KR100483317B1 - METHOD FOR THE PREPARATION OF α-PHENYL-α-PROPOXYBENZENEACETIC ACID 1-METHYL-4-PIPERIDINYL ESTER HYDROCHLORIDE - Google Patents
METHOD FOR THE PREPARATION OF α-PHENYL-α-PROPOXYBENZENEACETIC ACID 1-METHYL-4-PIPERIDINYL ESTER HYDROCHLORIDE Download PDFInfo
- Publication number
- KR100483317B1 KR100483317B1 KR10-2002-0080346A KR20020080346A KR100483317B1 KR 100483317 B1 KR100483317 B1 KR 100483317B1 KR 20020080346 A KR20020080346 A KR 20020080346A KR 100483317 B1 KR100483317 B1 KR 100483317B1
- Authority
- KR
- South Korea
- Prior art keywords
- formula
- compound
- acid
- methyl
- propoxybenzeneacetic
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/40—Oxygen atoms
- C07D211/44—Oxygen atoms attached in position 4
-
- 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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C19/00—Acyclic saturated compounds containing halogen atoms
- C07C19/01—Acyclic saturated compounds containing halogen atoms containing chlorine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/40—Unsaturated compounds
- C07C59/42—Unsaturated compounds containing hydroxy or O-metal groups
- C07C59/48—Unsaturated compounds containing hydroxy or O-metal groups containing six-membered aromatic rings
Abstract
본 발명에 따르면, 하기 반응식 5에 의해, 요실금 치료작용이 우수한 하기 화학식 1의 α-페닐-α-프로폭시벤젠아세트산 1-메틸-4-피페리디닐 에스테르 염산염을 용이하게 대량 생산할 수 있는 경제적인 제조방법이 제공된다.According to the present invention, it is economical to easily mass-produce α-phenyl-α-propoxybenzeneacetic acid 1-methyl-4-piperidinyl ester hydrochloride of the formula A manufacturing method is provided.
[화학식 1][Formula 1]
[반응식 5]Scheme 5
Description
본 발명은 요실금 (urinary incontinence) 치료에 우수한 하기 화학식 1의 α-페닐-α-프로폭시벤젠아세트산 1-메틸-4-피페리디닐 에스테르 염산염의 새로운 제조방법에 관한 것이다. The present invention relates to a new process for the preparation of α-phenyl-α-propoxybenzeneacetic acid 1-methyl-4-piperidinyl ester hydrochloride of formula (1), which is excellent for the treatment of urinary incontinence.
화학식 1의 화합물은 특히 비뇨기계통의 치료에 효과가 있다는 것이 발견되어, 비뇨기에 관련된 요실금 치료에 유효한 화합물로 알려져 있다.Compounds of formula (1) have been found to be particularly effective in the treatment of urinary system pain and are known as effective compounds for the treatment of urinary incontinence associated with urinary tract.
상기 화학식 1의 화합물은 1974년 독일 Schering사가 개발한 화합물로서, 화학물질 또는 제조방법에 관한 특허로는 [독일 특허 제106,643호] 및 [중국 특허 제1,285,348호] 등이 있다. The compound of Chemical Formula 1 is a compound developed by Schering, Germany in 1974. Patents related to chemicals or manufacturing methods include [German Patent No. 106,643] and [Chinese Patent No. 1,285,348].
상기 선행 특허들에 기재되어 있는 화학식 1의 화합물의 제조방법을 도식화하면 다음과 같다.Scheme of the preparation of the compound of formula (1) described in the preceding patents is as follows.
상기 반응식 1에 기재된 단위 첫 번째 반응은 벤젠과 톨루엔 혼합용매조건에서 반응을 진행시키고, 생성되는 물을 지속적으로 제거해야 되는 반응이다. 상기 반응을 완성하기 위해서는 많은 시간이 소요될 뿐 아니라 수율이 낮음으로 인하여 화합물 6을 순수하게 분리해야 되며, 다음 반응인 염화반응을 진행하여 화합물 7을 제조하는 등 반응상의 번거로움이 있다. The first reaction of the unit described in Scheme 1 is a reaction in which the reaction is carried out under mixed solvents of benzene and toluene, and the resulting water is continuously removed. In order to complete the reaction, a large amount of time is required and the yield is low, so that Compound 6 must be separated purely, and the reaction is troublesome, such as the preparation of Compound 7 by proceeding with the next reaction, chlorination.
