KR20190120112A - Intermediates of chiral piperidine derivatives and preparation method thereof - Google Patents

Intermediates of chiral piperidine derivatives and preparation method thereof Download PDF

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KR20190120112A
KR20190120112A KR1020190124891A KR20190124891A KR20190120112A KR 20190120112 A KR20190120112 A KR 20190120112A KR 1020190124891 A KR1020190124891 A KR 1020190124891A KR 20190124891 A KR20190124891 A KR 20190124891A KR 20190120112 A KR20190120112 A KR 20190120112A
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formula
compound
preparing
methylpiperidin
benzyl
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권재홍
김은선
이혁우
고동현
유재영
최광도
허승평
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씨제이헬스케어 주식회사
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    • 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
    • C07D211/68—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 one double bond between ring members or between a ring member and a non-ring member
    • C07D211/72—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 one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D211/74—Oxygen atoms
    • 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
    • A61K31/45—Non condensed piperidines, e.g. piperocaine having oxo groups directly attached to the heterocyclic ring, e.g. cycloheximide

Abstract

By a manufacturing method of the present invention, it is possible to manufacture tert-butyl 3-methyl-4-oxopiperidine-1-carboxylate having optical activity at a high yield while having high purity and optical activity by a method capable of industrially mass production by using commercially available reagents and solvents. In addition, by using a novel intermediate of the present invention, it is possible to manufacture tert-butyl 3-methyl-4-oxopiperidine-1-carboxylate having optical activity in a high purity and the high yield.

Description

광학활성을 갖는 피페리딘 유도체의 중간체 및 이의 제조방법 {Intermediates of chiral piperidine derivatives and preparation method thereof}Intermediates of piperidine derivatives having optical activity and preparation methods thereof Intermediates of chiral piperidine derivatives and preparation method

본 발명은 광학활성을 갖는 피페리딘 유도체의 중간체 및 이의 제조방법에 관한 것이다.The present invention relates to intermediates of piperidine derivatives having optical activity and methods for their preparation.

피페리딘 유도체는 의약 및 화학 분야에서 중요한 약물특이 분자단으로 널리 쓰이고 있다. 특히, 국제공개공보 WO 2004/041777, WO 2009/106534, WO 2008/119718, WO 2010/051374, WO 2005/040169, WO 2013/021052, WO 2004/058709, WO 2016/120849, WO 2014/023815, WO 2013/181579, WO 2016/120850 등에는 여러 약물을 합성하기 위한 중간체로 터트-부틸 3-메틸-4-옥소피페리딘-1-카르복실레이트를 개시하고 있고, 이를 제조하는 방법으로 아래의 반응식 I 내지 III의 방법을 개시하고 있다.Piperidine derivatives are widely used as important drug-specific molecular groups in medicine and chemistry. In particular, WO 2004/041777, WO 2009/106534, WO 2008/119718, WO 2010/051374, WO 2005/040169, WO 2013/021052, WO 2004/058709, WO 2016/120849, WO 2014/023815, WO 2013/181579, WO 2016/120850 and the like disclose tert-butyl 3-methyl-4-oxopiperidine-1-carboxylate as an intermediate for synthesizing various drugs, and as a method for preparing the same, The methods of Schemes I-III are disclosed.

[반응식 I]Scheme I

Figure pat00001
Figure pat00001

[반응식 II]Scheme II

Figure pat00002
Figure pat00002

[반응식 III]Scheme III

Figure pat00003
Figure pat00003

다만, 상기 특허문헌에 개시된 중간체 화합물은 라세미체로서 그 제조방법 역시 라세미체 만을 제조할 수 있으며, 광학활성을 갖는 터트-부틸 3-메틸-4-옥소피페리딘-1-카르복실레이트를 제조하는 방법에 대해서는 어떠한 개시도 없다.However, the intermediate compound disclosed in the patent document is a racemate, and the preparation method thereof can also prepare racemate only, tert-butyl 3-methyl-4-oxopiperidine-1-carboxylate having optical activity. There is no disclosure as to the method of making the.

그러나, 의약품은 광학활성에 따라 약리활성이나 부작용이 크게 차이가 날 수 있으며 이 때문에 많은 의약품이 특정 이성질체로 개발되고 있는데, 특정 이성질체의 터트-부틸 3-메틸-4-옥소피페리딘-1-카르복실레이트를 중간체로 제조되는 의약품의 경우 라세미체의 터트-부틸 3-메틸-4-옥소피페리딘-1-카르복실레이트를 중간체로 사용하여 제조할 경우보다 시약의 낭비가 커서 경제적으로 비효율적이고 제조수율이 낮아 대량생산에 적합하지 않은 문제점이 있다.However, pharmacological activity and side effects may vary greatly depending on the optical activity. Therefore, many pharmaceutical products are being developed as specific isomers. Tert-butyl 3-methyl-4-oxopiperidine-1- In the case of a pharmaceutical prepared by using carboxylate as an intermediate, it is more economical because the waste of reagent is greater than that produced by using tert-butyl 3-methyl-4-oxopiperidine-1-carboxylate of racemate as an intermediate. Inefficient and low production yield has a problem that is not suitable for mass production.

