JPH07316129A - Production of alkyl thioacetamide - Google Patents
Production of alkyl thioacetamideInfo
- Publication number
- JPH07316129A JPH07316129A JP6108831A JP10883194A JPH07316129A JP H07316129 A JPH07316129 A JP H07316129A JP 6108831 A JP6108831 A JP 6108831A JP 10883194 A JP10883194 A JP 10883194A JP H07316129 A JPH07316129 A JP H07316129A
- Authority
- JP
- Japan
- Prior art keywords
- diisopropylphenyl
- acetamide
- formula
- reacted
- base
- 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.)
- Granted
Links
- DLFVBJFMPXGRIB-UHFFFAOYSA-N thioacetamide Natural products CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 title claims abstract description 22
- -1 alkyl thioacetamide Chemical compound 0.000 title claims description 18
- 238000004519 manufacturing process Methods 0.000 title claims description 6
- WKBALTUBRZPIPZ-UHFFFAOYSA-N 2,6-di(propan-2-yl)aniline Chemical compound CC(C)C1=CC=CC(C(C)C)=C1N WKBALTUBRZPIPZ-UHFFFAOYSA-N 0.000 claims abstract description 9
- 150000003839 salts Chemical class 0.000 claims abstract description 9
- 239000002253 acid Substances 0.000 claims abstract description 7
- SQSUDYRMZQRNEX-UHFFFAOYSA-N 2-chloro-n-[2,6-di(propan-2-yl)phenyl]acetamide Chemical compound CC(C)C1=CC=CC(C(C)C)=C1NC(=O)CCl SQSUDYRMZQRNEX-UHFFFAOYSA-N 0.000 claims abstract description 4
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 claims abstract description 4
- SRUXSMWBGNQFTI-UHFFFAOYSA-N s-[2-[2,6-di(propan-2-yl)anilino]-2-oxoethyl] ethanethioate Chemical compound CC(C)C1=CC=CC(C(C)C)=C1NC(=O)CSC(C)=O SRUXSMWBGNQFTI-UHFFFAOYSA-N 0.000 claims abstract description 4
- 125000005843 halogen group Chemical group 0.000 claims abstract description 3
- KOUKXHPPRFNWPP-UHFFFAOYSA-N pyrazine-2,5-dicarboxylic acid;hydrate Chemical compound O.OC(=O)C1=CN=C(C(O)=O)C=N1 KOUKXHPPRFNWPP-UHFFFAOYSA-N 0.000 claims abstract description 3
- 125000004414 alkyl thio group Chemical group 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- 238000001953 recrystallisation Methods 0.000 claims description 3
- 150000001350 alkyl halides Chemical class 0.000 claims description 2
- 239000003112 inhibitor Substances 0.000 abstract description 4
- 239000007858 starting material Substances 0.000 abstract description 4
- 150000001875 compounds Chemical class 0.000 abstract 3
- 229910052736 halogen Inorganic materials 0.000 abstract 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 abstract 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 239000013078 crystal Substances 0.000 description 9
- 239000000243 solution Substances 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 239000003960 organic solvent Substances 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- JYWKEVKEKOTYEX-UHFFFAOYSA-N 2,6-dibromo-4-chloroiminocyclohexa-2,5-dien-1-one Chemical compound ClN=C1C=C(Br)C(=O)C(Br)=C1 JYWKEVKEKOTYEX-UHFFFAOYSA-N 0.000 description 2
- GNMYTZWBVZKWNH-UHFFFAOYSA-N 2-chloro-2-[2,6-di(propan-2-yl)phenyl]acetamide Chemical compound C(C)(C)C1=C(C(=CC=C1)C(C)C)C(C(N)=O)Cl GNMYTZWBVZKWNH-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- KOFZTCSTGIWCQG-UHFFFAOYSA-N 1-bromotetradecane Chemical compound CCCCCCCCCCCCCCBr KOFZTCSTGIWCQG-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 1
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000004703 alkoxides Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000001204 arachidyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- DUYAAUVXQSMXQP-UHFFFAOYSA-N ethanethioic S-acid Chemical class CC(S)=O DUYAAUVXQSMXQP-UHFFFAOYSA-N 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 125000001421 myristyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- VBFPXFNZWSRGTJ-UHFFFAOYSA-N n-[2,6-di(propan-2-yl)phenyl]hexadecanethioamide Chemical compound CCCCCCCCCCCCCCCC(=S)NC1=C(C(C)C)C=CC=C1C(C)C VBFPXFNZWSRGTJ-UHFFFAOYSA-N 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 125000002958 pentadecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000003444 phase transfer catalyst Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 1
- 229910000105 potassium hydride Inorganic materials 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- KQJWTIOZZLQART-UHFFFAOYSA-N s-(2-amino-2-oxoethyl) ethanethioate Chemical compound CC(=O)SCC(N)=O KQJWTIOZZLQART-UHFFFAOYSA-N 0.000 description 1
- VIFKUJWLJAAJDP-UHFFFAOYSA-N s-acetamido ethanethioate Chemical compound CC(=O)NSC(C)=O VIFKUJWLJAAJDP-UHFFFAOYSA-N 0.000 description 1
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- RBBWNXJFTBCLKT-UHFFFAOYSA-M sodium;ethanethioate Chemical compound [Na+].CC([S-])=O RBBWNXJFTBCLKT-UHFFFAOYSA-M 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
【０００１】[0001]
【産業上の利用分野】本発明は、国際公開ＷＯ９２／０
９５７２号公報に記載されているＡＣＡＴ阻害剤として
有用なＮ−（２，６−ジイソプロピルフェニル）−２−
（アルキルチオ）アセタミドの製造方法に関する。FIELD OF THE INVENTION The present invention relates to international publication WO92 / 0.
