JP4587139B2 - A method for producing an aminoalkoxycarbostyril derivative. - Google Patents
A method for producing an aminoalkoxycarbostyril derivative. Download PDFInfo
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- 238000004519 manufacturing process Methods 0.000 title claims description 11
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 16
- 239000000203 mixture Substances 0.000 claims description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- 239000003960 organic solvent Substances 0.000 claims description 9
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 6
- 238000002425 crystallisation Methods 0.000 claims description 6
- 230000008025 crystallization Effects 0.000 claims description 6
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 5
- 239000011707 mineral Substances 0.000 claims description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 239000007810 chemical reaction solvent Substances 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims 3
- 125000002431 aminoalkoxy group Chemical group 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 description 41
- 239000000243 solution Substances 0.000 description 26
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 16
- 238000004128 high performance liquid chromatography Methods 0.000 description 13
- JJJQHJZIUXHYKA-UHFFFAOYSA-N 2-[3-[(2-oxo-1h-quinolin-6-yl)oxy]propyl]isoindole-1,3-dione Chemical compound O=C1C2=CC=CC=C2C(=O)N1CCCOC1=CC=C(NC(=O)C=C2)C2=C1 JJJQHJZIUXHYKA-UHFFFAOYSA-N 0.000 description 11
- XNGIFLGASWRNHJ-UHFFFAOYSA-N phthalic acid Chemical compound OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 description 10
- 239000000126 substance Substances 0.000 description 10
- 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 9
- -1 amino compound Chemical class 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- PWHFSJTYJIXUOS-UHFFFAOYSA-N 6-(3-aminopropoxy)-1h-quinolin-2-one;hydrochloride Chemical compound Cl.N1C(=O)C=CC2=CC(OCCCN)=CC=C21 PWHFSJTYJIXUOS-UHFFFAOYSA-N 0.000 description 4
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine hydrate Chemical compound O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 230000003301 hydrolyzing effect Effects 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 2
- WIHNZWNZPDCQRG-UHFFFAOYSA-N 2-[4-[(2-oxo-1h-quinolin-6-yl)oxy]butyl]isoindole-1,3-dione Chemical compound O=C1C2=CC=CC=C2C(=O)N1CCCCOC1=CC=C(NC(=O)C=C2)C2=C1 WIHNZWNZPDCQRG-UHFFFAOYSA-N 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000007865 diluting Methods 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 229910017053 inorganic salt Inorganic materials 0.000 description 2
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical class C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- KGLPWQKSKUVKMJ-UHFFFAOYSA-N 2,3-dihydrophthalazine-1,4-dione Chemical compound C1=CC=C2C(=O)NNC(=O)C2=C1 KGLPWQKSKUVKMJ-UHFFFAOYSA-N 0.000 description 1
- LDXJRKWFNNFDSA-UHFFFAOYSA-N 2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-1-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]ethanone Chemical compound C1CN(CC2=NNN=C21)CC(=O)N3CCN(CC3)C4=CN=C(N=C4)NCC5=CC(=CC=C5)OC(F)(F)F LDXJRKWFNNFDSA-UHFFFAOYSA-N 0.000 description 1
- OQMOVLOOIDNTQX-UHFFFAOYSA-N 4-(3-bromopropyl)isoindole-1,3-dione Chemical compound BrCCCC1=CC=CC2=C1C(=O)NC2=O OQMOVLOOIDNTQX-UHFFFAOYSA-N 0.000 description 1
- ZXLYYQUMYFHCLQ-UHFFFAOYSA-N CN(C(c1c2cccc1)=O)C2=O Chemical compound CN(C(c1c2cccc1)=O)C2=O ZXLYYQUMYFHCLQ-UHFFFAOYSA-N 0.000 description 1
- AFCARXCZXQIEQB-UHFFFAOYSA-N N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CCNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 AFCARXCZXQIEQB-UHFFFAOYSA-N 0.000 description 1
- 0 O=C(c(cccc1)c1C1=O)N1NC*Oc(cc1)cc(C=C2)c1NC2=O Chemical compound O=C(c(cccc1)c1C1=O)N1NC*Oc(cc1)cc(C=C2)c1NC2=O 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 150000007514 bases Chemical class 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- AQLYZDRHNHZHIS-UHFFFAOYSA-N quinoline-2,6-diol Chemical compound N1C(=O)C=CC2=CC(O)=CC=C21 AQLYZDRHNHZHIS-UHFFFAOYSA-N 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- Quinoline Compounds (AREA)
Description
本発明は、アミノアルコキシカルボスチリル誘導体を製造する方法に関する。 The present invention relates to a method for producing an aminoalkoxycarbostyril derivative.