이에 본 발명자들은, 의약 및 화학분야에서 중간체로 유용한 터트-부틸 3-메틸-4-옥소피페리딘-1-카르복실레이트를, 통상적으로 사용 가능한 시약과 용매를 사용하여, 산업적으로 대량생산이 가능한 방법으로 고순도의 광학활성을 가지면서 고수율로 제조하는 본 발명을 완성하였다.Accordingly, the inventors have found that tert-butyl 3-methyl-4-oxopiperidine-1-carboxylate, which is useful as an intermediate in medicine and chemistry, can be industrially mass-produced using commonly available reagents and solvents. In a possible way, the present invention has been completed, which has high purity and high yield of optical activity.

국제공개공보 WO 2004/041777International Publication WO 2004/041777 국제공개공보 WO 2009/106534International Publication WO 2009/106534 국제공개공보 WO 2008/119718International Publication WO 2008/119718 국제공개공보 WO 2010/051374International Publication WO 2010/051374 국제공개공보 WO 2005/040169International Publication WO 2005/040169 국제공개공보 WO 2013/021052International Publication WO 2013/021052 국제공개공보 WO 2004/058709International Publication WO 2004/058709 국제공개공보 WO 2016/120849International Publication WO 2016/120849 국제공개공보 WO 2014/023815International Publication WO 2014/023815 국제공개공보 WO 2013/181579International Publication WO 2013/181579 국제공개공보 WO 2016/120850International Publication WO 2016/120850

본 발명은 의약 및 화학분야에서 중간체로 유용한 터트-부틸 3-메틸-4-옥소피페리딘-1-카르복실레이트를, 통상적으로 사용 가능한 시약과 용매를 사용하여, 산업적으로 대량생산이 가능한 방법으로 고순도의 광학활성을 가지면서 고수율로 제조할 수 있는 제조방법을 제공하고자 한다.The present invention provides a method for industrially mass production of tert-butyl 3-methyl-4-oxopiperidine-1-carboxylate, which is useful as an intermediate in medicine and chemistry, using commonly available reagents and solvents. To provide a manufacturing method that can be produced in high yield while having a high purity optical activity.

또한, 본 발명은 광학활성을 갖는 터트-부틸 3-메틸-4-옥소피페리딘-1-카르복실레이트를 제조하는데 유용하게 사용되는 신규한 중간체를 제공하고자 한다.It is also an object of the present invention to provide novel intermediates useful for preparing tert-butyl 3-methyl-4-oxopiperidine-1-carboxylate having optical activity.

상기 과제를 해결하기 위하여, 본 발명은 하기 화학식 I 화합물을 광학분할 (optical resolution)시켜 하기 화학식 II 화합물을 제조하는 단계 (단계 1)를 포함하는 하기 화학식 IV의 화합물의 제조방법을 제공한다.In order to solve the above problems, the present invention provides a method for preparing a compound of formula (IV) comprising the step (step 1) of preparing a compound of formula (II) by optical resolution of the compound of formula (I).

[화학식 I][Formula I]

Figure pat00004
Figure pat00004

[화학식 II][Formula II]

Figure pat00005
Figure pat00005

[화학식 IV][Formula IV]

Figure pat00006
Figure pat00006

본 발명의 구체예에 따르면, 본 발명의 제조방법은 상기 화학식 II의 화합물과 염기를 반응시켜 하기 화학식 III의 화합물을 제조하는 단계 (단계 2)를 더 포함할 수 있다.According to an embodiment of the present invention, the preparation method of the present invention may further include a step (step 2) of preparing a compound of formula III by reacting a compound of formula II with a base.

[화학식 III][Formula III]

Figure pat00007
Figure pat00007

또한 본 발명의 구체예에 따르면, 본 발명의 제조방법은 상기 화학식 III의 화합물과 디-터트-부틸-디카보네이트를 반응시켜 상기 화학식 IV의 화합물을 제조하는 단계 (단계 3)를 더 포함할 수 있다.In addition, according to an embodiment of the present invention, the preparation method of the present invention may further comprise the step of preparing a compound of formula (IV) by reacting the compound of formula III and di-tert-butyl-dicarbonate (step 3) have.

