KR20150117123A - Method for Preparing Blonancerin with Mild Condition - Google Patents
Method for Preparing Blonancerin with Mild Condition Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 36
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 12
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 8
- 150000001875 compounds Chemical class 0.000 claims description 7
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 5
- 239000000126 substance Substances 0.000 claims description 5
- WGCYRFWNGRMRJA-UHFFFAOYSA-N 1-ethylpiperazine Chemical compound CCN1CCNCC1 WGCYRFWNGRMRJA-UHFFFAOYSA-N 0.000 claims description 3
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 21
- 238000004519 manufacturing process Methods 0.000 abstract description 14
- XVGOZDAJGBALKS-UHFFFAOYSA-N Blonanserin Chemical compound C1CN(CC)CCN1C1=CC(C=2C=CC(F)=CC=2)=C(CCCCCC2)C2=N1 XVGOZDAJGBALKS-UHFFFAOYSA-N 0.000 abstract description 5
- 230000035484 reaction time Effects 0.000 abstract description 5
- 229950002871 blonanserin Drugs 0.000 abstract description 4
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 13
- 239000003693 atypical antipsychotic agent Substances 0.000 description 6
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 6
- 229940127236 atypical antipsychotics Drugs 0.000 description 5
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- LNEPOXFFQSENCJ-UHFFFAOYSA-N haloperidol Chemical compound C1CC(O)(C=2C=CC(Cl)=CC=2)CCN1CCCC(=O)C1=CC=C(F)C=C1 LNEPOXFFQSENCJ-UHFFFAOYSA-N 0.000 description 4
- 239000008213 purified water Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 201000000980 schizophrenia Diseases 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- PWYYKWZKLRXRSM-UHFFFAOYSA-N 2-chloro-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine Chemical compound C1=CC(F)=CC=C1C1=CC(Cl)=NC2=C1CCCCCC2 PWYYKWZKLRXRSM-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 239000000164 antipsychotic agent Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 2
- 230000008451 emotion Effects 0.000 description 2
- 229960003878 haloperidol Drugs 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 229960001534 risperidone Drugs 0.000 description 2
- RAPZEAPATHNIPO-UHFFFAOYSA-N risperidone Chemical compound FC1=CC=C2C(C3CCN(CC3)CCC=3C(=O)N4CCCCC4=NC=3C)=NOC2=C1 RAPZEAPATHNIPO-UHFFFAOYSA-N 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000011282 treatment Methods 0.000 description 2
- LOJBBLDAJBJVBZ-UHFFFAOYSA-N 3-(4-fluorophenyl)-3-oxopropanenitrile Chemical compound FC1=CC=C(C(=O)CC#N)C=C1 LOJBBLDAJBJVBZ-UHFFFAOYSA-N 0.000 description 1
- NHKNCECTTVQJJR-UHFFFAOYSA-N 4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydro-1h-cycloocta[b]pyridin-2-one Chemical compound C1=CC(F)=CC=C1C1=CC(=O)NC2=C1CCCCCC2 NHKNCECTTVQJJR-UHFFFAOYSA-N 0.000 description 1
- 206010003694 Atrophy Diseases 0.000 description 1
- 241001274613 Corvus frugilegus Species 0.000 description 1
- 206010012239 Delusion Diseases 0.000 description 1
- PLDUPXSUYLZYBN-UHFFFAOYSA-N Fluphenazine Chemical compound C1CN(CCO)CCN1CCCN1C2=CC(C(F)(F)F)=CC=C2SC2=CC=CC=C21 PLDUPXSUYLZYBN-UHFFFAOYSA-N 0.000 description 1
- 208000002705 Glucose Intolerance Diseases 0.000 description 1
- 206010018429 Glucose tolerance impaired Diseases 0.000 description 1
- 208000004547 Hallucinations Diseases 0.000 description 1
- 206010022998 Irritability Diseases 0.000 description 1
- 208000007101 Muscle Cramp Diseases 0.000 description 1
- 208000005392 Spasm Diseases 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000037444 atrophy Effects 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- 229920001400 block copolymer Polymers 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 229960001076 chlorpromazine Drugs 0.000 description 1