アミノ化合物を製造する方法としては、フタルイミド誘導体を酸や塩基性触媒存在下に加水分解させる方法、塩基性触媒存在下に加水分解させてフタルアミド酸にけん化後塩酸で加水分解する方法、あるいはヒドラジンと交換反応させる方法が知られている（例えば、非特許文献１参照。）。 As a method for producing an amino compound, a method in which a phthalimide derivative is hydrolyzed in the presence of an acid or a basic catalyst, a method in which hydrolysis is performed in the presence of a basic catalyst, saponification to phthalamic acid, and hydrolysis with hydrochloric acid, or hydrazine and A method of performing an exchange reaction is known (for example, see Non-Patent Document 1).
しかしながら、アミノアルコキシカルボスチリルの製造方法としては、例えば、６−（３−フタルイミドプロポキシ）カルボスチリルとヒドラジン１水和物をエタノール中で８時間加熱還流させたのち冷却してから析出結晶をろ別する工程、ろ液を水で希釈してから濃塩酸で酸性とし、１時間撹拌後に不溶物を再度ろ別する工程、次いでろ液を濃縮してエタノールを除去後、改めて水で希釈してからｐＨ７に調整して結晶を析出させる工程、析出結晶をエタノール、ジエチルエーテルの順に洗浄する工程からなる製造方法しか知られていない（例えば、特許文献１参照。）。しかしながら、この方法では安全性に問題のあるヒドラジン水和物を使用し、生成したアミノ化合物とフタルヒドラジドを分離するために種々の薬品を使用して繁雑な操作が必用であるなど、工業的に有利な方法とは言い難い。
本発明の目的は、安全性に問題のあるヒドラジン水和物を使用しない、工業的に生産可能な簡便な操作で、フタルイミドアルコキシカルボスチリル誘導体からアミノアルコキシカルボスチリル誘導体を製造する方法を提供することにある。 An object of the present invention is to provide a method for producing an aminoalkoxycarbostyril derivative from a phthalimidoalkoxycarbostyril derivative by a simple industrially producible operation that does not use hydrazine hydrate having a safety problem. It is in.
本発明者らは前記課題を解決する方法について鋭意検討した結果、フタルイミドアルコキシカルボスチリル誘導体をアルカリ金属水酸化物存在下で加熱し、次いで鉱酸を加えて加熱することにより、収率良く目的とするアミノアルコキシカルボスチリル誘導体が生成することを見出した。更に、不溶物を濾過したのちに反応液に有機溶媒を加えて晶析することによって工業的に生産可能な簡便な操作で高純度のアミノアルコキシカルボスチリル誘導体を収率良く製造できることを見出し、本発明に到達した。 As a result of earnestly examining the method for solving the above problems, the present inventors have heated the phthalimidoalkoxycarbostyril derivative in the presence of an alkali metal hydroxide , and then added and heated with a mineral acid. It has been found that an aminoalkoxycarbostyril derivative is produced. Furthermore, it has been found that a high-purity aminoalkoxycarbostyril derivative can be produced in high yield by a simple operation that can be industrially produced by adding an organic solvent to the reaction solution after crystallization after filtering insoluble matter. The invention has been reached.
すなわち、本発明は式（１） That is, the present invention provides the formula (1)
本発明によれば、安全性に問題のあるヒドラジンを使用しないで、フタルイミドアルコキシカルボスチリル誘導体を塩基性化合物存在下で加熱し、次いで酸性化合物を加えて加熱したのち、反応液に有機溶媒を加えて晶析させる工業的に生産可能な簡便な操作で高純度のアミノアルコキシカルボスチリル誘導体を製造することができる。 According to the present invention, a phthalimide alkoxycarbostyril derivative is heated in the presence of a basic compound without using a hydrazine having a safety problem, and then an acidic compound is added and heated, and then an organic solvent is added to the reaction solution. A highly pure aminoalkoxycarbostyril derivative can be produced by a simple operation that can be industrially produced by crystallization.