또한 본 발명의 다른 구체예에 따르면, 본 발명의 제조방법은 상기 단계 1에서 원하는 광학활성의 상기 화학식 II의 화합물을 제조한 후, 반대의 광학이성질체에 염기를 가하여 라세미화시켜 상기 화학식 I의 화합물을 다시 제조하고 이를 단계 1에서 재사용하는 단계 (단계 4)를 더 포함할 수 있다.According to another embodiment of the present invention, in the preparation method of the present invention, in step 1, the compound of Formula II of the desired optical activity is prepared, followed by racemization by adding a base to the opposite optical isomer of the compound of Formula I It may further comprise the step of preparing again and reusing it in step 1 (step 4).

본 발명에 있어서, 상기 단계 1 내지 단계 4를 종합하여 도식화하면 다음 반응식 IV로 나타낼 수 있다.In the present invention, when the synthesis of the above steps 1 to 4 can be represented by the following scheme IV.

[반응식 IV]Scheme IV

Figure pat00008
Figure pat00008

이하에서는 각 단계에 대하여 구체적으로 살핀다.The following is a detailed look at each step.

본 발명에 있어서, 상기 단계 1은 상기 화학식 I의 화합물을 하기 화학식 V-1 또는 V-2의 화합물과 결합시키는 것이다.In the present invention, step 1 is to combine the compound of formula I with a compound of formula V-1 or V-2.

[화학식 V-1][Formula V-1]

Figure pat00009
Figure pat00009

[화학식 V-2][Formula V-2]

Figure pat00010
Figure pat00010

상기 화학식 V-1 또는 V-2의 화합물은 무수물 또는 수화물일 수 있다. The compound of Formula V-1 or V-2 may be an anhydride or a hydrate.

또한, 상기 단계 1에서 사용되는 용매는 단계 1의 반응을 수행할 수 있는 것이라면 제한 없이 사용될 수 있으며, 예컨대 메탄올, 에탄올, 이소프로판올, 아세톤, 아세토니트릴, 에틸아세테이트, 디클로로메탄, 테트라히드로푸란 또는 이의 혼합용매에서 수행될 수 있다. In addition, the solvent used in step 1 may be used without limitation so long as it can carry out the reaction of step 1, for example methanol, ethanol, isopropanol, acetone, acetonitrile, ethyl acetate, dichloromethane, tetrahydrofuran or mixtures thereof It may be carried out in a solvent.

또한, 상기 단계 1의 반응은 0 내지 50 ℃에서 수행될 수 있으며, 바람직하게는 35 내지 45 ℃에서 수행될 수 있다. In addition, the reaction of step 1 may be carried out at 0 to 50 ℃, preferably may be carried out at 35 to 45 ℃.

본 발명에 있어서, 상기 단계 2에 사용된 염기는 단계 2의 반응을 수행할 수 있는 것이라면 제한 없이 사용될 수 있으며, 예컨대 수산화암모늄, 수산화나트륨, 수산화칼륨 또는 수산화리튬을 사용할 수 있다. 또한, 상기 염기를 사용함으로써 pH를 9.8 ~ 10.5 로 조절하는 것이 바람직하다.In the present invention, the base used in step 2 may be used without limitation so long as it can carry out the reaction of step 2, for example, ammonium hydroxide, sodium hydroxide, potassium hydroxide or lithium hydroxide may be used. Moreover, it is preferable to adjust pH to 9.8-10.5 by using the said base.

또한, 상기 단계 2에서 사용되는 용매는 단계 2의 반응을 수행할 수 있는 것이라면 제한 없이 사용될 수 있으며, 예컨대 디클로로메탄, 에틸아세테이트, 메틸에틸케톤 또는 이의 혼합용매에서 수행될 수 있다.In addition, the solvent used in step 2 may be used without limitation so long as it can carry out the reaction of step 2, for example, may be carried out in dichloromethane, ethyl acetate, methyl ethyl ketone or a mixed solvent thereof.

또한, 상기 단계 2의 반응은 15 내지 30 ℃에서 수행될 수 있으며, 바람직하게는 23 내지 28 ℃에서 수행될 수 있다. In addition, the reaction of step 2 may be carried out at 15 to 30 ℃, preferably may be carried out at 23 to 28 ℃.

본 발명에 있어서, 상기 단계 3은 팔라듐 촉매를 가하여 수행할 수 있다. 상기 팔라듐 촉매는 Pd/C, Pd(OH)2 또는 Pd(OH)2/C 일 수 있다.In the present invention, step 3 may be performed by adding a palladium catalyst. The palladium catalyst may be Pd / C, Pd (OH) 2 or Pd (OH) 2 / C.