- ZPEIMTDSQAKGNT-UHFFFAOYSA-N chlorpromazine Chemical compound C1=C(Cl)C=C2N(CCCN(C)C)C3=CC=CC=C3SC2=C1 ZPEIMTDSQAKGNT-UHFFFAOYSA-N 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 231100000868 delusion Toxicity 0.000 description 1
- 229960003638 dopamine Drugs 0.000 description 1
- 230000002996 emotional effect Effects 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 239000003344 environmental pollutant Substances 0.000 description 1
- -1 ethylpiperazine compound Chemical class 0.000 description 1
- 229960002690 fluphenazine Drugs 0.000 description 1
- PTCGDEVVHUXTMP-UHFFFAOYSA-N flutolanil Chemical compound CC(C)OC1=CC=CC(NC(=O)C=2C(=CC=CC=2)C(F)(F)F)=C1 PTCGDEVVHUXTMP-UHFFFAOYSA-N 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 208000031424 hyperprolactinemia Diseases 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 229960005017 olanzapine Drugs 0.000 description 1
- KVWDHTXUZHCGIO-UHFFFAOYSA-N olanzapine Chemical compound C1CN(C)CCN1C1=NC2=CC=CC=C2NC2=C1C=C(C)S2 KVWDHTXUZHCGIO-UHFFFAOYSA-N 0.000 description 1
- 230000008447 perception Effects 0.000 description 1
- OBCUTHMOOONNBS-UHFFFAOYSA-N phosphorus pentafluoride Chemical compound FP(F)(F)(F)F OBCUTHMOOONNBS-UHFFFAOYSA-N 0.000 description 1
- 231100000719 pollutant Toxicity 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 229960004431 quetiapine Drugs 0.000 description 1
- URKOMYMAXPYINW-UHFFFAOYSA-N quetiapine Chemical compound C1CN(CCOCCO)CCN1C1=NC2=CC=CC=C2SC2=CC=CC=C12 URKOMYMAXPYINW-UHFFFAOYSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000000698 schizophrenic effect Effects 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 230000004584 weight gain Effects 0.000 description 1
- 235000019786 weight gain Nutrition 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
본 발명은 블로난세린의 신규 제조방법에 관한 것이다. 구체적으로 본 발명은 블로난세린을 온화한 조건에서 제조하는 방법에 관한 것이다.The present invention relates to a novel process for the production of blownarcine. More specifically, the present invention relates to a method for producing the Bronan serine under mild conditions.
정신분열병은 복잡하고 다양한 양상을 지닌 정신과 질환으로 사고, 감정, 지각, 정서, 행동 등의 여러 측면에서 문제를 일으키고 사회 기능이나 직업 기능에도 심각한 영향을 끼친다. 정신분열병 치료는 1950년대 처음으로 사용하기 시작하였는데 크게 전형적 항정신병 약물과 비전형적 항정신병 약물로 나뉜다. 그중 전형적 항정신병 약물로는 대표적으로 할로페리돌, 클로로프로마진, 플루페나진 등이 있고, 강직, 근육경련, 진전, 초조 등의 부작용이 있었다. 이러한 부작용의 문제로 1990년대부터는 리스페리돈, 올란자핀, 퀴에티아핀 등의 비전형적 항정신병 약물로 상당부분 대체되었다. 하지만 비전형적 항정신병 약물도 특성에 따라 다르지만 체중 증가, 당 불내성과 같은 대사성 문제와 고프로락틴혈증 등의 부작용이 약물의 장기사용시 나타났다. 이에 따라 새로운 특성을 지닌 약물들이 개발되고 있다.Schizophrenia is a complex and diverse mental illness that causes problems in many aspects such as thinking, emotion, perception, emotion, and behavior, and it has serious effects on social functioning and occupational functioning. Schizophrenia treatments began to be used for the first time in the 1950s, largely divided into typical antipsychotic drugs and atypical antipsychotic drugs. Typical antipsychotic drugs include haloperidol, chlorpromazine, fluphenazine, and side effects such as stiffness, muscle spasms, progression, and irritability. Since the 1990s, it has been replaced by atypical antipsychotics such as risperidone, olanzapine, and quetiapine. However, although typical atypical antipsychotics vary in their characteristics, metabolic problems such as weight gain and glucose intolerance and adverse effects such as hyperprolactinemia have appeared in long-term use of the drug. Therefore, drugs with new characteristics are being developed.