本発明を具体的に述べる。原料の一般式（１）で表されるフタルイミドアルコキシカルボスチリル誘導体は、例えば６−ヒドロキシカルボスチリルに（３−ブロモプロピル）フタルイミドを反応させることによって製造できる（特開平９−１５７２５８号公報、参考例１）。 The present invention will be specifically described. The phthalimidoalkoxycarbostyril derivative represented by the general formula (1) as a raw material can be produced, for example, by reacting 6-hydroxycarbostyril with (3-bromopropyl) phthalimide (JP-A-9-157258, Reference Example). 1).
フタルイミドアルコキシカルボスチリル誘導体を加水分解してフタルアミド酸誘導体にする際に使用するアルカリ金属水酸化物としては、水酸化ナトリウム、水酸化カリウム、水酸化リチウム等が好適に使用できる。 As an alkali metal hydroxide used when hydrolyzing a phthalimidoalkoxycarbostyril derivative to a phthalamic acid derivative, sodium hydroxide, potassium hydroxide, lithium hydroxide and the like can be suitably used.
アルカリ金属水酸化物の使用量は、原料であるフタルイミドアルコキシカルボスチリル誘導体に対して０．８倍モル以上が好ましく、より好ましくは１．０〜２．０倍モルである。 As for the usage-amount of an alkali metal hydroxide , 0.8 times mole or more is preferable with respect to the phthalimide alkoxy carbostyryl derivative which is a raw material, More preferably, it is 1.0-2.0 times mole.
フタルアミド酸誘導体を加水分解してアミノアルコキシカルボスチリル誘導体にする際に使用する鉱酸としては、塩酸、硫酸、リン酸等が好適に使用できる。 As the mineral acid used when the phthalamic acid derivative is hydrolyzed to an aminoalkoxycarbostyril derivative, hydrochloric acid, sulfuric acid, phosphoric acid and the like can be suitably used.
鉱酸の使用量は、アルカリ金属水酸化物を中和するのに必用な量に加えて更に原料であるフタルイミドアルコキシカルボスチリル誘導体に対して０．８倍当量以上が好ましく、より好ましくは１．０〜２．０倍当量である。 In addition to the amount necessary to neutralize the alkali metal hydroxide , the amount of mineral acid used is preferably 0.8 equivalents or more relative to the phthalimidoalkoxycarbostyryl derivative which is a raw material, more preferably 1. 0 to 2.0 equivalents.
反応溶媒は水が好ましいが、反応を阻害しない有機溶媒が少量混入していても実施できる。使用量に制限は無いが、フタルイミドアルコキシカルボスチリル誘導体に対して２〜１０倍重量が好ましい。使用量が多いと反応終了後の濃縮操作で除去する水の量が多くなるので好ましくない。 The reaction solvent is preferably water, but the reaction can be carried out even if a small amount of an organic solvent that does not inhibit the reaction is mixed. Although there is no restriction | limiting in the usage-amount, 2-10 times weight is preferable with respect to a phthalimide alkoxy carbostyril derivative. If the amount used is large, the amount of water removed by the concentration operation after completion of the reaction increases, which is not preferable.
フタルイミドアルコキシカルボスチリル誘導体を加水分解してフタルアミド酸誘導体にする際の反応温度は３０℃以上であり、好ましくは５０℃〜１００℃である。この範囲であれば副反応もほとんど生起せず、短時間で反応が終結する。 The reaction temperature when hydrolyzing the phthalimidoalkoxycarbostyril derivative to a phthalamic acid derivative is 30 ° C. or higher, preferably 50 ° C. to 100 ° C. Within this range, side reactions hardly occur and the reaction is completed in a short time.
フタルアミド酸誘導体を加水分解してアミノアルコキシカルボスチリル誘導体にする際の反応温度は５０℃以上であり、好ましくは７０℃〜１００℃である。この範囲であれば副反応もほとんど生起せず、短時間で反応が終結する。 The reaction temperature when hydrolyzing the phthalamic acid derivative to an aminoalkoxycarbostyril derivative is 50 ° C. or higher, preferably 70 ° C. to 100 ° C. Within this range, side reactions hardly occur and the reaction is completed in a short time.