상기 단계 3에서, 화학식 III의 화합물, 팔라듐 촉매, 디-터트-부틸-디카보네이트의 반응 몰비는 1:0.03:1 내지 1:0.5:5 일 수 있다. In step 3, the reaction molar ratio of the compound of formula III, palladium catalyst, di-tert-butyl-dicarbonate may be 1: 0.03: 1 to 1: 0.5: 5.

또한, 상기 단계 3에서 사용되는 용매는 단계 3의 반응을 수행할 수 있는 것이라면 제한 없이 사용될 수 있으며, 예컨대 메탄올, 에탄올, 에틸아세테이트, 테트라히드로푸란 및 이들의 혼합물로 이루어진 군에서 선택되는 어느 하나의 용매에서 수행될 수 있다.In addition, the solvent used in step 3 may be used without limitation so long as it can perform the reaction of step 3, for example, any one selected from the group consisting of methanol, ethanol, ethyl acetate, tetrahydrofuran and mixtures thereof. It may be carried out in a solvent.

또한, 상기 단계 3의 반응은 20 내지 35 ℃에서 수행될 수 있으며, 바람직하게는 23 내지 28 ℃에서 수행될 수 있다.In addition, the reaction of step 3 may be carried out at 20 to 35 ℃, preferably may be carried out at 23 to 28 ℃.

본 발명에 있어서, 상기 단계 4에 사용된 염기는 단계 4의 반응을 수행할 수 있는 것이라면 제한 없이 사용될 수 있으며, 예컨대 수산화나트륨, 수산화암모늄, 수산화칼륨 또는 수산화리튬을 사용할 수 있다.In the present invention, the base used in step 4 may be used without limitation so long as it can perform the reaction of step 4, for example, sodium hydroxide, ammonium hydroxide, potassium hydroxide or lithium hydroxide may be used.

또한, 상기 단계 4에서 사용되는 용매는 단계 4의 반응을 수행할 수 있는 것이라면 제한 없이 사용될 수 있으며, 예컨대 정제수, 디클로로메탄, 톨루엔, 에틸아세테이트, 메틸에틸케톤 또는 이의 혼합용매에서 수행될 수 있다.In addition, the solvent used in step 4 may be used without limitation so long as it can perform the reaction of step 4, for example, may be performed in purified water, dichloromethane, toluene, ethyl acetate, methyl ethyl ketone or a mixed solvent thereof.

또한, 상기 단계 4의 반응은 20 내지 40 ℃에서 수행될 수 있으며, 바람직하게는 25 내지 35 ℃에서 수행될 수 있다.In addition, the reaction of step 4 may be carried out at 20 to 40 ℃, preferably may be carried out at 25 to 35 ℃.

본 발명의 제조방법에 따라, 광학활성을 갖는 터트-부틸 3-메틸-4-옥소피페리딘-1-카르복실레이트 (화학식 IV)를 제조할 수 있으며, 이를 중간체로 사용하여 광학 활성을 갖는 의약품을 제조할 수 있다.According to the preparation method of the present invention, tert-butyl 3-methyl-4-oxopiperidine-1-carboxylate (Formula IV) having optical activity can be prepared, which is used as an intermediate to have optical activity. Drugs can be manufactured.

본 발명의 제조방법은 고순도의 광학활성을 갖는 터트-부틸 3-메틸-4-옥소피페리딘-1-카르복실레이트를 고수율로 제조할 수 있다. 또한, 본 발명의 제조방법은 통상적으로 사용 가능한 시약과 용매를 사용함으로써 산업적으로 대량생산이 가능하다. 더 나아가, 본 발명의 제조방법은 화학식 II의 화합물을 제조한 후, 따로 분리된 반대의 광학이성질체를 라세미화시켜 화학식 I의 화합물로 다시 제조하는데 재활용할 수 있으므로, 수율을 더욱 높일 수 있으며 시약의 손실을 줄일 수 있어 경제적이다.The production method of the present invention can prepare tert-butyl 3-methyl-4-oxopiperidine-1-carboxylate having high purity optical activity in high yield. In addition, the production method of the present invention can be industrially mass-produced by using commonly available reagents and solvents. Furthermore, the preparation method of the present invention can prepare a compound of formula (II) and then recycle it to racemate the separated optoisomer separately to prepare it back into a compound of formula (I). It is economical because the loss can be reduced.