블로난세린(2-(4-에틸-1-피페라지닐)-4-(4-플루오로페닐)-5,6,7,8,9,10-헥사-하이드로사이클로옥타[b]피리딘)은 하기 화학식 1의 구조를 가지는 새로운 비전형적 항정신병 약물이다.(4-ethyl-1-piperazinyl) -4- (4-fluorophenyl) -5,6,7,8,9,10-hexa-hydrocycloocta [b] pyridine) Is a novel atypical antipsychotic drug having the structure of Formula 1 below.
[화학식 1] [Chemical Formula 1]
상기 블로난세린은 다이니폰사에 의하여 최초 개발되어 현재 정신분열병 치료제로서 로난센(Lonancen)이라는 상품명으로 일본 및 한국에서 시판 중이다.The Bronan serine was first developed by Dainippon Co., Ltd. and is currently being marketed in Japan and Korea under the trade name Lonancen as a treatment for schizophrenia.
미국등록특허 제5,021,421호에서 블로난세린이 처음으로 개시되었으며, 위 특허문헌에서 블로난세린은 기존의 비전형적 항정신병 약물과 화학 구조상 관련이 없고, 세로토닌(5-HT2A) 및 도파민(D2, D3) 수용체에 강력하게 결합하는 성질을 가지기 때문에 모노아민 대사산물이 뇌에 집중되는 효과를 증진시키고, D2 수용체에 대해 할로페리돌이나 리스페리돈보다 20배에서 94배까지 친화성이 높고, 대부분의 비정형 항정신병 약물과는 달리 5-HT2A 수용체보다 D2 수용체에 대한 친화성이 몇 배 높은 특성을 가지고 있어, 정신분열증에 의한 환각, 망상 등과 같은 양성 증상, 정서적 위축, 무감증(apathia) 등과 같은 음성 증상을 개선시키는데 사용될 수 있다고 개시되어 있다. Bronan serine has been disclosed for the first time in US Pat. No. 5,021,421. Bronan serine has no chemical structure with conventional atypical antipsychotics, and serotonin (5-HT 2A ) and dopamine (D 2 , D 3 ) receptors, thus enhancing the concentration of the monoamine metabolite in the brain, having affinity for D 2 receptors 20- to 94-fold higher than haloperidol or risperidone, and most Unlike atypical antipsychotics, the affinity for the D 2 receptor is several times higher than that of the 5-HT 2A receptor, and is associated with schizophrenic hallucinations, positive symptoms such as delusions, emotional atrophy, apathia Can be used to improve the same negative symptoms.
한편, 블로난세린의 합성 방법으로는 미국등록특허 제5,021,421호에서 하기 반응식 1과 같은 합성루트가 제시되었다.On the other hand, as a method for synthesizing blownan serine, US Patent No. 5,021,421 shows a synthesis route as shown in Reaction Scheme 1 below.
[반응식 1][Reaction Scheme 1]
상기 방법은 4-플루오로벤조일아세토니트릴을 주요 골격으로 블로난세린을 합성하고 있다. 하지만 반응온도가 170 ℃로 굉장히 높으며, 수율이 낮은 단점이 있다. This method synthesizes blownan serine with 4-fluorobenzoyl acetonitrile as the main skeleton. However, the reaction temperature is very high at 170 ° C and the yield is low.
중국등록특허 제101531634호에서는 하기 반응식 2와 같은 염화포스포릴을 사용한 합성방법이 제시되었다.In Chinese Patent No. 101531634, a synthesis method using a phosphoryl chloride as shown in the following Reaction Scheme 2 was proposed.
[반응식 2][Reaction Scheme 2]
하지만 상기 방법도 반응온도가 굉장히 높고, 용매를 사용하지 않아 강한 산성물질을 과량 사용하며, 고순도의 블로난세린을 얻기 위해서 수회의 재결정을 수행하여야 하는 문제점이 있다.However, this method also has a problem that the reaction temperature is extremely high, the solvent is not used, the strong acidic substance is used in excess, and the recrystallization is repeated several times in order to obtain high purity blonanserin.