反応終了後、反応液を濃縮して溶媒である水の一部を除去したのち、有機溶媒を加えて晶析させることによってアミノアルコキシカルボスチリル誘導体の塩の結晶が取得できる。反応に使用した水の使用量によって濃縮で除去する水の量は異なり、使用量を選択すれば濃縮操作を省略することもできる。また、反応液をろ過して析出したフタル酸等の不溶物を予め取り除いて、高純度のアミノアルコキシカルボスチリル誘導体の塩を収率良く得ることができる。 After completion of the reaction, the reaction solution is concentrated to remove a part of water as a solvent, and then an organic solvent is added for crystallization to obtain a crystal of an aminoalkoxycarbostyril derivative salt. The amount of water removed by concentration differs depending on the amount of water used in the reaction, and the concentration operation can be omitted if the amount used is selected. In addition, an insoluble matter such as phthalic acid deposited by filtering the reaction solution is removed in advance, whereby a high- purity aminoalkoxycarbostyril derivative salt can be obtained in high yield.
晶析に際して加える有機溶媒は、水と任意に混和し、副生するフタル酸を溶解するものであれば良く、好ましくはメタノール、エタノール、ｎ−プロパノール、イソプロパノール、アセトニトリル、テトラヒドロフラン、アセトン、メチルエチルケトン、ジメチルホルムアミド、あるいはこれらの混合物である。 The organic solvent to be added for crystallization is not particularly limited as long as it is arbitrarily mixed with water and dissolves by-produced phthalic acid, and is preferably methanol, ethanol, n-propanol, isopropanol, acetonitrile, tetrahydrofuran, acetone, methyl ethyl ketone, dimethyl. Formamide or a mixture thereof.
有機溶媒の使用量は、反応液に含まれるフタル酸や無機塩の量によって調整する。反応液に含まれるフタル酸や無機塩を充分に溶解せるように調整すれば高純度のアミノアルコキシカルボスチリル誘導体の塩を得ることができる。 The amount of the organic solvent used is adjusted according to the amount of phthalic acid or inorganic salt contained in the reaction solution. If the phthalic acid and inorganic salt contained in the reaction solution are adjusted so as to be sufficiently dissolved, a highly pure aminoalkoxycarbostyril derivative salt can be obtained.
以下、実施例で詳しく説明するが、本発明はこの範囲に限定されるものではない。なお、実施例において、反応液の組成や晶析品の純度はＨＰＬＣで分析した。ＨＰＬＣ分析条件を記載する。
ＨＰＬＣ分析条件
カラム ：Ｍｉｇｈｔｙｓｉｌ ＲＰ−１８ ＧＰ １５０ｍｍ−４．６ｍｍφ （５μｍ）
移動相 ：５ｍｍｏｌ／Ｌ ラウリル硫酸ナトリウム水溶液／アセトニトリル／トリフルオロ酢酸（７００ｍｌ：３００ｍｌ：１ｍｌ）
流量 ：１．０ｍｌ／ｍｉｎ
検出器 ：ＵＶ ２５４ｎｍ
分析時間：３０ｍｉｎ
温度 ：３０℃
Hereinafter, although an Example demonstrates in detail, this invention is not limited to this range. In the examples, the composition of the reaction solution and the purity of the crystallized product were analyzed by HPLC. The HPLC analysis conditions are described.
