JPS6312465B2 - - Google Patents
Info
- Publication number
- JPS6312465B2 JPS6312465B2 JP12366881A JP12366881A JPS6312465B2 JP S6312465 B2 JPS6312465 B2 JP S6312465B2 JP 12366881 A JP12366881 A JP 12366881A JP 12366881 A JP12366881 A JP 12366881A JP S6312465 B2 JPS6312465 B2 JP S6312465B2
- Authority
- JP
- Japan
- Prior art keywords
- reaction
- hydrochloride
- water
- chlorinated
- hydrogen chloride
- 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.)
- Expired
Links
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 41
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 24
- -1 alkylamine hydrochloride Chemical class 0.000 claims description 21
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 17
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 17
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 238000006243 chemical reaction Methods 0.000 description 30
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- 238000000034 method Methods 0.000 description 12
- 239000002994 raw material Substances 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- 150000003973 alkyl amines Chemical class 0.000 description 8
- 125000004432 carbon atom Chemical group C* 0.000 description 8
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 8
- 239000000047 product Substances 0.000 description 7
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 6
- 239000007789 gas Substances 0.000 description 6
- 239000008096 xylene Substances 0.000 description 6
- IHPRVZKJZGXTBQ-UHFFFAOYSA-N 3-chloropropan-1-amine;hydron;chloride Chemical compound Cl.NCCCCl IHPRVZKJZGXTBQ-UHFFFAOYSA-N 0.000 description 5
- 125000000217 alkyl group Chemical group 0.000 description 5
- 125000003277 amino group Chemical group 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 150000003840 hydrochlorides Chemical class 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- YMDNODNLFSHHCV-UHFFFAOYSA-N 2-chloro-n,n-diethylethanamine Chemical compound CCN(CC)CCCl YMDNODNLFSHHCV-UHFFFAOYSA-N 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 4
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 150000001414 amino alcohols Chemical class 0.000 description 3
- 150000001805 chlorine compounds Chemical class 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- TVZRAEYQIKYCPH-UHFFFAOYSA-N 3-(trimethylsilyl)propane-1-sulfonic acid Chemical compound C[Si](C)(C)CCCS(O)(=O)=O TVZRAEYQIKYCPH-UHFFFAOYSA-N 0.000 description 2
- BZFKSWOGZQMOMO-UHFFFAOYSA-N 3-chloropropan-1-amine Chemical compound NCCCCl BZFKSWOGZQMOMO-UHFFFAOYSA-N 0.000 description 2
- VIVLBCLZNBHPGE-UHFFFAOYSA-N 3-methoxy-n,n-dimethylpropan-1-amine Chemical compound COCCCN(C)C VIVLBCLZNBHPGE-UHFFFAOYSA-N 0.000 description 2
- FAXDZWQIWUSWJH-UHFFFAOYSA-N 3-methoxypropan-1-amine Chemical compound COCCCN FAXDZWQIWUSWJH-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical group [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
- WUGQZFFCHPXWKQ-UHFFFAOYSA-N Propanolamine Chemical compound NCCCO WUGQZFFCHPXWKQ-UHFFFAOYSA-N 0.000 description 2
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 2
- 125000002947 alkylene group Chemical group 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 238000010533 azeotropic distillation Methods 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 229910052698 phosphorus Inorganic materials 0.000 description 2
- 239000011574 phosphorus Chemical group 0.000 description 2
- 230000007017 scission Effects 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- KACSTQZHMHDNKL-UHFFFAOYSA-N 1-chloro-n,n-diethylpropan-2-amine Chemical compound CCN(CC)C(C)CCl KACSTQZHMHDNKL-UHFFFAOYSA-N 0.000 description 1