따라서, 상기 단점들을 극복하면서, 99.9% 이상의 순도를 가지는 개선된 블로난세린 제조방법의 필요성이 요구되고 있다.Accordingly, there is a need for an improved method for producing a blockanoserine having a purity of 99.9% or more while overcoming the above disadvantages.
본 발명의 목적은 온화한 조건에서 고순도의 블로난세린을 고수율로 제조하는 것이다.It is an object of the present invention to prepare a high purity blockylanine in a high yield under mild conditions.
본 발명의 또 다른 목적은 반응온도가 낮고 반응시간이 길지 않아 대량생산에 적합한 블로난세린 제조방법을 제공하는 것이다.Yet another object of the present invention is to provide a method for producing Bronan serine which is suitable for mass production because the reaction temperature is low and the reaction time is not long.
본 발명은 블로난세린의 새로운 제조방법을 제공한다. 본 발명의 제조방법은 (S1) 블로난세린 중간체인 2-클로로-4-(4-플루오로페닐)-5,6,7,8,9,10-헥사하이드로시클로옥타[b]피리딘을 제조하는 단계 및 (S2) 상기 중간체로부터 블로난세린을 제조하는 단계를 포함한다. The present invention provides a novel method for producing Bronan serine. The production method of the present invention is a process for producing (S1) a 2-chloro-4- (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocycloocta [b] And (S2) preparing the block copolymer from the intermediate.
본 발명의 제조방법에 따라 제조된 블로난세린은 고순도 및 고수율로 수득할 수 있으며, 반응조건이 온화하고 반응시간이 오래 걸리지 않아 대량생산에 적합하다.Bronan serine produced according to the production method of the present invention can be obtained at a high purity and a high yield and is suitable for mass production because the reaction conditions are mild and the reaction time is not long.
이하에서 본 발명의 (S1) 및 (S2) 단계를 상세히 설명한다.Hereinafter, steps (S1) and (S2) of the present invention will be described in detail.
(( S1S1 ) ) 블로난세린Bloonanserin 중간체의 제조 Preparation of intermediate
본 발명의 (S1) 단계는 하기 화학식 화학식 3의 화합물인 2-클로로-4-(4-플루오로페닐)-5,6,7,8,9,10-헥사하이드로시클로옥타[b]피리딘을 제조하는 단계로서, 하기 반응식 3에 따라 하기 화학식 2의 화합물인 4-(4-플루오로페닐)-5,6,7,8,9,10-헥사하이드로시클로옥타[b]피리딘-2(1H)-온과 오염화인(PCl5)을 유기용매 존재 하에서 반응시켜 제조할 수 있다.Step (S1) of the present invention comprises reacting 2-chloro-4- (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocycloocta [b] pyridine, (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocycloocta [b] pyridin-2 (1H) ) -On and a pollutant (PCl 5 ) in the presence of an organic solvent.
[반응식 3][Reaction Scheme 3]
본 발명의 (S1) 단계의 출발물질인 상기 화학식 2의 화합물은 공지된 블로난세린 중간체로서, 그 합성방법은 미국등록특허 제5,021,421호에 자세히 기재되어 있다.The compound of Formula 2, which is the starting material of step (S1) of the present invention, is a known blownarcine intermediate, and its synthesis is described in detail in U.S. Patent No. 5,021,421.
또한, 오염화인은 상기 화학식 2의 화합물 1.0몰 당량에 대하여 약 0.3 내지 1.0몰 당량, 바람직하게는 약 0.5 내지 0.7몰 당량을 사용할 수 있다.In addition, about 0.3 to 1.0 molar equivalents, preferably about 0.5 to 0.7 molar equivalents, relative to 1.0 molar equivalent of the compound of Formula 2 above may be used as phosphorus pentafluoride.