HPLC analysis conditions Column: Mightysil RP-18 GP 150 mm-4.6 mmφ (5 μm)
Mobile phase: 5 mmol / L sodium lauryl sulfate aqueous solution / acetonitrile / trifluoroacetic acid (700 ml: 300 ml: 1 ml)
Flow rate: 1.0 ml / min
Detector: UV 254nm
Analysis time: 30 min
Temperature: 30 ° C
実施例１
攪拌機、ジムロート、温度計を装着した容量２０００ｍｌの４口フラスコに、６−（３−フタルイミドプロポキシ）カルボスチリル１１０ｇ（化学純度９５％、０．３０モル）、４８％水酸化ナトリウム水溶液３０ｇ（０．３６モル）、水６２０ｇを仕込み、９０〜９５℃で１時間撹拌した。反応液の一部を採取してＨＰＬＣ分析したところ、６−（３−フタルイミドプロポキシ）カルボスチリルの転化率は９９％以上であった。次いで、３５％塩酸７８ｇ（０．７５モル）を加え、９０〜９５℃で３時間撹拌した。反応液の一部を採取してＨＰＬＣ分析したところ、フタルアミド酸の転化率は９９％以上であった。反応液を５５℃に冷却して熱時にろ過した。ろ液を、残液が３９０ｇになるまで、減圧下に濃縮したのち、メタノール２８０ｇを加えて６０〜６５℃で０．５時間撹拌した。２０℃まで冷却してからろ過し、ケークを６０ｇのメタノールを用いて洗浄した。４０〜５０℃で減圧下に乾燥し６−（３−アミノプロポキシ）カルボスチリル塩酸塩６７．８ｇを得た。化学純度９９．７ａｒｅａ％、含量９３．１％、水分６．６％。収率８３％。
Example 1
In a 4-neck flask with a capacity of 2000 ml equipped with a stirrer, a Dimroth, and a thermometer, 110 g of 6- (3-phthalimidopropoxy) carbostyril (chemical purity 95%, 0.30 mol), 30 g of a 48% sodium hydroxide aqueous solution (0. 36 mol) and 620 g of water were charged and stirred at 90 to 95 ° C. for 1 hour. When a part of the reaction solution was collected and analyzed by HPLC, the conversion of 6- (3-phthalimidopropoxy) carbostyril was 99% or more. Next, 78 g (0.75 mol) of 35% hydrochloric acid was added, and the mixture was stirred at 90 to 95 ° C. for 3 hours. When a part of the reaction solution was collected and analyzed by HPLC, the conversion rate of phthalamic acid was 99% or more. The reaction solution was cooled to 55 ° C. and filtered while hot. The filtrate was concentrated under reduced pressure until the residual liquid reached 390 g, 280 g of methanol was added, and the mixture was stirred at 60 to 65 ° C. for 0.5 hour. The solution was cooled to 20 ° C. and filtered, and the cake was washed with 60 g of methanol. It dried under reduced pressure at 40-50 degreeC, and obtained 67.8 g of 6- (3-aminopropoxy) carbostyril hydrochloride. Chemical purity 99.7 area%, content 93.1%, moisture 6.6%. Yield 83%.
参考例１
攪拌機、ジムロート、温度計を装着した容量２００ｍｌの４口フラスコに、６−（３−フタルイミドプロポキシ）カルボスチリル１１．０ｇ（化学純度９５％、０．０３０モル）、４８％水酸化ナトリウム水溶液３．０ｇ（０．０３６モル）、水３０ｇを仕込み、９０〜９５℃で１時間撹拌した。反応液の一部を採取してＨＰＬＣ分析したところ、６−（３−フタルイミドプロポキシ）カルボスチリルの転化率は９９％以上であった。次いで、３５％塩酸７．８ｇ（０．０７５モル）を加え、９０〜９５℃で３時間撹拌した。反応液の一部を採取してＨＰＬＣ分析したところ、フタルアミド酸の転化率は９９％以上であった。反応液にメタノール４０ｇを加えて６０〜６５℃で０．５時間撹拌した。２０℃まで冷却してからろ過し、ケークを６ｇのメタノールを用いて洗浄した。４０〜５０℃で減圧下に乾燥し６−（３−アミノプロポキシ）カルボスチリル塩酸塩６．４ｇを得た。化学純度９９．１ａｒｅａ％、含量９２．５％、水分６．４％。収率７７％。
Reference example 1
2. A 200 ml four-necked flask equipped with a stirrer, a Dimroth, and a thermometer is charged with 11.0 g of 6- (3-phthalimidopropoxy) carbostyril (chemical purity 95%, 0.030 mol), 48% aqueous sodium hydroxide solution. 0 g (0.036 mol) and 30 g of water were charged and stirred at 90 to 95 ° C. for 1 hour. When a part of the reaction solution was collected and analyzed by HPLC, the conversion of 6- (3-phthalimidopropoxy) carbostyril was 99% or more. Next, 7.8 g (0.075 mol) of 35% hydrochloric acid was added, and the mixture was stirred at 90 to 95 ° C. for 3 hours. When a part of the reaction solution was collected and analyzed by HPLC, the conversion rate of phthalamic acid was 99% or more. Methanol 40g was added to the reaction liquid, and it stirred at 60-65 degreeC for 0.5 hour. After cooling to 20 ° C., it was filtered and the cake was washed with 6 g of methanol. It dried under reduced pressure at 40-50 degreeC, and obtained 6.4g of 6- (3-aminopropoxy) carbostyril hydrochloride. Chemical purity 99.1 area%, content 92.5%, moisture 6.4%. Yield 77%.
