BG62091B1 - Method for the preparation of 1-n-cyclopantylpiperazine - Google Patents
Method for the preparation of 1-n-cyclopantylpiperazine Download PDFInfo
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- BG62091B1 BG62091B1 BG100767A BG10076796A BG62091B1 BG 62091 B1 BG62091 B1 BG 62091B1 BG 100767 A BG100767 A BG 100767A BG 10076796 A BG10076796 A BG 10076796A BG 62091 B1 BG62091 B1 BG 62091B1
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- Prior art keywords
- organochlorine
- alkylation
- solvent
- cyclopentylpiperazine
- piperazine
- Prior art date
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- 238000000034 method Methods 0.000 title claims abstract description 23
- 238000002360 preparation method Methods 0.000 title claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 13
- 238000005804 alkylation reaction Methods 0.000 claims abstract description 8
- 230000029936 alkylation Effects 0.000 claims abstract description 6
- BRTFVKHPEHKBQF-UHFFFAOYSA-N bromocyclopentane Chemical compound BrC1CCCC1 BRTFVKHPEHKBQF-UHFFFAOYSA-N 0.000 claims abstract description 5
- 238000004821 distillation Methods 0.000 claims abstract description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- 229960003506 piperazine hexahydrate Drugs 0.000 claims description 12
- AVRVZRUEXIEGMP-UHFFFAOYSA-N piperazine;hexahydrate Chemical compound O.O.O.O.O.O.C1CNCCN1 AVRVZRUEXIEGMP-UHFFFAOYSA-N 0.000 claims description 12
- PVMCQBPJKPMOKM-UHFFFAOYSA-N 1-cyclopentylpiperazine Chemical compound C1CCCC1N1CCNCC1 PVMCQBPJKPMOKM-UHFFFAOYSA-N 0.000 claims description 11
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 10
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 8
- 239000000284 extract Substances 0.000 claims description 6
- 229960005141 piperazine Drugs 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- UOCLXMDMGBRAIB-UHFFFAOYSA-N 1,1,1-trichloroethane Chemical compound CC(Cl)(Cl)Cl UOCLXMDMGBRAIB-UHFFFAOYSA-N 0.000 claims description 4
- 238000005292 vacuum distillation Methods 0.000 claims description 4
- 238000000605 extraction Methods 0.000 claims description 3
- 238000003756 stirring Methods 0.000 claims description 3
- 150000001298 alcohols Chemical class 0.000 claims description 2
- 229940100198 alkylating agent Drugs 0.000 claims description 2
- 239000002168 alkylating agent Substances 0.000 claims description 2
- 241000287828 Gallus gallus Species 0.000 claims 1
- 230000001476 alcoholic effect Effects 0.000 claims 1
- 150000001350 alkyl halides Chemical class 0.000 claims 1
- 235000013330 chicken meat Nutrition 0.000 claims 1
- WDZCUPBHRAEYDL-GZAUEHORSA-N rifapentine Chemical compound O([C@](C1=O)(C)O/C=C/[C@@H]([C@H]([C@@H](OC(C)=O)[C@H](C)[C@H](O)[C@H](C)[C@@H](O)[C@@H](C)\C=C\C=C(C)/C(=O)NC=2C(O)=C3C(O)=C4C)C)OC)C4=C1C3=C(O)C=2\C=N\N(CC1)CCN1C1CCCC1 WDZCUPBHRAEYDL-GZAUEHORSA-N 0.000 abstract description 2
- 238000013019 agitation Methods 0.000 abstract 1
- 239000003960 organic solvent Substances 0.000 abstract 1
- 235000019441 ethanol Nutrition 0.000 description 7
- 239000000203 mixture Substances 0.000 description 5
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- 238000010936 aqueous wash Methods 0.000 description 3
- 239000002026 chloroform extract Substances 0.000 description 3
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- BGTOWKSIORTVQH-UHFFFAOYSA-N cyclopentanone Chemical compound O=C1CCCC1 BGTOWKSIORTVQH-UHFFFAOYSA-N 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 150000003254 radicals Chemical class 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- -1 chlorobenzoyl Chemical group 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000004880 explosion Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 150000004885 piperazines Chemical class 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
Landscapes
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
Description
Област на техникатаTechnical field
Изобретението се отнася до метод за получаване на l-N-циклопентилпиперазин, който намира приложение във фармацевтичната промишленост.The invention relates to a process for the preparation of 1-N-cyclopentylpiperazine, which is useful in the pharmaceutical industry.