N- (2,6-diisopropylphenyl) -2-useful as an ACAT inhibitor described in Japanese Patent Publication No. 9572.
The present invention relates to a method for producing (alkylthio) acetamide.
【０００２】[0002]
【従来の技術】Ｎ−（２，６−ジイソプロピルフェニ
ル）−２−（アルキルチオ）アセタミドの製造方法とし
て、本発明者らが、国際公開ＷＯ９２／０９５７２号公
報及び特開平６−４０８９８号公報に記載しているが、
いずれの方法も原料に空気中で不安定なメルカプタンを
用いるため、大量に簡便かつ高収率に製造するには十分
な方法ではない。2. Description of the Related Art As a method for producing N- (2,6-diisopropylphenyl) -2- (alkylthio) acetamide, the present inventors have described it in International Publication WO92 / 09572 and JP-A-6-40898. But
Since neither of the methods uses mercaptan which is unstable in air as a raw material, it is not a sufficient method for mass production in a simple and high yield.
【０００３】また、出発原料として用いる工業的に安価
で大量に供給されている２，６−ジイソプロピルアニリ
ン中には、異性体等の不純物が多く含まれているため
に、中間体であるＮ−（２，６−ジイソプロピルフェニ
ル）−２−クロロアセタミド、Ｎ−（２，６−ジイソプ
ロピルフェニル）−２−（アセチルチオ）アセタミド及
び最終生成物であるＮ−（２，６−ジイソプロピルフェ
ニル）−２−（アルキルチオ）アセタミド中に異性体等
の不純物が多量に混入し、工業的に安価にしかも大量に
実施が可能な再結晶等の精製操作による不純物の除去が
困難であることが大きな問題となっていた。The industrially inexpensive and large-scale supply of 2,6-diisopropylaniline used as a starting material contains a large amount of impurities such as isomers, so that it is an intermediate N-. (2,6-Diisopropylphenyl) -2-chloroacetamide, N- (2,6-diisopropylphenyl) -2- (acetylthio) acetamide and the final product N- (2,6-diisopropylphenyl) -2- ( A large problem was that impurities such as isomers were mixed in (alkylthio) acetamide, and it was difficult to remove the impurities by a refining operation such as recrystallization that was industrially inexpensive and could be carried out in large quantities. .
【０００４】[0004]
【発明が解決しようとする課題】ＡＣＡＴ阻害剤として
有用なＮ−（２，６−ジイソプロピルフェニル）−２−
（アルキルチオ）アセタミドを高純度にしかも工業的に
安価で大量に簡便かつ高収率に製造することである。DISCLOSURE OF THE INVENTION N- (2,6-diisopropylphenyl) -2-useful as an ACAT inhibitor
It is to produce (alkylthio) acetamide with high purity, industrially, inexpensively, in large quantities, easily and in high yield.