- ONRREFWJTRBDRA-UHFFFAOYSA-N 2-chloroethanamine;hydron;chloride Chemical compound [Cl-].[NH3+]CCCl ONRREFWJTRBDRA-UHFFFAOYSA-N 0.000 description 1
- BFSVOASYOCHEOV-UHFFFAOYSA-N 2-diethylaminoethanol Chemical compound CCN(CC)CCO BFSVOASYOCHEOV-UHFFFAOYSA-N 0.000 description 1
- PMUNIMVZCACZBB-UHFFFAOYSA-N 2-hydroxyethylazanium;chloride Chemical compound Cl.NCCO PMUNIMVZCACZBB-UHFFFAOYSA-N 0.000 description 1
- ASUDFOJKTJLAIK-UHFFFAOYSA-N 2-methoxyethanamine Chemical compound COCCN ASUDFOJKTJLAIK-UHFFFAOYSA-N 0.000 description 1
- AUTGLOVESHJPKT-UHFFFAOYSA-N 3-chloro-2h-pyran-2-amine;hydrochloride Chemical compound Cl.NC1OC=CC=C1Cl AUTGLOVESHJPKT-UHFFFAOYSA-N 0.000 description 1
- UGXACBBAXFABGT-UHFFFAOYSA-N 3-chloro-n,n,2-trimethylpropan-1-amine Chemical compound ClCC(C)CN(C)C UGXACBBAXFABGT-UHFFFAOYSA-N 0.000 description 1
- WVUULNDRFBHTFG-UHFFFAOYSA-N 3-chloro-n,n-diethylpropan-1-amine Chemical compound CCN(CC)CCCCl WVUULNDRFBHTFG-UHFFFAOYSA-N 0.000 description 1
- NYYRRBOMNHUCLB-UHFFFAOYSA-N 3-chloro-n,n-dimethylpropan-1-amine Chemical compound CN(C)CCCCl NYYRRBOMNHUCLB-UHFFFAOYSA-N 0.000 description 1
- GXNIROADVJTKCR-UHFFFAOYSA-N 3-methoxypropan-1-amine;hydrochloride Chemical compound Cl.COCCCN GXNIROADVJTKCR-UHFFFAOYSA-N 0.000 description 1
- OOWFYDWAMOKVSF-UHFFFAOYSA-N 3-methoxypropanenitrile Chemical compound COCCC#N OOWFYDWAMOKVSF-UHFFFAOYSA-N 0.000 description 1
- VHYUNSUGCNKWSO-UHFFFAOYSA-N 3-propan-2-yloxypropan-1-amine Chemical compound CC(C)OCCCN VHYUNSUGCNKWSO-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- NLHHRLWOUZZQLW-UHFFFAOYSA-N Acrylonitrile Chemical compound C=CC#N NLHHRLWOUZZQLW-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000005262 alkoxyamine group Chemical group 0.000 description 1
- 150000001348 alkyl chlorides Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 239000012320 chlorinating reagent Substances 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 150000004292 cyclic ethers Chemical class 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 238000006266 etherification reaction Methods 0.000 description 1
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229910000043 hydrogen iodide Inorganic materials 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 125000001484 phenothiazinyl group Chemical class C1(=CC=CC=2SC3=CC=CC=C3NC12)* 0.000 description 1
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 125000002112 pyrrolidino group Chemical group [*]N1C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229940066768 systemic antihistamines aminoalkyl ethers Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
この発明は医薬,農薬の原料など合成中間体と
して有用な塩素化されたアルキルアミンを塩酸塩
の形で製造する方法に関する。
塩素化されたアルキルアミンを得る方法として
は、対応するアミノアルコールを塩素化する方法
が一般的に知られている。例えば3―アミノプロ
パノールを塩化チオニルで塩素化すると3―クロ
ロプロピルアミンが塩酸塩として得られる(ケミ
カルアブストラクツ77巻52331t参照)。しかしな
がら、上記方法は原料が高価であり、かつ工程も
複雑なため効率的な合成法とは言えない。特に塩
化チオニルは取り扱いが困難であり、反応の際は
有毒な亜硫酸ガスが発生する欠点がある。
上記の例はNに置換基のない塩素化されたアル
キルアミン、即ち一般式
The present invention relates to a method for producing a chlorinated alkylamine, which is useful as a synthetic intermediate such as a raw material for medicines and agricultural chemicals, in the form of a hydrochloride. As a method for obtaining a chlorinated alkylamine, a method of chlorinating a corresponding amino alcohol is generally known. For example, when 3-aminopropanol is chlorinated with thionyl chloride, 3-chloropropylamine is obtained as a hydrochloride (see Chemical Abstracts Vol. 77, 52331t). However, the above method cannot be said to be an efficient synthesis method because the raw materials are expensive and the steps are complicated. In particular, thionyl chloride is difficult to handle and has the drawback of generating toxic sulfur dioxide gas during the reaction. The above example is a chlorinated alkylamine with no substituents on N, i.e. the general formula