상기 반응식 3의 반응에서 사용되는 용매는 디메틸포름아미드(DMF) 또는 디메틸술폭사이드(DMSO) 등으로 이루어진 군에서 1종 이상 선택될 수 있으며, 디메틸포름아미드(DMF)를 사용하는 것이 바람직하다.The solvent used in the reaction of Scheme 3 may be at least one selected from the group consisting of dimethylformamide (DMF) and dimethylsulfoxide (DMSO), and it is preferable to use dimethylformamide (DMF).
본 발명의 구체예에 따르면, 상기 반응식 3의 반응은 0 ℃ 내지 80 ℃의 온도에서 1 내지 10 시간 동안 진행될 수 있으며, 바람직하게는 5 ℃ 내지 15 ℃ 에서 3 내지 8 시간 동안 진행될 수 있다. According to an embodiment of the present invention, the reaction of Scheme 3 may be carried out at a temperature of 0 ° C to 80 ° C for 1 to 10 hours, preferably at 5 ° C to 15 ° C for 3 to 8 hours.
(( S2S2 ) ) 블로난세린의Bronnan Serine 제조 Produce
본 발명의 (S2) 단계는 상기 (S1) 단계에서 제조된 블로난세린 중간체로부터 블로난세린을 제조하는 단계로서, 하기 화학식 1의 블로난세린은 하기 반응식 4에 따라 하기 화학식 3의 화합물을 하기 화학식 4의 에틸피페라진과 유기용매 및 염기 존재 하에서 제조할 수 있다.The step (S2) of the present invention is a step of preparing a solution of blownan serine from the blownan serine intermediate prepared in the step (S1), wherein the blownarcine of the following formula (1) Can be prepared in the presence of ethyl piperazine of formula (4) in the presence of an organic solvent and a base.
[반응식 4][Reaction Scheme 4]
상기 화학식 4의 화합물인 에틸피페라진은 화학식 3의 화합물 1.0몰당량에 대하여 약 1.0 내지 3.0몰당량, 바람직하게는 약 1.5 내지 2.0몰당량을 사용할 수 있다.The ethylpiperazine compound represented by Formula 4 may be used in an amount of about 1.0 to 3.0 molar equivalents, preferably about 1.5 to 2.0 molar equivalents based on 1.0 molar equivalent of the compound of Formula 3.
본 발명의 구체예에 따르면, 상기 염기는 디이소프로필에틸아민 또는 트리에틸아민을 사용할 수 있으며, 디이소프로필에틸아민을 사용하는 것이 바람직하다. 상기 염기는 화학식 3의 화합물 1.0몰당량에 대하여 약 1.0 내지 2.0몰당량, 바람직하게는 약 1.2 내지 1.5몰당량을 사용할 수 있다.According to an embodiment of the present invention, the base may be diisopropylethylamine or triethylamine, preferably diisopropylethylamine. The base may be used in an amount of about 1.0 to 2.0 molar equivalents, preferably about 1.2 to 1.5 molar equivalents relative to 1.0 molar equivalent of the compound of formula (3).
또한, 상기 반응식 4의 반응에서 사용되는 용매는 디메틸포름아미드(DMF) 또는 디메틸술폭사이드(DMSO) 등으로 이루어진 군에서 1종 이상 선택될 수 있으며, 디메틸포름아미드(DMF)를 사용하는 것이 바람직하다.The solvent used in the reaction of Scheme 4 may be selected from the group consisting of dimethylformamide (DMF) or dimethylsulfoxide (DMSO), and it is preferable to use dimethylformamide (DMF) .
본 발명의 구체예에 따르면, 상기 반응식 4의 반응은 25 ℃ 내지 150 ℃의 온도에서 1 내지 10 시간 동안 진행될 수 있으며, 바람직하게는 50 ℃ 내지 80 ℃ 에서 4 내지 8시간 동안 진행될 수 있다.According to an embodiment of the present invention, the reaction of Scheme 4 may be carried out at a temperature of 25 ° C to 150 ° C for 1 to 10 hours, preferably at 50 ° C to 80 ° C for 4 to 8 hours.