【０００５】[0005]
【課題を解決するための手段】本発明者らは、上記の課
題解決を目的に鋭意検討した結果、工業的に安価で大量
に供給されている２，６−ジイソプロピルアニリンを出
発原料とし、それを酸で処理し塩に導いた後に以下の反
応経路に示す方法に従って製造すると、高純度のＮ−
（２，６−ジイソプロピルフェニル）−２−（アルキル
チオ）アセタミドが簡便にかつ高収率に得られることを
見いだし、本発明を完成した。Means for Solving the Problems As a result of intensive investigations aimed at solving the above problems, the present inventors have used industrially inexpensive and large-scale supply of 2,6-diisopropylaniline as a starting material. Is treated with an acid and converted into a salt, and then produced according to the method shown in the following reaction route, a high-purity N-
The present invention has been completed by finding that (2,6-diisopropylphenyl) -2- (alkylthio) acetamide can be easily obtained in high yield.
【０００６】［反応経路］[Reaction path]
【０００７】[0007]
【化２】 [Chemical 2]
【０００８】すなわち本発明は、式That is, the present invention has the formula
【０００９】[0009]
【化１】 [Chemical 1]
【００１０】（式中、Ｒは炭素原子数１〜２０のアルキ
ル基を示す。）で表されるＮ−（２，６−ジイソプロピ
ルフェニル）−２−（アルキルチオ）アセタミドを製造
するに当り、２，６−ジイソプロピルアニリンを酸で処
理して塩とし、再結晶法による精製を行った後に塩基の
存在下に２−クロロアセチルクロリドと反応させてＮ−
（２，６−ジイソプロピルフェニル）−２−クロロアセ
タミドとし、これを塩基の存在下あるいは非存在下にチ
オ酢酸もしくはその塩と反応することによってＮ−
（２，６−ジイソプロピルフェニル）−２−（アセチル
チオ）アセタミドとし、これをで塩基の存在下に式 Ｒ−Ｘ （式中、Ｒは前記と同意義であり、Ｘはハロゲン原子を
示す。）で示されるアルキルハライドと反応促進剤の存
在下あるいは非存在下に反応することを特徴とするＮ−
（２，６−ジイソプロピルフェニル）−２−（アルキル
チオ）アセタミドの製造方法である。In producing N- (2,6-diisopropylphenyl) -2- (alkylthio) acetamide represented by the formula (wherein R represents an alkyl group having 1 to 20 carbon atoms), 2 , 6-Diisopropylaniline was treated with an acid to give a salt, which was purified by a recrystallization method and then reacted with 2-chloroacetyl chloride in the presence of a base to give N-.
(2,6-diisopropylphenyl) -2-chloroacetamide, which is reacted with thioacetic acid or a salt thereof in the presence or absence of a base to give N-
(2,6-Diisopropylphenyl) -2- (acetylthio) acetamide, which is represented by the formula R—X in the presence of a base (wherein R has the same meaning as described above and X represents a halogen atom). N-, which reacts in the presence or absence of a reaction accelerator with an alkyl halide represented by
This is a method for producing (2,6-diisopropylphenyl) -2- (alkylthio) acetamide.
【００１１】以下本発明について更に詳細に説明する。The present invention will be described in more detail below.
【００１２】本発明の炭素原子数１〜２０のアルキル基
とは、直鎖または分枝鎖状のアルキル基であり、たとえ
ば、メチル基、エチル基、プロピル基、イソプロピル
基、ブチル基、イソブチル基、ｔ−ブチル基、オクチル
基、デシル基、ドデシル基、テトラデシル基、ペンタデ
シル基、エイコサニル基などである。The alkyl group having 1 to 20 carbon atoms in the present invention is a linear or branched alkyl group, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group. , T-butyl group, octyl group, decyl group, dodecyl group, tetradecyl group, pentadecyl group, eicosanyl group and the like.
【００１３】塩基とは、たとえば、炭酸カリウム、炭酸
ナトリウム、水酸化ナトリウム、水酸化カリウム等の無
機塩基、トリエチルアミン、ジイソプロピルエチルアミ
ン、ピリジン等の有機塩基、ナトリウムメトキシド、ナ
トリウムエトキシド、ｔ−ブトキシカリウム等のアルコ
キシドのほか、水素化ナトリウム、水素化カリウム、ナ
トリウムアミド等である。Examples of the base include inorganic bases such as potassium carbonate, sodium carbonate, sodium hydroxide and potassium hydroxide, organic bases such as triethylamine, diisopropylethylamine and pyridine, sodium methoxide, sodium ethoxide and potassium t-butoxide. In addition to alkoxides such as sodium hydride, sodium hydride, potassium hydride, sodium amide and the like.
【００１４】酸とは、たとえば、塩酸、硫酸、硝酸、臭
化水素酸、ヨウ化水素酸等の鉱酸類である。The acid is, for example, a mineral acid such as hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid or hydroiodic acid.