【式】におい
てR1=R2=Hの場合であつたが、R1,R2として
アルキル基などをもつN―置換アミノアルキルク
ロライドも有用なことで知られている。例えば特
公昭29―2434,同36―21342などには医薬として
用いられるフエノチアジン化合物を合成するため
に第3級アミノアルキルハライドが用いられるこ
とが記されている。ここで用いられている化合物
は上記一般式においてAが炭素数2〜6、なるべ
くは3〜4の2価の低級アルキレン基であり、
R1とR2とは低級アルキル基、なるべくはメチル
基、エチル基またはイソプロピル基で、R1とR2
が窒素原子と結合して複素環、なるべくはピロリ
ジノ基またはピペリジノ基を形成することもある
ようなものである(特公昭36―21342)。
またジエチルアミノエチルクロライド(A=エ
チレン基、R1=R2=エチル基)は、医薬原料の
他に澱粉変性剤としても有用である。
ジエチルアミノエチルクロライドの如き置換ア
ミノ基をもつクロライドの合成法についても一般
的なアミノアルコールの塩素化法が適用でき、ジ
エチルアミノエタノールの塩素化剤としては塩化
チオニル,含リン塩化物,塩酸などが用いられる
が、塩化チオニルは前記のような欠点の他に製品
に着色を起す点で問題があり、含リン塩化物はリ
ン酸との分離や蒸溜時の重合ロスに、塩酸はエー
テル化などの副反応により不純物が生じ品質が悪
い点に問題がある。
本発明は上に示したようなNに置換基のあるも
のとないものとを含めて、塩素化されたアルキル
アミンを有利に得る方法を提供するものである。
即ち本発明者はこれらの先行技術をふまえて
種々検討した結果、出発物としてアミノアルキル
エーテルを選び、これを塩酸塩の形で用い、溶融
状態のアミノアルキルエーテル塩酸塩()と塩
化水素とを水を除きつつ反応させ、エーテル結合
を塩化水素で開裂させることにより塩素化された
アルキルアミン塩酸塩()が得られることを見
出し本発明を完成した。
本発明の方法を反応式で示せば次の通りであ
る。
ここでR1,R2は先に説明したように水素又は
低級アルキル基(炭素数1〜5、環形成の場合を
含む)であり、AはN原子とCl原子の間を2〜6
個の炭素原子鎖で結ぶ低級アルキレン基(直鎖又
は側鎖)であるものに適用できる。Rは
In the formula, R 1 =R 2 =H, but N-substituted aminoalkyl chlorides having alkyl groups as R 1 and R 2 are also known to be useful. For example, Japanese Patent Publications No. 29-2434 and No. 36-21342 describe the use of tertiary aminoalkyl halides to synthesize phenothiazine compounds used as medicines. The compound used here is a divalent lower alkylene group having 2 to 6 carbon atoms, preferably 3 to 4 carbon atoms in the above general formula,
R 1 and R 2 are lower alkyl groups, preferably methyl , ethyl or isopropyl;
may be combined with a nitrogen atom to form a heterocycle, preferably a pyrrolidino group or a piperidino group (Japanese Patent Publication No. 36-21342). Furthermore, diethylaminoethyl chloride (A=ethylene group, R 1 =R 2 =ethyl group) is useful as a starch modifier as well as a pharmaceutical raw material. General amino alcohol chlorination methods can be applied to the synthesis of chlorides with substituted amino groups such as diethylaminoethyl chloride, and thionyl chloride, phosphorus-containing chlorides, hydrochloric acid, etc. are used as chlorinating agents for diethylaminoethanol. However, in addition to the above-mentioned drawbacks, thionyl chloride has the problem of coloring the product; phosphorus-containing chloride may cause separation from phosphoric acid and polymerization loss during distillation, and hydrochloric acid may cause side reactions such as etherification. The problem is that the quality is poor due to impurities. The present invention provides a method for advantageously obtaining chlorinated alkyl amines with and without substituents on N as shown above. That is, as a result of various studies based on these prior art, the present inventor selected an aminoalkyl ether as a starting material, used it in the form of a hydrochloride, and combined the molten aminoalkyl ether hydrochloride () with hydrogen chloride. The present invention was completed by discovering that chlorinated alkylamine hydrochloride (2) can be obtained by reacting while removing water and cleaving the ether bond with hydrogen chloride. The reaction formula of the method of the present invention is as follows. Here, R 1 and R 2 are hydrogen or a lower alkyl group (1 to 5 carbon atoms, including the case of ring formation) as explained above, and A is 2 to 6 carbon atoms between the N atom and the Cl atom.