상기 반응식 1의 제조방법을 더욱 구체적으로 살펴보면 다음과 같다.Looking at the production method of the reaction scheme 1 in more detail as follows.
상기 반응식 2에서 화합물 5를 벤젠과 톨루엔 혼합용매 중에서 소듐 메트옥사이드와 혼합한 후, 반응온도를 용매의 환류조건으로 조절하여 반응을 진행하였고, 생성되는 물을 계속 제거함으로써 반응을 완성하였다. 상기 반응의 수율은 60~70% 이고, 순수한 화합물 6을 얻기 위하여 별도의 정제공정 (1-부탄올 용매조건에서 재결정) 이 필요하다. 이와 같이, 반응조건 및 순수한 화합물 6을 분리하기 위한 정제공정을 요구하는 등의 반응상에서의 번거로움 때문에 대량생산시 경제적으로 불리하다.Compound 5 in Scheme 2 was mixed with sodium methoxide in a mixed solvent of benzene and toluene, and then the reaction temperature was controlled by reflux conditions of the solvent, and the reaction was completed by continuing to remove the generated water. The yield of the reaction is 60-70%, and a separate purification process (recrystallization in 1-butanol solvent conditions) is required to obtain pure compound 6. As such, it is economically disadvantageous in mass production due to the reaction conditions and the troublesome reaction conditions such as requiring a purification process for separating pure Compound 6.
상기 반응식 3에 기재된 단위 첫 번째 반응은 톨루엔 용매조건에서 적당한 염기를 사용하여 에스테르화 반응을 진행시킨 것이다. 상기 반응을 완성하기 위해서는 중간체를 활성화시킨 후 반응을 진행시켜야 하기 때문에 대량생산시 경제적으로 불리하다.The first reaction of the unit described in Scheme 3 was to proceed with the esterification reaction using a suitable base under toluene solvent conditions. In order to complete the reaction, it is economically disadvantageous in mass production because the reaction must proceed after activating the intermediate.
상기 반응식 3의 제조방법을 더욱 구체적으로 살펴보면 다음과 같다.Looking at the production method of Scheme 3 in more detail as follows.
상기 반응식 4에서 화합물 8을 톨루엔 용매조건에서 5% 소듐 하이드록사이드를 사용하여 에스테르화 반응을 진행시키기 위하여, 전 단계로 피페리딘 유도체를 염화반응을 진행하여 4-클로로피페리딘 유도체를 합성한 후 에스테르화 반응을 진행하였다. 또한 화합물 10의 합성단계인 염화반응을 진행시키기 위하여 화합물 9를 고품질로 정제할 필요가 있기 때문에 대량생산시 사용되는 원료의 가격 및 반응상의 복잡함 등을 고려할 때 경제적으로 불리하다. In order to proceed with the esterification of compound 8 using 5% sodium hydroxide in toluene solvent in Scheme 4, a piperidine derivative was subjected to a chlorination reaction as a previous step to synthesize 4-chloropiperidine derivative. After the esterification reaction was carried out. In addition, since the compound 9 needs to be purified to a high quality in order to proceed with the chlorination reaction, which is the synthesis step of the compound 10, it is economically disadvantageous in consideration of the cost and reaction complexity of the raw materials used in mass production.
따라서, 선행기술, 특히 상술한 독일 특허 및 중국 특허 등의 문제점을 보완하고 동시에 반응조건을 간결하게 함으로써, 산업상 이용가능성을 극대화할 수 있는 새로운 제조방법에 대한 필요성이 요구되어 왔다.Therefore, there is a need for a new manufacturing method that can maximize the industrial applicability by supplementing the problems of the prior art, in particular the above-described German patent and Chinese patent, and at the same time concise the reaction conditions.
본 발명자들은 요실금 치료에 우수한 화학식 1의 α-페닐-α-프로폭시벤젠아세트산 1-메틸-4-피페리디닐 에스테르 염산염을 용이하고 경제적으로 합성할 수 있는 새로운 제조방법을 개발하기 위해 연구하였으며, 그 결과, 기존의 방법과는 다른 새로운 반응 경로 및 적절한 반응 조건을 찾아내어 고순도의 화학식 1의 화합물을 제조함으로써 본 발명을 완성하였다. The present inventors studied to develop a novel method for easily and economically synthesizing α-phenyl-α-propoxybenzeneacetic acid 1-methyl-4-piperidinyl ester hydrochloride of Formula 1, which is excellent in treating urinary incontinence, As a result, the present invention was completed by finding a new reaction route different from the existing method and appropriate reaction conditions to prepare a compound of formula 1 having high purity.