【００１５】本発明における反応は、有機溶媒、水中ま
たは有機溶媒と水の混合物中で行わる。有機溶媒とは、
酢酸等の有機酸類、メタノール、エタノール、２−プロ
パノール、ｔ−ブチルアルコール等のアルコール類、ジ
オキサン、テトラヒドロフラン等のエーテル類、Ｎ，Ｎ
−ジメチルホルムアミド、ジメチルスルホキシド、塩化
メチレン、クロロホルム、アセトン、トルエン等であ
る。The reaction in the present invention is carried out in an organic solvent, water or a mixture of an organic solvent and water. What is an organic solvent?
Organic acids such as acetic acid, alcohols such as methanol, ethanol, 2-propanol and t-butyl alcohol, ethers such as dioxane and tetrahydrofuran, N, N
-Dimethylformamide, dimethylsulfoxide, methylene chloride, chloroform, acetone, toluene and the like.
【００１６】チオ酢酸の塩とは、たとえば、チオ酢酸カ
リウム、チオ酢酸ナトリウム等のアルカリ金属塩等であ
る。The thioacetic acid salt is, for example, an alkali metal salt such as potassium thioacetate or sodium thioacetate.
【００１７】本発明における反応促進剤とは、たとえ
ば、ヨウ化カリウムあるいはトリブチルベンジルアンモ
ニウムハライド等の相間移動触媒などである。The reaction accelerator in the present invention is, for example, a phase transfer catalyst such as potassium iodide or tributylbenzylammonium halide.
【００１８】[0018]
【発明の効果】本発明により、工業的に安価で大量に供
給されている２，６−ジイソプロピルアニリンを出発原
料として用いた場合でも、酸で処理し塩に導いた後、再
結晶することにより、多種の異性体を除去することがで
き、ＡＣＡＴ阻害剤として有用な高純度のＮ−（２，６
−ジイソプロピルフェニル）−２−（アルキルチオ）ア
セタミド化合物を安価で大量に簡便かつ高収率に製造す
ることが可能になり、工業的な供給が可能となった。INDUSTRIAL APPLICABILITY According to the present invention, even when 2,6-diisopropylaniline, which is industrially inexpensive and supplied in large quantities, is used as a starting material, it is treated with an acid to lead to a salt and then recrystallized. , High-purity N- (2,6) which can remove various isomers and is useful as an ACAT inhibitor.
It has become possible to inexpensively produce a large amount of a -diisopropylphenyl) -2- (alkylthio) acetamide compound in a simple manner and in a high yield, and industrially supply it.
【００１９】[0019]
【実施例】以下に実施例を挙げて本発明をさらに具体的
に説明する。EXAMPLES The present invention will be described in more detail with reference to the following examples.
【００２０】実施例１ （１）２，６−ジイソプロピルアニリン（４．０ｋｇ）
と２−プロパノール（２０Ｌ）の混合物に９５％硫酸
（１ｋｇ）を滴下した。反応混合物を６３℃に加温して
均一な溶液とした後撹拌下徐々に冷却後析出した結晶を
濾取した。結晶を２Ｌの２−プロパノールで洗浄した後
２０Ｌの２−プロパノールに再度加温溶解して均一な溶
液とした後撹拌下徐々に冷却後析出した結晶を濾取、乾
燥して２，６−ジイソプロピルアニリン・１／２硫酸塩
３．１ｋｇ（収率６１％）を得た。このものの純度を高
速液体クロマトグラフィーで測定したところ９９．５％
であった。（融点１７３〜１７４．５℃） （２）２，６−ジイソプロピルアニリン・１／２硫酸塩
（３．１ｋｇ）のトルエン（１５Ｌ）懸濁液に水酸化ナ
トリウム水溶液（９５％水酸化ナトリウム１．７３３ｋ
ｇ、水４．８Ｌ）を加えた後クロロアセチルクロリド
（１．３７Ｌ）を４０℃以下で約９０分かけて滴下した
後室温で１時間撹拌した。反応混合物に塩酸水（濃塩酸
０．７Ｌ／水８Ｌ）を加えた後有機溶媒層と水層を分離
した。有機溶媒層を５５〜６０℃の温水で３回洗浄後減
圧下に留去してＮ−（２，６−ジイソプロピルフェニ
ル）−２−クロロアセタミドの粗生成物を得た。Example 1 (1) 2,6-Diisopropylaniline (4.0 kg)
95% sulfuric acid (1 kg) was added dropwise to a mixture of and 2-propanol (20 L). The reaction mixture was heated to 63 ° C. to form a uniform solution, which was gradually cooled with stirring and the precipitated crystals were collected by filtration. The crystals were washed with 2 L of 2-propanol, and then dissolved in 20 L of 2-propanol with heating again to form a uniform solution, which was gradually cooled with stirring and the precipitated crystals were collected by filtration and dried to give 2,6-diisopropyl. 3.1 kg (yield 61%) of aniline 1/2 sulfate was obtained. The purity of this product was measured by high performance liquid chromatography to be 99.5%.