It can be applied to lower alkylene groups (straight chain or side chain) connected by a chain of carbon atoms. R is
【式】又はアルキル基であり、ア
ルキル基の炭素数に特に制限はないが、炭素数の
少ない方がアミン塩を目的物とする場合は経済的
に有利であり、通常C1〜C4のアルキルが用いら
れる。またアミノ基など塩化水素に対し安定な置
換基で置換されていても良い。
本発明を用いて有利に製造できる化合物として
は、例えば次に示す化合物の塩酸塩が挙げられ
る。3―クロロプロピルアミン、N,N―ジメチ
ル―3―クロロプロピルアミン、N,N―ジエチ
ル―3―クロロプロピルアミン、N,N―ジエチ
ル―2―クロロエチルアミン(ジエチルアミノエ
チルクロライド)、N,N―ジエチル―2―クロ
ロ―1―メチルエチルアミン、N,N―ジメチル
―3―クロロ―2―メチルプロピルアミン。
本発明の出発物として用いられるアミノアルキ
ルエーテルは、例えば次のような公知方法(特公
昭52―29290など)を用いて容易に合成できる。
即ち塩基触媒の存在下メタノールをアクリロニト
リルに付加すると3―メトキシプロピオニトリル
が95%以上の収率で得られ、これを接触水素化す
ると3―メトキシプロピルアミンとなる。またこ
の化合物をホルムアルデヒド・ギ酸でN―メチル
化すればN,N―ジメチル―3―メトキシプロピ
ルアミンが得られる。
また前記一般式において[Formula] or an alkyl group, and there is no particular restriction on the number of carbon atoms in the alkyl group, but a smaller number of carbon atoms is economically advantageous when the target product is an amine salt, and usually C 1 to C 4 Alkyl is used. Further, it may be substituted with a substituent that is stable against hydrogen chloride, such as an amino group. Compounds that can be advantageously produced using the present invention include, for example, the hydrochloride salts of the following compounds. 3-chloropropylamine, N,N-dimethyl-3-chloropropylamine, N,N-diethyl-3-chloropropylamine, N,N-diethyl-2-chloroethylamine (diethylaminoethyl chloride), N,N- Diethyl-2-chloro-1-methylethylamine, N,N-dimethyl-3-chloro-2-methylpropylamine. The aminoalkyl ether used as a starting material in the present invention can be easily synthesized using, for example, the following known method (Japanese Patent Publication No. 52-29290, etc.).
That is, when methanol is added to acrylonitrile in the presence of a base catalyst, 3-methoxypropionitrile is obtained in a yield of 95% or more, and catalytic hydrogenation of this yields 3-methoxypropylamine. If this compound is N-methylated with formaldehyde/formic acid, N,N-dimethyl-3-methoxypropylamine can be obtained. Also, in the general formula
【式】であ
る場合は例えば次の反応で得られる。
このような対称形のアミノアルキルエーテルの
塩酸塩を原料として用いると、塩化水素との反応
によつて生ずる2つの塩化物(RClと
[Formula] can be obtained, for example, by the following reaction. When the hydrochloride of such a symmetrical aminoalkyl ether is used as a raw material, two chlorides (RC1 and RCl) are produced by the reaction with hydrogen chloride.
【式】)共に目的物であるという利
点がある。
その他アミノアルキルエーテルは任意の方法で
合成できまた市販品もある。
従来行なわれていたアミノアルコールの塩素化
方法に対し、本発明ではアミノアルキルエーテル
のエーテル結合を塩化水素で開裂させる。一般に
ハロゲン化水素によるエーテル結合の開裂につ
き、ヨウ化水素,臭化水素では比較的容易である
が、塩化水素はそれに比べて反応し難いことが知
られており(例えばJ.March,Ad―vanced
organic Chemistry P.344参照)、アミノ基をも
たない環状エーテルにHClガスを還流温度で反応
させ塩素化されたアルコールを得ている例はある
が収率は60%前後である(例えばOrg.Synth.