본 발명의 목적은 요실금 치료 작용이 우수한 화학식 1의 α-페닐-α-프로폭시벤젠아세트산 1-메틸-4-피페리디닐 에스테르 염산염의 제조방법을 제공하는 것이다. An object of the present invention is to provide a method for preparing α-phenyl-α-propoxybenzeneacetic acid 1-methyl-4-piperidinyl ester hydrochloride of formula (1) having excellent urinary incontinence treatment action.
[화학식 1][Formula 1]
구체적으로, 본 발명의 방법은 하기 단계를 포함한다: Specifically, the method of the present invention comprises the following steps:
(1) 화학식 2의 화합물을 티오닐 클로라이드와 반응시켜 화학식 3의 에시드 클로라이드 유도체를 제조하고; (1) reacting a compound of Formula 2 with thionyl chloride to prepare an acid chloride derivative of Formula 3;
(2) 화학식 3의 에시드 클로라이드 유도체에 4-하이드록시피페리딘 유도체를 도입하여 화학식 4의 에스테르 유도체를 제조하고; (2) introducing an 4-hydroxypiperidine derivative into the acid chloride derivative of Formula 3 to prepare an ester derivative of Formula 4;
(3) 화학식 4의 에스테르 유도체에 시약 및 원료로 1-프로판올을 사용하여 화학식 1의 α-페닐-α-프로폭시벤젠아세트산 1-메틸-4-피페리디닐 에스테르 염산염을 제조하고; (3) preparing α-phenyl-α-propoxybenzeneacetic acid 1-methyl-4-piperidinyl ester hydrochloride of formula 1 using 1-propanol as a reagent and raw material in an ester derivative of formula 4;
(4) 필요에 따라 이를 정제함:(4) Purify it as needed:
본 발명에 따른 제조방법 즉, 화학식 1의 화합물의 제조방법은 다음 반응식 5와 같이 도식화될 수 있다:The preparation method according to the present invention, i.e., the preparation method of the compound of Formula 1, may be represented as in Scheme 5.
본 발명의 α-페닐-α-프로폭시벤젠아세트산 1-메틸-4-피페리디닐 에스테르 염산염을 합성하는 제조공정은 선행 기술의 제조방법과는 다른 것으로, 그 반응 과정이 상이하며, 상대적으로 반응을 간결하게 실시함으로써, 산업상 이용가능성을 증가시켰다는 점에서 장점을 보유하고 있다.The production process for synthesizing the α-phenyl-α-propoxybenzeneacetic acid 1-methyl-4-piperidinyl ester hydrochloride of the present invention is different from the preparation method of the prior art, the reaction process is different, and the reaction is relatively The concise implementation of this has the advantage of increasing industrial availability.
즉, 종래 기술의 합성방법은 반응조건, 중간체의 정제공정 및 원료의 가격 등 많은 번거로움을 내포하고 있었으나, 본 발명은 상대적으로 반응을 간결하게 실시함으로써, 일반적인 실시가 가능한 보다 온화한 반응 조건을 이용하여 목적화합물을 제조하는 방법을 제공한다. That is, the synthesis method of the prior art has a lot of trouble, such as reaction conditions, intermediate purification process and the price of the raw material, but the present invention uses a more mild reaction conditions that can be generally carried out by relatively simple reaction To provide a method for preparing the target compound.
하기 실시예에 의하여 본 발명을 구체적으로 설명한다. 다만 하기 실시예에 의하여 본 발명이 한정되는 것은 아니다.The present invention is explained in detail by the following examples. However, the present invention is not limited by the following examples.
실시예 1: 클로로디페닐아세틸 클로라이드의Example 1 Chlorodiphenylacetyl Chloride 합성 (화합물 3)Synthesis (Compound 3)
화합물 2 (50.0 g, 219.0 mmol) 를 톨루엔 (250 mL) 에 현탁시키고 실온 (~25℃) 에서 티오닐 클로라이드 (87.0 g, 731.3 mmol) 와 N,N-디메틸포름아미드 (10.0 ml) 를 반응용액에 넣은 다음 4.0시간 환류 교반하였다. 반응용액을 감압증류하여 유기용매 및 사용된 시약을 제거하여 담황색의 표제화합물을 유상물질 (55.8 g, 수율 96.1%) 로 수득하였다. Compound 2 (50.0 g, 219.0 mmol) was suspended in toluene (250 mL), and thionyl chloride (87.0 g, 731.3 mmol) and N, N-dimethylformamide (10.0 ml) were reacted at room temperature (˜25 ° C.). It was added to and then stirred under reflux for 4.0 hours. The reaction solution was distilled under reduced pressure to remove the organic solvent and the used reagent to obtain the pale yellow title compound as an oily substance (55.8 g, yield 96.1%).