본 발명은 광학활성을 갖는 터트-부틸 3-메틸-4-옥소피페리딘-1-카르복실레이트의 제조에 사용되는 새로운 중간체인 하기 화학식 II의 화합물과 화학식 III의 화합물 및 이들의 제조방법을 제공한다. The present invention provides a compound of formula (II), a compound of formula (III) and a method for preparing the same, which are novel intermediates for the preparation of tert-butyl 3-methyl-4-oxopiperidine-1-carboxylate having optical activity. to provide.

[화학식 II][Formula II]

Figure pat00011
Figure pat00011

[화학식 III][Formula III]

Figure pat00012
Figure pat00012

본 발명의 화학식 II의 화합물은 하기 화학식 I의 화합물을 광학분할시키는 단계를 통하여 제조될 수 있다:Compounds of formula (II) of the present invention may be prepared through optical splitting of compounds of formula (I):

[화학식 I][Formula I]

Figure pat00013
Figure pat00013

본 발명에 있어서, 상기 화학식 II의 화합물을 제조하는 방법은 위에서 설명한 단계 1과 동일한 공정으로 수행될 수 있다. In the present invention, the method for preparing the compound of Formula II may be carried out in the same process as in step 1 described above.

또한, 본 발명의 화학식 III의 화합물은 상기 화학식 II의 화합물과 염기를 반응시키는 단계를 통하여 제조될 수 있다. 본 발명에 있어서, 상기 화학식 III의 화합물을 제조하는 방법은 위에서 설명한 단계 2와 동일한 공정으로 수행될 수 있다. In addition, the compound of Formula III of the present invention may be prepared through the step of reacting the compound of Formula II with a base. In the present invention, the method for preparing the compound of Formula III may be carried out in the same process as in step 2 described above.

본 발명의 화학식 II의 화합물 및 화학식 III의 화합물은 광학활성을 갖는 터트-부틸 3-메틸-4-옥소피페리딘-1-카르복실레이트의 제조에 중간체로서 유용하게 사용된다.Compounds of formula (II) and (III) of the present invention are usefully used as intermediates in the preparation of tert-butyl 3-methyl-4-oxopiperidine-1-carboxylates having optical activity.

본 발명에 있어서, 상기 화학식 II의 화합물은 (R)-1-벤질-3-메틸피페리딘-4-온 (2S,3S)-2,3-비스((4-메틸벤조일)옥시)숙신산 염 또는 (S)-1-벤질-3-메틸피페리딘-4-온 (2R,3R)-2,3-비스((4-메틸벤조일)옥시)숙신산 염이다. 본 발명에서, 라세미체의 화학식 I의 화합물을 광학분할시키기 위하여 광학활성을 갖는 2,3-비스((4-메틸벤조일)옥시)숙신산을 사용하며, 화학식 II의 화합물을 99% ee 이상의 광학순도를 가지면서 고수율로 제조할 수 있다. 더불어, 상기 화학식 II의 화합물을 제조한 후 원하지 않는 반대 광학이성질체는 단계 4에서 언급한 바와 같이 염기를 가하여 간단하게 라세미체화시켜 화학식 I의 화합물을 다시 제조할 수 있으므로 재활용이 가능하며, 이를 통하여 전체 공정의 수율을 높이고 생산단가를 개선할 수 있다.In the present invention, the compound of formula II is (R) -1-benzyl-3-methylpiperidin-4-one (2S, 3S) -2,3-bis ((4-methylbenzoyl) oxy) succinic acid Salt or (S) -1-benzyl-3-methylpiperidin-4-one (2R, 3R) -2,3-bis ((4-methylbenzoyl) oxy) succinic acid salt. In the present invention, 2,3-bis ((4-methylbenzoyl) oxy) succinic acid having optical activity is used for optically dividing the compound of formula (I) of the racemate, and the compound of formula (II) is not less than 99% ee It can be produced in high yield with purity. In addition, after preparing the compound of Formula II, the unwanted counter-isomer is recycled because the compound of Formula I can be prepared by simply racemization by adding a base as mentioned in Step 4. It can increase the yield of the whole process and improve the production cost.

본 발명에 있어서, 상기 화학식 III의 화합물은 (R)-1-벤질-3-메틸피페리딘-4-온 또는 (S)-1-벤질-3-메틸피페리딘-4-온이다. 본 발명에서, 상기 화학식 III의 화합물은 화학식 II의 화합물과 마찬가지로 99% ee 이상의 광학순도를 가지면서 고수율로 제조할 수 있으며, 이를 통하여 최종 원하는 물질인 화학식 IV의 화합물 역시 99% ee 이상의 광학순도를 가지면서 고수율로 제조할 수 있다.In the present invention, the compound of formula III is (R) -1-benzyl-3-methylpiperidin-4-one or (S) -1-benzyl-3-methylpiperidin-4-one. In the present invention, the compound of Formula III can be prepared in high yield with an optical purity of 99% ee or more like the compound of Formula II, through which the compound of Formula IV, which is the final desired material, also has an optical purity of 99% ee or more. It can be produced in high yield.