571)。
本発明は出発物のアミノアルキルエーテルをそ
のままの形でなく塩酸塩の形で用い、これを溶融
状態において塩化水素と脱水的に反応させること
に特色があり、このような従来行なわれていなか
つた反応方法をとることにより、塩化水素による
エーテル結合の開裂は困難であるという従来の常
識に反して、きわめて容易にほぼ定量的に塩素化
されたアルキルアミンを塩酸塩で得ることができ
る。
本発明においては、次式で表わされる式につい
てほぼ理論量の水が生成することが認められ、塩
素化されたアルキルアミン塩酸塩を得ると共に、
原料の選択により所望の塩化アルキルRClを併産
することができる。
この反応を定量的に進行させるためには、反応
系から水を速やかに除去することが望ましい。そ
のためには塩化水素の吹き込み速度を早めたり、
高温を確保すれば良い。しかしながら、あまり高
い温度にすると一部分解し、着色や、不純物を生
じる。反応温度は原料アルコキシアミン塩酸塩に
よつて異なるが、一般に140〜250℃の範囲が適し
ている。反応系からの水の除去は他に、キシレン
のような、水と共沸する物質を反応途中数回に分
けて加え、共沸蒸溜させることによつても可能で
ある。反応の終点は、生ずる水の量、あるいは遊
離アミンが安定なものは、一部をアルカリ処理
し、ガスクロ分析を行なうことなどによつて知る
ことができる。
本発明で得られる塩素化されたアルキルアミン
塩の純度は極めて高く、末処理の反応生成物は、
目的物に相当する純粋なNMRスペクトルを与え
た。反応生成物は、そのままフレーカーを用いた
り、不溶性溶媒中で懸濁後、分離乾燥するなど
し、固体として、又水,アルコール等に溶かし、
溶液として製品化することが可能である。
なおアミノ基を持つエーテルの塩酸塩から塩素
化されたアルキルアミンを得る反応については、
次に示す様な特殊な例が知られている。即ち、α
―ジアルキルアミノエーテルの塩酸塩を減圧で加
熱することにより、脱アルコールが起こりα―ハ
ロゲン化されたアミン(塩酸塩ではない)が得ら
れる〔Chem.Ber.,92,2976(1959)〕。
しかしながら上記反応はこの文献に記載されて
いる反応機構からも明らかなように、アルコキシ
基とアミノ基が1個の炭素を隔てて結合している
特別の場合だけについて成り立つもので、3―ク
ロロプロピルアミンの如き、有用な塩素化された
アルキルアミンの合成法として一般的に適用でき
るものではなかつた。
本発明者らが開発した方法は、上記反応と反応
機構が異なり、水の生成を伴なつて進行する反応
であり、窒素原子とアルコキシ酸素との間の炭素
数が2個以上でも適用でき、より一般的な塩素化
されたアルキルアミンの合成法と言える。
以下実施例により本発明を更に詳細に説明する
が、本発明はこれらの実施例により限定されるも
のではない。
実施例 1
3―メトキシプロピルアミン15.84g(0.178モ
ル)を氷浴で冷却した35%塩酸22.27g(0.214モ
ル)中に撹拌しながら滴下した。滴下終了後減圧
加熱して水を留去した。得られた3―メトキシプ
ロピルアミン塩酸塩を180〜190℃に加熱(120℃
付近で溶融)し、マグネチツクスターラーで撹拌
しながら塩化水素ガスを1時間20分通した。途中
でキシレンを数回に分けて加え、生じた水を共沸
蒸留させることにより、反応系から除去して、水
を除去しつつ反応させた。反応終了後、室温まで
冷却することにより吸湿性あるワツクス状の3―
クロロプロピルアミン塩酸塩23.22gを得た。こ
のものはNMRで純粋な3―クロロプロピルアミ
ン塩酸塩のスペクトルを与えた。収率100%。
H1―NMR(60MHz,溶媒D2O,内標DSS)
原料に由来するメトキシのメチル水素のピーク
は完全に消失している。
IR (KBr):2850,1560,1490,1260,1120,
1040,970,770,640cm-1
元素分析:
分析値 C%27.46 H%7.13 N%10.85
C3H9NCl2としての理論値
27.71 6.98 10.77
m.p. 151〜153℃(無補正,IPA再結晶品,文献
値148〜150℃)
実施例 2
N,N―ジメチル―3―メトキシプロピルアミ
ン20.00g(0.171モル)を氷浴で冷却した35%塩
酸22.00g(0.211モル)中に撹拌しながら滴下し
た。滴下終了後、減圧加熱して水を留去した。得
られた塩酸塩を180〜200℃に加熱し、マグネチツ
クスターラーで撹拌しながら、塩化水素ガスを1
時間通した。途中生じた水は実施例1と同様にキ
シレンを用いて除去し、水を除きつつ反応させ
た。反応後、室温まで冷却することにより強い吸
湿性をもつワツクス状のN,N′―ジメチル―3