실시예 1에서 제조한 화합물 3을 추가의 정제공정없이 실시예 2에서 사용하였다. Compound 3 prepared in Example 1 was used in Example 2 without further purification.
1H NMR(400MHz, CDCl3) 7.43~7.37 (10H, m) 1 H NMR (400MHz, CDCl 3 ) 7.43 ~ 7.37 (10H, m)
13C NMR(400MHz, CDCl3) 172.36, 137.94, 129.16, 128.67, 128.35, 82.85. 13 C NMR (400 MHz, CDCl 3 ) 172.36, 137.94, 129.16, 128.67, 128.35, 82.85.
실시예 2: 클로로디페닐아세트산 1-메틸-4-피페리디닐 에스테르의Example 2: Chlorodiphenylacetic acid 1-methyl-4-piperidinyl ester 합성 (화합물 4)Synthesis (Compound 4)
실시예 1에서 수득한 화합물 3 (58.0 g, 218.7 mmol) 을 톨루엔 (580 mL) 에 용해시킨 후 트리에틸아민 (44.3 g, 437.8 mmol) 과 4-하이드록시-1-메틸피페리딘 (37.8 g, 328.2 mmol) 을 실온 (~25℃) 에서 순서대로 넣고 2.5시간 동안 교반하였다. 반응혼합물을 10% 염산 수용액 (580 mL) 과 10% 소듐 카보네이트 수용액 (580 mL) 으로 연속하여 세척하였다. 분리한 유기 용액층을 포화 소금물용액과 물로 연속하여 세척한 다음 무수 황산마그네슘으로 건조, 여과 및 농축하여 화합물 4를 담황색의 유상물질 (64.8g, 수율 86.1%) 로 수득하였다.Compound 3 (58.0 g, 218.7 mmol) obtained in Example 1 was dissolved in toluene (580 mL), followed by triethylamine (44.3 g, 437.8 mmol) and 4-hydroxy-1-methylpiperidine (37.8 g , 328.2 mmol) were added sequentially at room temperature (˜25 ° C.) and stirred for 2.5 hours. The reaction mixture was washed successively with 10% aqueous hydrochloric acid solution (580 mL) and 10% aqueous sodium carbonate solution (580 mL). The separated organic solution layer was washed successively with saturated brine solution and water, dried over anhydrous magnesium sulfate, filtered and concentrated to give compound 4 as pale yellow oil (64.8 g, yield 86.1%).
1H NMR(400MHz, CDCl3) 1.77(2H, m), 2.03(2H, m), 2.26(2H, m), 2.50(2H, m), 5.03(1H, m), 7.38(10H, m). 1 H NMR (400 MHz, CDCl 3 ) 1.77 (2H, m), 2.03 (2H, m), 2.26 (2H, m), 2.50 (2H, m), 5.03 (1H, m), 7.38 (10H, m) .
실시예 3: α-페닐-α-프로폭시벤젠아세트산 1-메틸-4-피페리디닐 에스테르 염산염의 합성 (화합물 1) Example 3: Synthesis of α-phenyl-α-propoxybenzeneacetic acid 1-methyl-4-piperidinyl ester hydrochloride (Compound 1)
실시예 2에서 수득한 화합물 4 (55.1 g, 160.2 mmol) 를 1-프로판올 (220 mL) 용액에 용해시킨 후 반응용액을 8시간 동안 환류시켰다. 반응 용액을 감압증류하여 용매를 제거하고, 에틸 아세테이트 (551 mL) 를 넣어 용해하고 실온 (~25℃) 에서 천천히 교반하였다. 결정이 석출된 후 추가로 2.0시간 동안 교반 후 여과하고 에틸 아세테이트 (110 mL) 로 세척한 다음 여과물을 40~45℃ 에서 건조하여 백색의 고순도 화합물 1 (61.2 g, 151.5 mmol, 순도 99.2%, 수율 94.5%)을 수득하였다.Compound 4 (55.1 g, 160.2 mmol) obtained in Example 2 was dissolved in 1-propanol (220 mL) solution, and the reaction solution was refluxed for 8 hours. The reaction solution was distilled under reduced pressure to remove the solvent, ethyl acetate (551 mL) was added thereto to dissolve, and the mixture was stirred slowly at room temperature (˜25 ° C.). After the crystals were precipitated, the mixture was stirred for a further 2.0 hours, filtered, washed with ethyl acetate (110 mL), and the filtrate was dried at 40-45 ° C. to give a white high purity Compound 1 (61.2 g, 151.5 mmol, 99.2% purity), Yield 94.5%).