본 발명의 제조방법을 통하여 광학활성을 갖는 터트-부틸 3-메틸-4-옥소피페리딘-1-카르복실레이트를 통상적으로 사용 가능한 시약과 용매를 사용하여, 산업적으로 대량생산이 가능한 방법으로 고순도의 광학활성을 가지면서 고수율로 제조할 수 있다.Tert-butyl 3-methyl-4-oxopiperidine-1-carboxylate having optical activity through the manufacturing method of the present invention using a reagent and a solvent that can be used in a commercial manner, industrially mass production method It can be produced in high yield while having high purity optical activity.

또한, 본 발명의 신규 중간체를 통하여 광학활성을 갖는 터트-부틸 3-메틸-4-옥소피페리딘-1-카르복실레이트를 고순도 및 고수율로 제조할 수 있다.In addition, tert-butyl 3-methyl-4-oxopiperidine-1-carboxylate having optical activity can be prepared with high purity and high yield through the novel intermediate of the present invention.

이하, 하기 실시예 및 실험예를 통하여 본 발명을 보다 상세히 설명하고자 한다. 그러나, 하기 실시예 및 실험예는 본 발명을 예시하기 위한 것으로 이들 실시예 및 실험예에 의하여 본 발명의 범위가 한정되는 것은 아니다. Hereinafter, the present invention will be described in more detail with reference to the following examples and experimental examples. However, the following Examples and Experimental Examples are provided to illustrate the present invention, and the scope of the present invention is not limited by these Examples and Experimental Examples.

실시예 1: (R)-1-벤질-3-메틸피페리딘-4-온 (2S,3S)-2,3-비스((4-메틸벤조일)옥시)숙신산 염 (화학식 II의 화합물)의 제조 Example 1: (R) -1-benzyl-3-methylpiperidin-4-one (2S, 3S) -2,3-bis ((4-methylbenzoyl) oxy) succinic acid salt (compound of formula II) Manufacture

반응기에 아세토니트릴 278.0 kg과 1-벤질-3-메틸피페리딘-4-온 58.9 kg을 투입하고 40±2 ℃로 승온하였다. (2S,3S)-2,3-비스((4-메틸벤조일)옥시)숙신산 수화물 129.0 kg을 투입하였다. 40±2 ℃에서 12±2 시간 동안 교반하였다. 여과 후 아세토니트릴 92.7 kg으로 세척하였다. 40 ℃에서 진공건조하여 표제 화합물 (70.7 kg, 83%, 99% ee)을 수득하였다. 278.0 kg of acetonitrile and 58.9 kg of 1-benzyl-3-methylpiperidin-4-one were added to the reactor, and the temperature was raised to 40 ± 2 ° C. 129.0 kg of (2S, 3S) -2,3-bis ((4-methylbenzoyl) oxy) succinic acid hydrate was added. Stir at 40 ± 2 ° C. for 12 ± 2 hours. After filtration it was washed with 92.7 kg of acetonitrile. Drying in vacuo at 40 ° C. gave the title compound (70.7 kg, 83%, 99% ee).

1H-NMR (400MHz, DMSO-d6): δ = 0.84 (d, 3H), 2.16-2.40 (m, 2H), 2.45 (s, 6H), 2.58-2.71 (m, 3H), 3.08-3.11 (m, 2H), 3.74 (s, 2H), 5.79 (s, 2H), 7.27-7.40 (m, 9), 7.89 (d, 4H) 1 H-NMR (400 MHz, DMSO-d6): δ = 0.84 (d, 3H), 2.16-2.40 (m, 2H), 2.45 (s, 6H), 2.58-2.71 (m, 3H), 3.08-3.11 ( m, 2H), 3.74 (s, 2H), 5.79 (s, 2H), 7.27-7.40 (m, 9), 7.89 (d, 4H)

광학회전: [α]Optical rotation: [α] DD 20 20 = 96.0 °= 96.0 °

([α]([α] DD 2020 : 20 ℃, D line of sodium spectrum (589 nm), 1% solution): 20 ℃, D line of sodium spectrum (589 nm), 1% solution)