―クロロプロピルアミン塩酸塩を27.90g得た。
このものはNMRで純粋なN,N′―ジメチル―3
―クロロプロピルアミン塩酸塩のスペクトルを与
えた。収率100%。
H1―NMR(100MHz,溶媒D2O,内標DSS)
IR(KBr):2650,1460,1380,1290,1160,
1005,970,650cm-1
m.p. 144〜146℃(無補正,文献値142〜145℃)
実施例 3
3―イソプロポキシプロピルアミン17.58g
(0.150モル)を氷浴で冷却した35%塩酸18.77g
(0.180モル)中に撹拌しながら滴下した。滴下終
了後、減圧加熱して水を留去した。得られた塩酸
塩を180〜220℃に加熱し、撹拌しながら塩化水素
ガスを1時間通した。生成する水は実施例1と同
様にキシレンを用いて除去し、水を除きつつ反応
させた。反応後、室温まで冷却することにより、
ワツクス状の3―クロロピルアミン塩酸塩18.5g
を得た。(理論量より約1g少いのは主として操
作上のロス)。実施例1で得たものとほぼ同様な
NMRスペクトルを示すが、イソプロピル基をも
つ不純物(原料でもイソプロピルアルコールでも
ない)がわずかに存在し純度約96%である。
実施例 4
35%塩酸25.00g(0.240モル)を冷却、撹拌し
ながらその中に2―メトキシエチルアミン15.00
g(0.200モル)を滴下した。滴下終了後減圧加
熱し、水を留去した。得られた塩酸塩を180〜210
℃に加熱し、撹拌しながら塩化水素を3時間通
し、生成する水は実施例1と同様にキシレンを用
いて除去し、水を除きつつ反応させた。反応後、
室温まで冷却することにより、ワツクス状の結晶
21.7gを得た。NMRスペクトルにより主成分が
目的物の2―クロロエチルアミン塩酸塩であるこ
とを確認したが、2―ヒドロキシエチルアミン塩
酸塩と考えられる不純物が少量存在することが認
められた。後者は2―メトキシアミン塩酸塩から
目的物になる迄の中間生成物と考えられ、塩化水
素の通し方がやや不足のため残存したものと思わ
れる。
実施例 5
3,3′―オキサビスプロピルアミンO
(CH2CH2CH2NH2)210g(純度86.1%)を、氷
浴で冷却した35%塩酸18.94g中を撹拌している
中に滴下した。滴下終了後減圧加熱して水を留去
した。得られた塩酸塩を加熱し、180〜210℃にて
塩化水素ガスを1時間通した。生成する水は実施
例1と同様にキシレンを用いて除去し、水を除き
つつ反応させた。反応後、室温に冷却することに
より3―クロロプロピルアミン塩酸塩の結晶
17.98gを得た(NMRスペクトルは純品と一致)。
原料中に5.9%含まれていた3―アミノプロパノ
ールに相当する1.02gを差し引くと収量は16.96
gで、これは3,3′―オキサビスプロピルアミン
に対して約100%の収率に相当する。[Formula]) Both have the advantage of being objects. Other aminoalkyl ethers can be synthesized by any method, and commercially available products are also available. In contrast to conventional methods for chlorinating amino alcohols, in the present invention the ether bond of the aminoalkyl ether is cleaved with hydrogen chloride. In general, it is known that cleavage of ether bonds by hydrogen halides is relatively easy with hydrogen iodide and hydrogen bromide, but hydrogen chloride is more difficult to react with (for example, J. March, Advanced
organic chemistry (see page 344), there are examples of chlorinated alcohols being obtained by reacting HCl gas at reflux temperature with cyclic ethers that do not have amino groups, but the yield is around 60% (for example, Org. Synth.