Met. (Melting point 173 to 174.5 ° C) (2) A suspension of 2,6-diisopropylaniline 1/2 sulfate (3.1 kg) in toluene (15 L) was added to an aqueous sodium hydroxide solution (95% sodium hydroxide 1. 733k
g, 4.8 L of water), chloroacetyl chloride (1.37 L) was added dropwise at 40 ° C. or lower over about 90 minutes, and the mixture was stirred at room temperature for 1 hour. Hydrochloric acid (concentrated hydrochloric acid 0.7 L / 8 water 8 L) was added to the reaction mixture, and then the organic solvent layer and the aqueous layer were separated. The organic solvent layer was washed with warm water at 55 to 60 ° C. three times and then distilled under reduced pressure to obtain a crude product of N- (2,6-diisopropylphenyl) -2-chloroacetamide.
【００２１】（３）上記で得たＮ−（２，６−ジイソプ
ロピルフェニル）−２−クロロアセタミドをＮ，Ｎ−ジ
メチルホルムアミド（１０Ｌ）に溶解し、これにチオ酢
酸カリウム（１．７７ｋｇ）を加えた（反応混合物の温
度は室温から約４５℃に上昇した）後１時間撹拌した。
反応混合物に水（１０Ｌ）を加え、析出した結晶を濾
取、乾燥してＮ−（２，６−ジイソプロピルフェニル）
−２−（アセチルチオ）アセタミド３．９６ｋｇを得
た。（収率９８％） （４）Ｎ−（２，６−ジイソプロピルフェニル）−２−
（アセチルチオ）アセタミド（３．９６ｋｇ）の２−プ
ロパノール（１８Ｌ）懸濁液に水酸化ナトリウム水溶液
（９５％水酸化ナトリウム１．４３７ｋｇ／水４Ｌ）を
加え室温で２０分間撹拌して均一な溶液を得た。反応液
に１−ブロモテトラデカン（３．７４ｋｇ）を加え１時
間加熱還流した後反応混合物中に含まれる２−プロパノ
ールを減圧留去した。残渣にｎ−ヘプタン（１８Ｌ）を
加え、約６０℃の温水（５Ｌ）で３回洗浄後撹拌下放冷
して析出した結晶を濾取した。この結晶と、濾液を濃縮
（約７Ｌ）後撹拌下放冷、濾取して得た結晶を合わせて
２−プロパノール（１７Ｌ）に加熱溶解した。この溶液
に撹拌下水（３Ｌ）を加え、撹拌下に放冷して析出した
結晶を濾取してＮ−（２，６−ジイソプロピルフェニ
ル）−２−テトラデシルチオアセタミド５．０１ｋｇを
得た。この結晶を再度２−プロパノール（２０Ｌ）に加
熱溶解した溶液に水（５Ｌ）を加え撹拌下放冷して析出
した結晶を濾取、乾燥してＮ−（２，６−ジイソプロピ
ルフェニル）−２−テトラデシルチオアセタミド４．５
７ｋｇ（収率７５．８％）を得た。(3) The N- (2,6-diisopropylphenyl) -2-chloroacetamide obtained above was dissolved in N, N-dimethylformamide (10 L), and potassium thioacetate (1.77 kg) was added thereto. (The temperature of the reaction mixture rose from room temperature to about 45 ° C.) and then stirred for 1 hour.
Water (10 L) was added to the reaction mixture, and the precipitated crystals were collected by filtration, dried and N- (2,6-diisopropylphenyl).