ΜθΗθ-Ν-заместените пиперазини играят важна роля при синтеза на физиологично активни вещества. Така l-N-циклопентилпиперазинът е междинен продукт в процеса на получаване на антибиотика рифапентин.ΜθΗθ-Ν-substituted piperazines play an important role in the synthesis of physiologically active substances. Thus, N-cyclopentylpiperazine is an intermediate in the process of preparing the antibiotic rifapentin.
Предшестващо състояние на техникатаBACKGROUND OF THE INVENTION
Известен е метод за получаване на l-Nциклопентилпиперазин, при който пиперазин и циклопентанон, смесени в моларно съотношение 1:1,5 се подлагат на хидриране в присъствието на катализатор, например чист никел или паладий. Процесът протича при температура 130°С и налягане 50 at /JP 61158973/.A method for the preparation of 1-Ncyclopentylpiperazine is known, in which piperazine and cyclopentanone mixed in a 1: 1.5 molar ratio are hydrogenated in the presence of a catalyst, for example pure nickel or palladium. The process is carried out at a temperature of 130 ° C and a pressure of 50 at / JP 61158973 /.
Недостатъците на метода са взриво- и пожароопасността на процеса, както и относително ниския добив на получения l-N-циклопентилпиперазин.The disadvantages of the process are the explosion and fire hazard of the process, as well as the relatively low yield of the obtained 1-N-cyclopentylpiperazine.
Известни са методи за получаване на 1 N-алкилпиперазини, при които първоначално пиперазинът взаимодейства с леснохидролизиращи се заместители, с които дава чисти монозаместени производни, най-често хлорбензоил, които се алкилират за въвеждане на втория желан радикал, след което блокиращият радикал се отделя чрез хидролиза /ХФЖ, 1974, 8(12), 24-27/.Methods for the preparation of 1 N-alkylpiperazines are known, in which the piperazine is first reacted with readily hydrolyzable substituents to give pure monosubstituted derivatives, most commonly chlorobenzoyl, which are alkylated to introduce the second desired radical, after which the blocking radical is released through hydrolysis / CFC, 1974, 8 (12), 24-27 /.
Недостатъците на тези методи са многостадийността на процеса, както и получаването на известни количества ди-И-алкилпиперазини, вследствие на което се затруднява изолирането на моноалкилпиперазини в чист вид и се понижават добивите на желания моΗθ-Ν-алкилпиперазин.The disadvantages of these methods are the multi-stage process as well as the production of known amounts of di-N-alkylpiperazines, which makes it difficult to isolate the monoalkylpiperazines in pure form and reduce the yields of the desired mo-t-alkyl-piperazine.
Известен е метод за получаване на моΗθ-Ν-алкилпиперазин чрез алкилиране на пиперазин, с еквимоларни количества алкилиращ агент /J.Chem.Soc., 66, 263 (1944)/. Недостатъците на този метод са, че се получава трудно разделяща се смес от нереагирал пиперазин, моно- и ди-И-заместени алкилпиперазини в съотношение 1:2:1, поради което добивите на желания моно-И-алкилпиперазин са ниски.A method is known for the preparation of moΗθ-лки-alkylpiperazine by alkylation of piperazine with equimolar amounts of an alkylating agent (J.Chem.Soc., 66, 263 (1944)). The disadvantages of this method are that a difficult-to-separate mixture of unreacted piperazine, mono- and di-N-substituted alkylpiperazines is obtained in a 1: 2: 1 ratio, so the yields of the desired mono-N-alkylpiperazine are low.
Техническа същност на изобретениетоSUMMARY OF THE INVENTION
При метода съгласно изобретението разтворен в алкохол пиперазин хексахидрат при температура 50-70°С и непрекъснато разбъркване се алкилира с 0,1-0,4 mol/mol циклопентилбромид.In the process of the invention, piperazine hexahydrate dissolved in alcohol at 50-70 ° C and stirred continuously with 0.1-0.4 mol / mol cyclopentyl bromide.
Като разтворител в процеса на алкилиране може да се използват метанол, етанол и други алкохоли.Methanol, ethanol and other alcohols may be used as the solvent in the alkylation process.