실시예 2: (S)-1-벤질-3-메틸피페리딘-4-온 (2R,3R)-2,3-비스((4-메틸벤조일)옥시)숙신산 염 (화학식 II의 화합물)의 제조 Example 2: (S) -1-benzyl-3-methylpiperidin-4-one (2R, 3R) -2,3-bis ((4-methylbenzoyl) oxy) succinic acid salt (compound of formula II) Manufacture

반응기에 아세토니트릴 18.7 kg과 1-벤질-3-메틸피페리딘-4-온 3.4 kg을 투입하고 40±2 ℃로 승온하였다. (2R,3R)-2,3-비스((4-메틸벤조일)옥시)숙신산 수화물 7.4 kg을 투입하였다. 40±2 ℃에서 12±2 시간 교반하였다. 여과 후 아세토니트릴 5.3 kg으로 세척하였다. 40 ℃에서 진공건조하여 표제 화합물 (4.0 kg, 81%, 99% ee)을 수득하였다. 18.7 kg of acetonitrile and 3.4 kg of 1-benzyl-3-methylpiperidin-4-one were added to the reactor, and the temperature was raised to 40 ± 2 ° C. 7.4 kg of (2R, 3R) -2,3-bis ((4-methylbenzoyl) oxy) succinic acid hydrate was added. Stirred at 40 ± 2 ° C. for 12 ± 2 hours. After filtration it was washed with 5.3 kg of acetonitrile. Drying in vacuo at 40 ° C. gave the title compound (4.0 kg, 81%, 99% ee).

1H-NMR (400MHz, DMSO-d6): δ = 0.83 (d, 3H), 2.18-2.27 (m, 2H), 2.40 (s, 6H), 2.56-2.72 (m, 3H), 3.09-3.13 (m, 2H), 3.74 (s, 2H), 5.79 (s, 2H), 7.28-7.40 (m, 9), 7.89 (d, 4H) 1 H-NMR (400 MHz, DMSO-d6): δ = 0.83 (d, 3H), 2.18-2.27 (m, 2H), 2.40 (s, 6H), 2.56-2.72 (m, 3H), 3.09-3.13 ( m, 2H), 3.74 (s, 2H), 5.79 (s, 2H), 7.28-7.40 (m, 9), 7.89 (d, 4H)

실시예 3: (R)-1-벤질-3-메틸피페리딘-4-온 (화학식 III의 화합물)의 제조Example 3: Preparation of (R) -1-benzyl-3-methylpiperidin-4-one (compound of Formula III)

반응기에 디클로로메탄 469.1 kg, 실시예 1에서 제조된 (R)-1-벤질-3-메틸피페리딘-4-온 (2S,3S)-2,3-비스((4-메틸벤조일)옥시)숙신산 염 70.7 kg을 투입하고 정제수 353.5 kg을 투입하고 교반하였다. 수산화암모늄 26.2 L를 투입하여 pH 10으로 조절하였다. 유기층을 분리하고, 정제수 353.5 kg을 투입하고 교반하였다. 유기층을 분리하고, 40 ℃에서 진공농축하여 n-헵탄으로 결정화를 하여 표제 화합물 (22.4 kg, 92%, 99.8% ee)을 수득하였다. 469.1 kg of dichloromethane in the reactor, (R) -1-benzyl-3-methylpiperidin-4-one (2S, 3S) -2,3-bis ((4-methylbenzoyl) oxy, prepared in Example 1 70.7 kg of succinic acid salt was added thereto, and 353.5 kg of purified water was added thereto, followed by stirring. 26.2 L of ammonium hydroxide was added to adjust the pH to 10. The organic layer was separated and 353.5 kg of purified water was added and stirred. The organic layer was separated and concentrated in vacuo at 40 ° C. to crystallize with n-heptane to give the title compound (22.4 kg, 92%, 99.8% ee).

1H-NMR (400MHz, DMSO-d6): δ = 0.85 (d, 3H), 2.03 (t, 1H), 2.16 (d, 1H), 2.33 (t, 1H), 2.53-2.66 (m, 2H), 2.99-3.05 (m, 2H), 3.59 (s, 2H), 7.25-7.35 (m, 5H) 1 H-NMR (400 MHz, DMSO-d6): δ = 0.85 (d, 3H), 2.03 (t, 1H), 2.16 (d, 1H), 2.33 (t, 1H), 2.53-2.66 (m, 2H) , 2.99-3.05 (m, 2H), 3.59 (s, 2H), 7.25-7.35 (m, 5H)

광학회전: [α]Optical rotation: [α] DD 20 20 = 18.3 °= 18.3 °

([α]([α] DD 2020 : 20 ℃, D line of sodium spectrum (589 nm), 1% solution): 20 ℃, D line of sodium spectrum (589 nm), 1% solution)