2- (Acetylthio) acetamide (3.96 kg) was obtained. (Yield 98%) (4) N- (2,6-diisopropylphenyl) -2-
An aqueous solution of sodium hydroxide (95% sodium hydroxide 1.437 kg / 4 L of water) was added to a 2-propanol (18 L) suspension of (acetylthio) acetamide (3.96 kg), and the mixture was stirred at room temperature for 20 minutes to form a uniform solution. Obtained. 1-Bromotetradecane (3.74 kg) was added to the reaction solution, the mixture was heated under reflux for 1 hour, and then 2-propanol contained in the reaction mixture was distilled off under reduced pressure. N-Heptane (18 L) was added to the residue, washed three times with warm water (5 L) at about 60 ° C., and allowed to cool with stirring, and the precipitated crystals were collected by filtration. The crystals and the filtrate were concentrated (about 7 L), allowed to cool with stirring, and collected by filtration. The crystals were combined and dissolved in 2-propanol (17 L) with heating. Water (3 L) was added to this solution with stirring, the mixture was allowed to cool with stirring, and the precipitated crystals were collected by filtration to obtain 5.01 kg of N- (2,6-diisopropylphenyl) -2-tetradecylthioacetamide. It was This crystal was again dissolved in 2-propanol (20 L) by heating, and water (5 L) was added to the solution. Tetradecyl thioacetamide 4.5
7 kg (yield 75.8%) was obtained.
───────────────────────────────────────────────────── フロントページの続き (72)発明者 野口 寿也 東京都豊島区高田３丁目24番１号 大正製 薬株式会社内 (72)発明者 五井 正美 東京都豊島区高田３丁目24番１号 大正製 薬株式会社内 (72)発明者 畑山 勝男 東京都豊島区高田３丁目24番１号 大正製 薬株式会社内 ─────────────────────────────────────────────────── ─── Continuation of front page (72) Inventor Toshiya Noguchi 3-24-1 Takada, Toshima-ku, Tokyo Within Taisho Pharmaceutical Co., Ltd. (72) Masami Goi 3-24-1 Takada, Toshima-ku, Tokyo In Taisho Pharmaceutical Co., Ltd. (72) Inventor Katsuo Hatayama 3-24-1 Takada, Toshima-ku, Tokyo Inside Taisho Pharmaceutical Co., Ltd.
Claims (1)
す。）で表されるＮ−（２，６−ジイソプロピルフェニ
ル）−２−（アルキルチオ）アセタミドを製造するに当
り、２，６−ジイソプロピルアニリンを酸で処理して塩
とし、再結晶法による精製を行った後に塩基の存在下に
２−クロロアセチルクロリドと反応させてＮ−（２，６
−ジイソプロピルフェニル）−２−クロロアセタミドと
し、これを塩基の存在下あるいは非存在下にチオ酢酸も
しくはその塩と反応することによってＮ−（２，６−ジ
イソプロピルフェニル）−２−（アセチルチオ）アセタ
ミドとし、これを塩基の存在下に式 Ｒ−Ｘ （式中、Ｒは前記と同意義であり、Ｘはハロゲン原子を
示す。）で示されるアルキルハライドと反応促進剤の存
在下あるいは非存在下に反応することを特徴とするＮ−
（２，６−ジイソプロピルフェニル）−２−（アルキル
チオ）アセタミドの製造方法。1. The formula: (In the formula, R represents an alkyl group having 1 to 20 carbon atoms.) In producing N- (2,6-diisopropylphenyl) -2- (alkylthio) acetamide, 2,6- Diisopropylaniline is treated with an acid to form a salt, purified by a recrystallization method, and then reacted with 2-chloroacetyl chloride in the presence of a base to give N- (2,6
-Diisopropylphenyl) -2-chloroacetamide, which is reacted with thioacetic acid or a salt thereof in the presence or absence of a base to give N- (2,6-diisopropylphenyl) -2- (acetylthio) acetamide, This is reacted with an alkyl halide represented by the formula R-X (wherein R has the same meaning as described above and X represents a halogen atom) in the presence of a base in the presence or absence of a reaction accelerator. N- characterized by
A method for producing (2,6-diisopropylphenyl) -2- (alkylthio) acetamide.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP10883194A JP3538889B2 (en) | 1994-05-24 | 1994-05-24 | Method for producing alkylthioacetamide |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP10883194A JP3538889B2 (en) | 1994-05-24 | 1994-05-24 | Method for producing alkylthioacetamide |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH07316129A true JPH07316129A (en) | 1995-12-05 |
| JP3538889B2 JP3538889B2 (en) | 2004-06-14 |
Family
ID=14494662
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP10883194A Expired - Fee Related JP3538889B2 (en) | 1994-05-24 | 1994-05-24 | Method for producing alkylthioacetamide |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP3538889B2 (en) |
-
1994
- 1994-05-24 JP JP10883194A patent/JP3538889B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| JP3538889B2 (en) | 2004-06-14 |
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