1H NMR(400MHz, CDCl3) 0.92(3H, t), 1.62(2H, m), 1.91(2H, d), 2.09(2H, m), 2.46(5H, m), 3.03(2H, d), 3.23(2H, t), 5.30(1H, m), 7.40(10H, m). 1 H NMR (400 MHz, CDCl 3 ) 0.92 (3H, t), 1.62 (2H, m), 1.91 (2H, d), 2.09 (2H, m), 2.46 (5H, m), 3.03 (2H, d) , 3.23 (2H, t), 5.30 (1H, m), 7.40 (10H, m).
융점 213.3~214.2℃Melting Point 213.3 ~ 214.2 ℃
실시예 4: α-페닐-α-프로폭시벤젠아세트산 1-메틸-4-피페리디닐 에스테르 염산염의 정제 (화합물 1) Example 4: Purification of α-phenyl-α-propoxybenzeneacetic acid 1-methyl-4-piperidinyl ester hydrochloride (Compound 1)
실시예 3에서 수득한 화합물 1 (50.0 g, 순도 99.2%) 을 디클로로메탄 (100 mL) 에 실온 (~25℃) 에서 용해하고 에틸 아세테이트 (250 mL) 를 30분간 천천히 적가하였다. 반응용액을 실온 (~25℃) 에서 2시간 방치 후, 0~5℃ 로 냉각하여 1시간 교반 후 여과하고 40~45℃ 에서 건조하여 백색의 고순도 화합물 1 (47.3 g, 순도 99.8%) 을 수득하였다. Compound 1 (50.0 g, purity 99.2%) obtained in Example 3 was dissolved in dichloromethane (100 mL) at room temperature (˜25 ° C.) and ethyl acetate (250 mL) was slowly added dropwise for 30 minutes. The reaction solution was left at room temperature (˜25 ° C.) for 2 hours, cooled to 0-5 ° C., stirred for 1 hour, filtered, and dried at 40 ° C. to 45 ° C. to obtain white high purity Compound 1 (47.3 g, purity 99.8%). It was.
융점 213.5~214.2℃Melting Point 213.5 ~ 214.2 ℃
본 발명의 방법은 α-페닐-α-프로폭시벤젠아세트산 1-메틸-4-피페리디닐 에스테르 염산염 외에, 이의 유도체의 제조에도 적용할 수 있음은 물론이며, 이러한 방법도 본 발명의 범주에 포함된다. In addition to α-phenyl-α-propoxybenzeneacetic acid 1-methyl-4-piperidinyl ester hydrochloride, the method of the present invention can be applied to the preparation of derivatives thereof, and such a method is also included in the scope of the present invention. do.
본 발명에 따르면, 요실금 치료에 우수한 화학식 1의 α-페닐-α-프로폭시벤젠아세트산 1-메틸-4-피페리디닐 에스테르 염산염을 용이하고 경제적으로, 그리고 고순도 및 고수율로 제조할 수 있다. According to the present invention, the α-phenyl-α-propoxybenzeneacetic acid 1-methyl-4-piperidinyl ester hydrochloride of formula 1, which is excellent in treating urinary incontinence, can be prepared easily and economically, with high purity and high yield.