Полученият разтвор се дестилира под вакуум на ректифицирана колонка до пълно отделяне на алкохола, екстрахира се в алкална среда с хлорорганичен разтворител, водната фаза се отделя за вторична обработка, полученият хлорорганичен екстракт на циклопентилпиперазин се промива неколкократно с вода, а получените водни промивки се екстрахират с нови количества хлорорганичен разтворител.The resulting solution was distilled in vacuo on a rectified column until complete separation of the alcohol, extracted into an alkaline medium with an organochlorine solvent, the aqueous phase was separated for secondary treatment, the resulting organochlorine extract of cyclopentylpiperazine was washed several times with water, and the resulting extracts were washed with water. new amounts of organochlorine solvent.
Екстракцията може да се извърши с един от следните хлорорганични разтворители: хлороформ, метиленхлорид, 1,1,1-трихлоретан, трихлоретан и други.The extraction can be carried out with one of the following organochlorine solvents: chloroform, methylene chloride, 1,1,1-trichloroethane, trichloroethane and the like.
Всички получени хлорорганични екстракти се обединяват, дестилират се под вакуум до масло, а полученият маслен остатък се подлага на фракционна вакуумдестилация до отделяне на циклопентилпиперазина.All organochlorine extracts obtained were combined, distilled in vacuo to an oil, and the resulting oily residue was subjected to fractional vacuum distillation until cyclopentylpiperazine was separated.
Обединените водни екстракционни фази се концентрират под вакуум с използване на ректифицираща колона, охлаждат се до 0°С, филтруват се, а утайката от изкристализирал пиперазин хексахидрат се филтрува и суши. Изсушеният пиперазин хексахидрат се влага отново за алкилиране.The combined aqueous extraction phases were concentrated in vacuo using a distillation column, cooled to 0 ° C, filtered and the precipitate of crystallized piperazine hexahydrate filtered and dried. The dried piperazine hexahydrate was re-alkylated.
Предимство на метода съгласно изобретението е получаването на продукт с висока чистота и добив.An advantage of the process according to the invention is the production of a product of high purity and yield.
Примери за изпълнение на изобретениетоExamples of carrying out the invention
Изобретението се пояснява със следните примери.The invention is illustrated by the following examples.
Пример 1. Към разтвор на 500 g пиперазин хексахидрат /2,58 mol в 1200 ml етилов алкохол, загрят до 60°С, на порции при разбъркване за около 20 min се прибавя 76,45 g циклопентилбромид /0,513 mol/. Сместа се разбърква 7 h, след което алкохолът се дестилира под слаб вакуум на колонка на Вигрьо до остатъчен обем 350 ml. Към разтвора се прибавят 23 g натриева основа, разтворена в 600 ml вода, и сместа се екстрахира с хлороформ /общ обем 2,5 1/. Водната фаза се отделя за вторична обработка, а хлороформният екстракт се промива трикратно с по 250 ml вода, като обединената водна промивка се екстрахира с 200 ml хлороформ. Обединените хлороформни екстракти се дестилират под слаб вакуум на колонка на Вигрьо, а масленият остатък се подлага на фракционна вакуумдестилация до получаване на циклопентилпиперазин. Получава се 61,6 g циклопентилпиперазин с чистота 99,2% (GC). Добив 77,35% (0,397 mol).Example 1. To a solution of 500 g of piperazine hexahydrate (2.58 mol in 1200 ml of ethyl alcohol heated to 60 ° C) 76.45 g of cyclopentyl bromide (0.513 mol) was added portionwise with stirring for about 20 min. The mixture was stirred for 7 h, then the alcohol was distilled under a gentle vacuum on a Vigreau column to a residual volume of 350 ml. To the solution was added 23 g of a sodium hydroxide solution dissolved in 600 ml of water, and the mixture was extracted with chloroform (total volume 2.5 l). The aqueous phase was separated for secondary treatment, and the chloroform extract was washed three times with 250 ml of water each, and the combined aqueous wash was extracted with 200 ml of chloroform. The combined chloroform extracts were distilled under low vacuum on a Vigreau column, and the oily residue was subjected to fractional vacuum distillation to give cyclopentylpiperazine. 61.6 g of cyclopentylpiperazine are obtained with a purity of 99.2% (GC). Yield 77.35% (0.397 mol).
Н-ЯМР-спектърът на продукта показва квинтет в интервала 1,3-1,9 ppm /циклопентил/.The product's H-NMR spectrum showed a quintet in the range of 1.3-1.9 ppm (cyclopentyl).