実施例２
攪拌機、ジムロート、温度計を装着した容量２００ｍｌの４口フラスコに、６−（４−フタルイミドブトキシ）カルボスチリル１１．６ｇ（化学純度９４％、０．０３０モル）、４８％水酸化ナトリウム水溶液３．０ｇ（０．３６モル）、水６２ｇを仕込み、９０〜９５℃で１時間撹拌した。反応液の一部を採取してＨＰＬＣ分析したところ、６−（４−フタルイミドブトキシ）カルボスチリルの転化率は９９％以上であった。次いで、３５％塩酸７．８ｇ（０．０７５モル）を加え、９０〜９５℃で３時間撹拌した。反応液の一部を採取してＨＰＬＣ分析したところ、フタルアミド酸の転化率は９９％以上であった。反応液を６０℃に冷却して熱時にろ過した。ろ液を、残液が４１ｇになるまで、減圧下に濃縮したのち、メタノール２８ｇを加えて６０〜６５℃で０．５時間撹拌した。２０℃まで冷却してからろ過し、ケークを６ｇのメタノールを用いて洗浄した。４０〜５０℃で減圧下に乾燥し６−（４−アミノブトキシ）カルボスチリル塩酸塩７．１ｇを得た。化学純度９９．５ａｒｅａ％、含量９３．２％、水分６．３％。収率８２％。
Example 2
In a 200 ml four-necked flask equipped with a stirrer, a Dimroth, and a thermometer, 11.6 g of 6- ( 4 -phthalimidobutoxy) carbostyril (chemical purity 94%, 0.030 mol), 48% aqueous sodium hydroxide solution 3. 0 g (0.36 mol) and 62 g of water were charged, and the mixture was stirred at 90 to 95 ° C. for 1 hour. When a part of the reaction solution was collected and analyzed by HPLC, the conversion of 6- ( 4 -phthalimidobutoxy) carbostyril was 99% or more. Next, 7.8 g (0.075 mol) of 35% hydrochloric acid was added, and the mixture was stirred at 90 to 95 ° C. for 3 hours. When a part of the reaction solution was collected and analyzed by HPLC, the conversion rate of phthalamic acid was 99% or more. The reaction solution was cooled to 60 ° C. and filtered while hot. The filtrate was concentrated under reduced pressure until the residual liquid reached 41 g, 28 g of methanol was added, and the mixture was stirred at 60 to 65 ° C. for 0.5 hour. After cooling to 20 ° C., it was filtered and the cake was washed with 6 g of methanol. It dried under reduced pressure at 40-50 degreeC, and obtained 6- ( 4 -aminobutoxy) carbostyril hydrochloride 7.1g. Chemical purity 99.5 area%, content 93.2%, moisture 6.3%. Yield 82%.
比較例１
攪拌機、ジムロート、温度計を装着した容量２００ｍｌの４口フラスコに、６−（３−フタルイミドプロポキシ）カルボスチリル１１．０ｇ（化学純度９５％、０．０３０モル）、４８％水酸化ナトリウム水溶液９．０ｇ（０．１０８モル）、水６２ｇを仕込み、９０〜９５℃で４時間撹拌した。反応液の一部を採取してＨＰＬＣ分析したところ、６−（３−フタルイミドプロポキシ）カルボスチリルの転化率は９９％以上であり、６−（３−アミノプロポキシ）カルボスチリル塩酸塩の収率は３％以下であった。
Comparative Example 1
Into a 200 ml four-necked flask equipped with a stirrer, a Dimroth, and a thermometer, 11.0 g of 6- (3-phthalimidopropoxy) carbostyril (chemical purity 95%, 0.030 mol), 48% aqueous sodium hydroxide solution 9. 0 g (0.108 mol) and 62 g of water were charged, and the mixture was stirred at 90 to 95 ° C. for 4 hours. When a part of the reaction solution was collected and analyzed by HPLC, the conversion rate of 6- (3-phthalimidopropoxy) carbostyril was 99% or more, and the yield of 6- (3-aminopropoxy) carbostyril hydrochloride was 3% or less.