본 발명에 따라 제조된 블로난세린은99.9% 이상의 고순도 및 고수율로 수득할 수 있으며, 본 발명의 제조방법은 반응조건이 온화하고 반응시간이 길지 않아 대량생산에 적합하므로 산업적 가치가 매우 높은 방법이다.The blonanserin prepared according to the present invention can be obtained at a high purity of 99.9% or higher and a high yield. The production method of the present invention is suitable for mass production because the reaction conditions are mild and the reaction time is not long, to be.
본 발명의 제조방법은 반응온도가 온화하고 반응시간이 짧으며, 고순도의 블로난세린을 고수율로 제조할 수 있으므로 대량생산에 적합하다.The production method of the present invention is suitable for mass production because it can produce a high purity bromanecerine at a high yield with a mild reaction temperature and a short reaction time.
이하, 본 발명의 이해를 돕기 위하여 바람직한 실시예를 제시한다. 그러나 하기의 실시예들은 본 발명을 예시하고 위한 것일 뿐, 본 발명을 이들만으로 한정하는 것은 아니다.Hereinafter, preferred embodiments of the present invention will be described in order to facilitate understanding of the present invention. However, it should be understood that the following examples are intended to illustrate and not limit the present invention.
[[ 사용기기Used equipment 및 측정조건] And measurement conditions]
- 1H NMR : 400 MHz FT-NMR Spectrometer (Varian Unityinova 400)≪ 1 > H NMR: 400 MHz FT-NMR Spectrometer (Varian Unityinova 400)
- MS : Varian MS System with 3800 GC- MS: Varian MS System with 3800 GC
- HPLC : Varian Prostar- HPLC: Varian Prostar
[[ 실시예Example 1] One]
단계 1: 2-Step 1: 2- 클로로Chloro -4-(4--4- (4- 플루오로페닐Fluorophenyl )-5,6,7,8,9,10-) -5,6,7,8,9,10- 헥사하이드로시클Hexahydrocycl 로옥Rook 타[However, b]피리딘의b] pyridine 제조 Produce
4-(4-플루오로페닐)-5,6,7,8,9,10-헥사하이드로시클로옥타[b]피리딘-2(1H)-온 80.0 g을 투입하고 디메틸포름아미드 520 ml를 주입한다. 온도를 5 ℃로 냉각하고 오염화인 36.84 g을 10회에 나누어 투입한다. 온도를 15 ℃로 올린 후에 3 시간 동안 반응시켰다. 정제수 520 ml를 주입하고 10 ℃에서 1 시간 동안 교반하였다. 이 반응액에서 석출된 결정을 누체여과기(Buchner funnel, Coors)로 여과하고 잔사를 정제수 300 ml로 세척하였다. 이 결정을 70 ℃에서 건조시켜 회백색의 2-클로로-4-(4-플루오로페닐)-5,6,7,8,9,10-헥사하이드로시클로옥타 [b]피리딘 80.0 g(수율 93.6 %)을 수득하였다.80.0 g of 4- (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocycloocta [b] pyridin-2 (1H) -one and 520 ml of dimethylformamide . Cool the temperature to 5 ° C and add 36.84 g of the contamination powder in 10 divided doses. After raising the temperature to 15 캜, the reaction was carried out for 3 hours. And 520 ml of purified water was added thereto, followed by stirring at 10 ° C for 1 hour. The crystals precipitated in this reaction solution were filtered with a Buchner funnel (Coors) and the residue was washed with 300 ml of purified water. The crystals were dried at 70 占 폚 to obtain 80.0 g (yield 93.6%) of 2-chloro-4- (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocycloocta [ ).