571). The present invention is characterized in that the starting aminoalkyl ether is used not as it is but in the form of a hydrochloride, and this is dehydrated and reacted with hydrogen chloride in the molten state, which has not been done in the past. By employing this reaction method, a chlorinated alkylamine can be obtained very easily and almost quantitatively in the form of a hydrochloride, contrary to the conventional wisdom that cleavage of an ether bond by hydrogen chloride is difficult. In the present invention, it is recognized that approximately the theoretical amount of water is generated for the formula represented by the following formula, and chlorinated alkylamine hydrochloride is obtained,
Depending on the selection of raw materials, the desired alkyl chloride RCl can be co-produced. In order for this reaction to proceed quantitatively, it is desirable to quickly remove water from the reaction system. To achieve this, the speed of hydrogen chloride injection must be increased,
Just make sure it's at a high temperature. However, if the temperature is too high, it will partially decompose, producing coloration and impurities. Although the reaction temperature varies depending on the raw material alkoxyamine hydrochloride, a range of 140 to 250°C is generally suitable. Alternatively, water can be removed from the reaction system by adding a substance that is azeotropic with water, such as xylene, in several portions during the reaction and carrying out azeotropic distillation. The end point of the reaction can be determined by the amount of water produced, or if the free amine is stable, by alkali treatment of a portion and gas chromatography analysis. The purity of the chlorinated alkylamine salt obtained in the present invention is extremely high, and the reaction product of the final treatment is
A pure NMR spectrum corresponding to the target product was given. The reaction product can be used as it is in a flaker, or suspended in an insoluble solvent and then separated and dried to form a solid, or dissolved in water, alcohol, etc.
It is possible to commercialize it as a solution. Regarding the reaction to obtain a chlorinated alkylamine from the hydrochloride of an ether having an amino group,
The following special examples are known. That is, α
- By heating the hydrochloride of a dialkylamino ether under reduced pressure, dealcoholization occurs and an α-halogenated amine (not a hydrochloride) is obtained [Chem.Ber., 92 , 2976 (1959)]. However, as is clear from the reaction mechanism described in this document, the above reaction only holds true in the special case where an alkoxy group and an amino group are bonded with one carbon in between, and 3-chloropropyl This method has not been generally applicable as a method for synthesizing useful chlorinated alkyl amines such as amines. The method developed by the present inventors has a different reaction mechanism from the above reaction, and is a reaction that proceeds with the production of water, and can be applied even when the number of carbon atoms between the nitrogen atom and the alkoxy oxygen is 2 or more. This can be said to be a more general method for synthesizing chlorinated alkylamines. EXAMPLES The present invention will be explained in more detail with reference to Examples below, but the present invention is not limited to these Examples. Example 1 15.84 g (0.178 mol) of 3-methoxypropylamine was added dropwise to 22.27 g (0.214 mol) of 35% hydrochloric acid cooled in an ice bath with stirring. After the dropwise addition was completed, water was distilled off by heating under reduced pressure. The obtained 3-methoxypropylamine hydrochloride was heated to 180-190℃ (120℃
Hydrogen chloride gas was passed through it for 1 hour and 20 minutes while stirring with a magnetic stirrer. During the reaction, xylene was added in several portions, and the resulting water was removed from the reaction system by azeotropic distillation, and the reaction was carried out while removing water. After the reaction is complete, a hygroscopic wax-like 3-
23.22 g of chloropropylamine hydrochloride was obtained. This gave the spectrum of pure 3-chloropropylamine hydrochloride in NMR. Yield 100%. H 1 -NMR (60MHz, solvent D 2 O, internal standard DSS) The methoxy methyl hydrogen peak derived from the raw material has completely disappeared. IR (KBr): 2850, 1560, 1490, 1260, 1120,
1040, 970, 770, 640cm -1 Elemental analysis: Analysis value C%27.46 H%7.13 N%10.85 Theoretical value as C 3 H 9 NCl 2 27.71 6.98 10.77 mp 151-153℃ (Uncorrected, IPA recrystallized product, (Literature value 148-150°C) Example 2 20.00 g (0.171 mol) of N,N-dimethyl-3-methoxypropylamine was added dropwise to 22.00 g (0.211 mol) of 35% hydrochloric acid cooled in an ice bath with stirring. After the dropwise addition was completed, water was distilled off by heating under reduced pressure. The obtained hydrochloride was heated to 180-200℃, and while stirring with a magnetic stirrer, hydrogen chloride gas was added to the
I passed the time. Water generated during the reaction was removed using xylene in the same manner as in Example 1, and the reaction was carried out while removing water. After the reaction, by cooling to room temperature, a wax-like N,N'-dimethyl-3 with strong hygroscopic properties is formed.
-27.90g of chloropropylamine hydrochloride was obtained.
This substance was found to be pure N,N'-dimethyl-3 by NMR.
