Limited | Method for producing 5-(aminomethyl)-2-chlorothiazole |
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