- MS (m/z); 이론치 289.77 / 실측치 289.7- MS (m / z); Theoretical value 289.77 / Found 289.7
- 1H-NMR (δ, CDCl3): 7.2(2H, m), 7.1(2H, t), 6.8(1H, s), 2.9(2H, t), 2.7(2H, t), 1.8(2H, m), 1.4(4H, m), 1.3(2H, m) - 1 H-NMR (δ, CDCl 3): 7.2 (2H, m), 7.1 (2H, t), 6.8 (1H, s), 2.9 (2H, t), 2.7 (2H, t), 1.8 (2H , < / RTI > m), 1.4 (4H, m), 1.3 (2H, m)
- 순도 : 98.7% - Purity: 98.7%
단계 2 : Step 2: 블로난세린의Bronnan Serine 제조 Produce
단계 1에서 수득한 2-클로로-4-(4-플루오로페닐) -5,6,7,8,9,10-헥사하이드로시클로옥타 [b]피리딘 80.0 g을 디메틸포름아미드 560 ml 에 묽히고, 에틸피페라진 47.29 g과 디이소프로필에틸아민 46.38 g을 투입 후 온도를 70 ℃로 올려 5 시간 동안 반응시켰다. 이 반응액의 온도를 실온으로 냉각하고 정제수 560ml를 주입한 후 10℃로 냉각하였다. 여기서 생성된 결정을 누체여과기(Buchner funnel, Coors)로 여과하고 잔사를 정제수 250 ml로 세척하였다. 이 결정을 에탄올로 재결정하고 70 ℃에서 건조시켜 백색의 블로난세린 100 g (수율 98.6 %)을 수득하였다.80.0 g of the 2-chloro-4- (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocycloocta [b] pyridine obtained in the step 1 was diluted with 560 ml of dimethylformamide , 47.29 g of ethylpiperazine and 46.38 g of diisopropylethylamine were charged and the temperature was raised to 70 ° C and the reaction was carried out for 5 hours. The temperature of the reaction solution was cooled to room temperature, 560 ml of purified water was injected, and the solution was cooled to 10 캜. The resulting crystals were filtered through a Buchner funnel (Coors) and the residue was washed with 250 ml of purified water. The crystals were recrystallized from ethanol and dried at 70 캜 to obtain 100 g of white colored blancerine (yield: 98.6%).
- MS (m/z); 이론치 367.50 / 실측치 367.5- MS (m / z); Theoretical value 367.50 / Found 367.5
- 1H-NMR (δ, CDCl3): 7.1(2H, t), 7.0(2H, t), 6.2(1H, s), 3.5(4H, t), 2.8(2H, m), 2.5(6H, m), 2.4(2H, m), 1.7(2H, m), 1.3(6H, m), 1.0(3H, t) - 1 H-NMR (δ, CDCl 3): 7.1 (2H, t), 7.0 (2H, t), 6.2 (1H, s), 3.5 (4H, t), 2.8 (2H, m), 2.5 (6H m), 2.4 (2H, m), 1.7 (2H, m), 1.3 (6H,
- 순도 : 99.9%- Purity: 99.9%
Claims (3)
(S2) (S1) 단계에서 제조된 화학식 3의 화합물과 하기 화학식 4의 에틸피페라진을 유기용매 및 염기 존재 하에 25 ℃ 내지 150 ℃의 온도에서 반응시켜 화학식 1의 블로난세린을 제조하는 단계;
를 포함하는 블로난세린의 제조방법.
[화학식 1]
[화학식 2]
[화학식 3]
[화학식 4]
(S2) reacting the compound of formula (3) prepared in step (S1) with ethyl piperazine of the following formula (4) in the presence of an organic solvent and a base at a temperature of 25 ° C to 150 ° C to prepare a blonaccharin of formula (1);
≪ / RTI >
[Chemical Formula 1]
(2)
(3)
[Chemical Formula 4]
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105837504A (en) * | 2016-04-25 | 2016-08-10 | 河北国龙制药有限公司 | Preparation method of blonanserin intermediate |
| IT201600092469A1 (en) * | 2016-09-14 | 2018-03-14 | Lundbeck Pharmaceuticals Italy S P A | Blonanserine production process |
| CN110563648A (en) * | 2018-06-06 | 2019-12-13 | 湖南省湘中制药有限公司 | Method for preparing blonanserin intermediate (BN-04) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105837504A (en) * | 2016-04-25 | 2016-08-10 | 河北国龙制药有限公司 | Preparation method of blonanserin intermediate |
| IT201600092469A1 (en) * | 2016-09-14 | 2018-03-14 | Lundbeck Pharmaceuticals Italy S P A | Blonanserine production process |
| CN110563648A (en) * | 2018-06-06 | 2019-12-13 | 湖南省湘中制药有限公司 | Method for preparing blonanserin intermediate (BN-04) |
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