-Gives the spectrum of chloropropylamine hydrochloride. Yield 100%. H 1 -NMR (100MHz, solvent D 2 O, internal standard DSS) IR (KBr): 2650, 1460, 1380, 1290, 1160,
1005, 970, 650cm -1 mp 144-146℃ (Uncorrected, literature value 142-145℃) Example 3 3-isopropoxypropylamine 17.58g
18.77g of 35% hydrochloric acid (0.150mol) cooled in an ice bath
(0.180 mol) was added dropwise while stirring. After the dropwise addition was completed, water was distilled off by heating under reduced pressure. The obtained hydrochloride was heated to 180-220°C and hydrogen chloride gas was passed through it for 1 hour while stirring. The produced water was removed using xylene in the same manner as in Example 1, and the reaction was carried out while removing water. After the reaction, by cooling to room temperature,
Waxy 3-chloropyramine hydrochloride 18.5g
I got it. (The reason why the amount is about 1 g less than the theoretical amount is mainly due to operational loss. Almost similar to that obtained in Example 1
The NMR spectrum shows that there is a small amount of impurity with an isopropyl group (not a raw material or isopropyl alcohol), and the purity is approximately 96%. Example 4 25.00 g (0.240 mol) of 35% hydrochloric acid was cooled and 15.00 g of 2-methoxyethylamine was added thereto while stirring.
g (0.200 mol) was added dropwise. After the dropwise addition was completed, the mixture was heated under reduced pressure to distill off water. The obtained hydrochloride from 180 to 210
The mixture was heated to .degree. C. and hydrogen chloride was passed therein for 3 hours while stirring, and the water produced was removed using xylene in the same manner as in Example 1, and the reaction was carried out while removing the water. After the reaction,
By cooling to room temperature, wax-like crystals are formed.
21.7g was obtained. Although it was confirmed by NMR spectrum that the main component was the target 2-chloroethylamine hydrochloride, a small amount of impurity thought to be 2-hydroxyethylamine hydrochloride was observed to exist. The latter is considered to be an intermediate product from 2-methoxyamine hydrochloride to the target product, and it is thought that it remained because hydrogen chloride did not pass through it slightly. Example 5 3,3′-oxabispropylamine O
10 g (CH 2 CH 2 CH 2 NH 2 ) 2 (purity 86.1%) was added dropwise to 18.94 g of 35% hydrochloric acid cooled in an ice bath while stirring. After the dropwise addition was completed, water was distilled off by heating under reduced pressure. The obtained hydrochloride was heated and hydrogen chloride gas was passed through it at 180-210°C for 1 hour. The produced water was removed using xylene in the same manner as in Example 1, and the reaction was carried out while removing water. After the reaction, crystals of 3-chloropropylamine hydrochloride are formed by cooling to room temperature.
17.98g was obtained (NMR spectrum matched with pure product).
After subtracting 1.02g, which corresponds to 3-aminopropanol, which contained 5.9% in the raw material, the yield was 16.96.
g, which corresponds to a yield of about 100% based on 3,3'-oxabispropylamine.
Claims (1)
塩化水素とを水を除きつつ反応させることを特徴
とする塩素化されたアルキルアミン塩酸塩の製造
法。1. A method for producing a chlorinated alkylamine hydrochloride, which comprises reacting a molten aminoalkyl ether hydrochloride with hydrogen chloride while removing water.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP12366881A JPS5824544A (en) | 1981-08-07 | 1981-08-07 | Preparation of chlorinated alkylamine hydrochloride |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP12366881A JPS5824544A (en) | 1981-08-07 | 1981-08-07 | Preparation of chlorinated alkylamine hydrochloride |
Publications (2)
Publication Number | Publication Date |
---|---|
JPS5824544A JPS5824544A (en) | 1983-02-14 |
JPS6312465B2 true JPS6312465B2 (en) | 1988-03-18 |
Family
ID=14866334
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP12366881A Granted JPS5824544A (en) | 1981-08-07 | 1981-08-07 | Preparation of chlorinated alkylamine hydrochloride |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPS5824544A (en) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS63145886U (en) * | 1987-03-18 | 1988-09-27 | ||
JP2013124236A (en) * | 2011-12-15 | 2013-06-24 | Sumitomo Chemical Co Ltd | Process for producing hydrohalide salt of halogenated alkylamine |
-
1981
- 1981-08-07 JP JP12366881A patent/JPS5824544A/en active Granted
Also Published As
Publication number | Publication date |
---|---|
JPS5824544A (en) | 1983-02-14 |
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