比較例２
攪拌機、ジムロート、温度計を装着した容量１００ｍｌの４口フラスコに、６−（３−フタルイミドプロポキシ）カルボスチリル１１．０ｇ（化学純度９５％、０．０３０モル）、３５％塩酸水溶液１１．２ｇ（０．１０８モル）、水６２ｇを仕込み、９０〜９５℃で４時間撹拌した。反応液の一部を採取してＨＰＬＣ分析したところ、６−（３−フタルイミドプロポキシ）カルボスチリルの転化率は３％以下であり、６−（３−アミノプロポキシ）カルボスチリル塩酸塩の収率は３％以下であった。
Comparative Example 2
In a 100 ml four-necked flask equipped with a stirrer, a Dimroth, and a thermometer, 11.0 g of 6- (3-phthalimidopropoxy) carbostyril (chemical purity 95%, 0.030 mol), 11.2 g of 35% aqueous hydrochloric acid ( 0.108 mol) and 62 g of water were charged, and the mixture was stirred at 90 to 95 ° C. for 4 hours. When a part of the reaction solution was collected and analyzed by HPLC, the conversion of 6- (3-phthalimidopropoxy) carbostyril was 3% or less, and the yield of 6- (3-aminopropoxy) carbostyril hydrochloride was 3% or less.
比較例３
攪拌機、ジムロート、温度計を装着した容量２００ｍｌの４口フラスコに、６−（３−フタルイミドプロポキシ）カルボスチリル１１．０ｇ（化学純度９５％、０．０３０モル）、４８％水酸化ナトリウム水溶液３．０ｇ（０．０３６モル）、水６２ｇを仕込み、９０〜９５℃で１時間撹拌した。反応液の一部を採取してＨＰＬＣ分析したところ、６−（３−フタルイミドプロポキシ）カルボスチリルの転化率は９９％以上であった。次いで、３５％塩酸７．８ｇ（０．０７５モル）を加え、９０〜９５℃で３時間撹拌した。反応液の一部を採取してＨＰＬＣ分析したところ、フタルアミド酸の転化率は９９％以上であった。反応液を５５℃に冷却して熱時にろ過した。ろ液を、残液が４０ｇになるまで、減圧下に濃縮したのち、６０〜６５℃で０．５時間撹拌した。ろ液を２０℃まで冷却してからろ過し、ケークを６ｇの水を用いて洗浄した。４０〜５０℃で減圧下に乾燥し６−（３−アミノプロポキシ）カルボスチリル塩酸塩９．０ｇを得た。含量７２．２％、水分５．１％、フタル酸含量２２．０％。収率８５％。
Comparative Example 3
2. A 200 ml four-necked flask equipped with a stirrer, a Dimroth, and a thermometer is charged with 11.0 g of 6- (3-phthalimidopropoxy) carbostyril (chemical purity 95%, 0.030 mol), 48% aqueous sodium hydroxide solution. 0 g (0.036 mol) and 62 g of water were charged and stirred at 90 to 95 ° C. for 1 hour. When a part of the reaction solution was collected and analyzed by HPLC, the conversion of 6- (3-phthalimidopropoxy) carbostyril was 99% or more. Next, 7.8 g (0.075 mol) of 35% hydrochloric acid was added, and the mixture was stirred at 90 to 95 ° C. for 3 hours. When a part of the reaction solution was collected and analyzed by HPLC, the conversion rate of phthalamic acid was 99% or more. The reaction solution was cooled to 55 ° C. and filtered while hot. The filtrate was concentrated under reduced pressure until the residual liquid became 40 g, and then stirred at 60 to 65 ° C. for 0.5 hour. The filtrate was cooled to 20 ° C. and filtered, and the cake was washed with 6 g of water. It dried under reduced pressure at 40-50 degreeC, and obtained 9.0 g of 6- (3-amino propoxy) carbostyryl hydrochloride. Content 72.2%, moisture 5.1%, phthalic acid content 22.0%. Yield 85%.
本発明により製造された高純度アミノアルコキシカルボスチリルは、医薬原料として有用である。 The high purity aminoalkoxycarbostyril produced according to the present invention is useful as a pharmaceutical raw material.
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