Claims (3)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR10-2002-0080346A KR100483317B1 (en) | 2002-12-16 | 2002-12-16 | METHOD FOR THE PREPARATION OF α-PHENYL-α-PROPOXYBENZENEACETIC ACID 1-METHYL-4-PIPERIDINYL ESTER HYDROCHLORIDE |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR10-2002-0080346A KR100483317B1 (en) | 2002-12-16 | 2002-12-16 | METHOD FOR THE PREPARATION OF α-PHENYL-α-PROPOXYBENZENEACETIC ACID 1-METHYL-4-PIPERIDINYL ESTER HYDROCHLORIDE |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| KR20040053886A KR20040053886A (en) | 2004-06-25 |
| KR100483317B1 true KR100483317B1 (en) | 2005-04-18 |
Family
ID=37347031
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR10-2002-0080346A KR100483317B1 (en) | 2002-12-16 | 2002-12-16 | METHOD FOR THE PREPARATION OF α-PHENYL-α-PROPOXYBENZENEACETIC ACID 1-METHYL-4-PIPERIDINYL ESTER HYDROCHLORIDE |
Country Status (1)
| Country | Link |
|---|---|
| KR (1) | KR100483317B1 (en) |
-
2002
- 2002-12-16 KR KR10-2002-0080346A patent/KR100483317B1/en active IP Right Grant
Also Published As
| Publication number | Publication date |
|---|---|
| KR20040053886A (en) | 2004-06-25 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN110590635A (en) | Preparation method of levetiracetam and intermediate thereof | |
| JP2691442B2 (en) | Novel proline derivative | |
| JPS626718B2 (en) | ||
| KR100483317B1 (en) | METHOD FOR THE PREPARATION OF α-PHENYL-α-PROPOXYBENZENEACETIC ACID 1-METHYL-4-PIPERIDINYL ESTER HYDROCHLORIDE | |
| KR100915551B1 (en) | Process for the efficient preparation of 3-hydroxy pyrrolidine and derivatives thereof | |
| KR100743617B1 (en) | Process for the preparation of chiral 3-hydroxy pyrrolidine compound and derivatives thereof having high optical purity | |
| EP1554235B1 (en) | Process for synthesizing l-y-methylene glutamic acid and analogs | |
| KR100491748B1 (en) | Optically active erythro-3-amino-2-hydroxybutyric esters and process for preparing said esters | |
| JPH0737440B2 (en) | Method for producing sulfonium compound | |
| KR100330609B1 (en) | Process for producing 3-isoxazolecarboxylic acid | |
| JP3207018B2 (en) | Method for producing benzylsuccinic acid derivative and intermediate for producing the same | |
| CN113651715B (en) | Method for synthesizing coumaroyl dopamine by one-pot method | |
| KR100407720B1 (en) | Preparing Method for N-[3-{3-(1-Piperidinylmethyl)phenoxy}propyl]acetoxyacetamide | |
| KR100856133B1 (en) | Improved process for preparing atorvastatin | |
| JP3740783B2 (en) | Process for producing 4- (2-alkenyl) -2,5-oxazolidinediones | |
| KR100503267B1 (en) | Method for the preparation of 2-acetyloxy-4-trifluoromethyl benzoic acid | |
| KR100432587B1 (en) | Method of preparing levosulpiride and intermediates used therein | |
| JP2003137835A (en) | Method for producing (r)-3-hydroxy-3-(2-phenyl)hexanoic acid | |
| KR100468314B1 (en) | Intermediate for preparing levosulpiride and preparation method thereof | |
| JP2015040200A (en) | Manufacturing method of (2s,5s)-5-hydroxy-2-piperidinecarboxylic acid as well as manufacturing intermediate of the same and method for manufacturing the same | |
| JP2005298337A (en) | METHOD FOR PRODUCING beta-HYDROXYAMINO ACID DERIVATIVE AND INTERMEDIATE OF THE SAME | |
| KR100806731B1 (en) | New synthetic method of 2',6'-pipecoloxylidide | |
| KR100834387B1 (en) | Novel method for producing benzamide derivative and intermediate thereof | |
| JP2003160560A (en) | Method for producing trans-4-substituted piperidine-2- carboxylate | |
| KR20050103610A (en) | Process for preparing hydrochloride propiverin |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A201 | Request for examination | ||
| E902 | Notification of reason for refusal | ||
| E701 | Decision to grant or registration of patent right | ||
| GRNT | Written decision to grant | ||
| FPAY | Annual fee payment |
Payment date: 20130405 Year of fee payment: 9 |
|
| FPAY | Annual fee payment |
Payment date: 20140404 Year of fee payment: 10 |
|
| FPAY | Annual fee payment |
Payment date: 20150806 Year of fee payment: 11 |
|
| FPAY | Annual fee payment |
Payment date: 20180312 Year of fee payment: 14 |
|
| FPAY | Annual fee payment |
Payment date: 20190710 Year of fee payment: 15 |