Отделеният за вторична обработка воден остатък се охлажда до 0°С, а изкристализиралият пиперазин хексахидрат се филтрува и суши. Получава се 195 g пиперазин хексахидрат. Филтратът се обединява с вече екстрахираните водни промивки. Разтворът се концентрира под вакуум на колонка на Вигрьо до обем 900 ml и след кристализация при 0°С, филтруване и сушене се получава допълнително 175 g пиперазин хексахидрат. Така отделеният пиперазин хексахидрат се влага отново за алкилиране.The recovered aqueous residue was cooled to 0 ° C and the crystallized piperazine hexahydrate was filtered and dried. 195 g of piperazine hexahydrate are obtained. The filtrate is combined with the already extracted aqueous washes. The solution was concentrated in vacuo under a Vigreux column to a volume of 900 ml and after crystallization at 0 ° C, filtration and drying, an additional 175 g of piperazine hexahydrate was obtained. The piperazine hexahydrate thus obtained is again recovered for alkylation.
Пример 2. Към разтвор на 500 g пиперазин хексахидрат /2,58 mol/ в 1200 ml метанол, загрят до 55°С, на порции при разбъркване за около 20 min се прибавят 76,45 g циклопентилбромид /0,513 mol/. Сместа се разбърква 10 h при температура 55°С, след което алкохолът се дестилира при слаб вакуум през колонка на Вигрьо до остатъчен обем 350 ml. Полученият разтвор се обработва по метода, описан в пример 1. Получава се 60,8 g циклопентилпиперазин с чистота 99,1 % (GC). Добив 76,27%.Example 2. To a solution of 500 g of piperazine hexahydrate (2.58 mol) in 1200 ml of methanol heated to 55 ° C, 76.45 g of cyclopentyl bromide (0.513 mol) was added portionwise with stirring for about 20 minutes. The mixture was stirred for 10 h at 55 ° C, then the alcohol was distilled under low vacuum through a Vigreau column to a residual volume of 350 ml. The resulting solution was treated according to the method described in Example 1. 60.8 g of cyclopentylpiperazine was obtained with a purity of 99.1% (GC). Yield 76.27%.
Водният остатък се обработва по метода, описан в пример 1.The aqueous residue was treated by the method described in Example 1.
Пример 3. Пиперазин хексахидрат 500 g се обработва по метода, описан в примери 1 и 2, след което сместа се екстрахира с метиленхлорид /общ обем 2,5 1/. Водната фаза се отделя за вторична обработка, а метиленхлоридният екстракт се промива трикратно с по 100 ml вода. Обединената водна промивка се екстрахира с 300 ml хлороформ. Обединените хлороформни екстракти се дестилират под слаб вакуум през колонка на Вигрьо, а масленият остатък се подлага на фракционна вакуумдестилация до получаване на циклопентилпиперазин. Получава се 61,0 g циклопентилпиперазин с чистота 99,2% (GC). Добив 76,6%.Example 3. Piperazine hexahydrate 500 g was treated by the method described in Examples 1 and 2, after which the mixture was extracted with methylene chloride (total volume 2.5 L). The aqueous phase was separated for secondary treatment and the methylene chloride extract washed three times with 100 ml of water each. The combined aqueous wash was extracted with 300 ml of chloroform. The combined chloroform extracts were distilled under low vacuum through a Vigro column, and the oily residue was subjected to fractional vacuum distillation to give cyclopentylpiperazine. 61.0 g of cyclopentylpiperazine are obtained with a purity of 99.2% (GC). Yield 76.6%.
Водният остатък се обработва по методиката, описана в пример 1.The aqueous residue was treated according to the procedure described in Example 1.
Claims (3)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| BG100767A BG62091B1 (en) | 1996-08-02 | 1996-08-02 | Method for the preparation of 1-n-cyclopantylpiperazine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| BG100767A BG62091B1 (en) | 1996-08-02 | 1996-08-02 | Method for the preparation of 1-n-cyclopantylpiperazine |
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| Publication Number | Publication Date |
|---|---|
| BG100767A BG100767A (en) | 1998-02-27 |
| BG62091B1 true BG62091B1 (en) | 1999-02-26 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| BG100767A BG62091B1 (en) | 1996-08-02 | 1996-08-02 | Method for the preparation of 1-n-cyclopantylpiperazine |
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| Country | Link |
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| BG (1) | BG62091B1 (en) |
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- 1996-08-02 BG BG100767A patent/BG62091B1/en unknown
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| Publication number | Publication date |
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| BG100767A (en) | 1998-02-27 |
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