실시예 4: (S)-1-벤질-3-메틸피페리딘-4-온 (화학식 III의 화합물)의 제조Example 4: Preparation of (S) -1-benzyl-3-methylpiperidin-4-one (compound of Formula III)

반응기에 디클로로메탄 26.4 kg, 실시예 2에서 제조된 (S)-1-벤질-3-메틸피페리딘-4-온 (2R,3R)-2,3-비스((4-메틸벤조일)옥시)숙신산 염 4.0 kg을 투입하고 정제수 19.9 kg을 투입하고 교반하였다. 수산화암모늄 1.5 L를 투입하여 pH 10으로 조절하였다. 유기층을 분리하고, 정제수 19.9 kg을 투입하고 교반하였다. 유기층을 분리하고, 40 ℃에서 진공농축하였다. n-헵탄으로 결정화를 진행하여 표제 화합물 (1.2 kg, 89%, 99.5% ee)을 수득하였다. 26.4 kg dichloromethane in the reactor, (S) -1-benzyl-3-methylpiperidin-4-one (2R, 3R) -2,3-bis ((4-methylbenzoyl) oxy prepared in Example 2 4.0 kg of succinate was added and 19.9 kg of purified water was added thereto and stirred. 1.5 L of ammonium hydroxide was added to adjust the pH to 10. The organic layer was separated and 19.9 kg of purified water was added and stirred. The organic layer was separated and concentrated in vacuo at 40 ° C. Crystallization with n-heptane gave the title compound (1.2 kg, 89%, 99.5% ee).

1H-NMR (400MHz, CDCl3): δ = 1.04 (d, 3H), 2.08 (t, 1H), 2.32-2.54 (m, 2H), 2.60-2.78 (m, 2H), 3.03-3.24 (m, 2H), 3.64 (S, 2H), 7.46 (s, 5H) 1 H-NMR (400 MHz, CDCl 3 ): δ = 1.04 (d, 3H), 2.08 (t, 1H), 2.32-2.54 (m, 2H), 2.60-2.78 (m, 2H), 3.03-3.24 (m , 2H), 3.64 (S, 2H), 7.46 (s, 5H)

실시예 5: 터트-부틸 (R)-3-메틸-4-옥소피페리딘-1-카르복실레이트 (화학식 IV의 화합물)의 제조Example 5: Preparation of tert-butyl (R) -3-methyl-4-oxopiperidine-1-carboxylate (compound of Formula IV)

수소반응기에 아세트산에틸 141.6 kg, 실시예 3에서 제조된 (R)-1-벤질-3-메틸피페리딘-4-온 22.4 kg을 투입하고 교반하여 완전히 용해하였다. 디-터트-부틸 디카보네이트 28.9 kg, 10% 팔라듐/탄소 1.12 kg을 투입하고 교반하였다. 25±2 ℃, 수소 50 psi (3.7±0.2 atm)로 조절하여 24 시간 동안 교반하였다. 반응이 완결되면 팔라듐/탄소를 여과하고 40 ℃에서 진공농축하였다. n-헵탄 15.3 kg 투입 후 0±5 ℃로 냉각하여 결정화하였다. 여과하고 실온에서 진공건조하여 표제 화합물 (21.4 kg, 91%, 99.5% ee)를 수득하였다. 141.6 kg of ethyl acetate and 22.4 kg of (R) -1-benzyl-3-methylpiperidin-4-one prepared in Example 3 were added to a hydrogen reactor, followed by stirring to dissolve completely. 28.9 kg of di-tert-butyl dicarbonate and 1.12 kg of 10% palladium / carbon were added and stirred. The mixture was adjusted to 25 ± 2 ° C. and 50 psi of hydrogen (3.7 ± 0.2 atm) and stirred for 24 hours. Upon completion of the reaction, the palladium / carbon was filtered off and concentrated in vacuo at 40 ° C. After 15.3 kg of n-heptane was added, the mixture was cooled to 0 ± 5 ° C. to crystallize. Filtration and vacuum drying at room temperature gave the title compound (21.4 kg, 91%, 99.5% ee).

1H-NMR (400MHz, CDCl3): δ = 1.02 (d, 3H), 1.47 (s, 9H), 2.36-2.55 (m, 3H), 2.55 (m, 1H), 3.24 (t, 1H), 4.15-4.19 (m, 2H) 1 H-NMR (400 MHz, CDCl 3 ): δ = 1.02 (d, 3H), 1.47 (s, 9H), 2.36-2.55 (m, 3H), 2.55 (m, 1H), 3.24 (t, 1H), 4.15-4.19 (m, 2H)

광학회전: [α]Optical rotation: [α] DD 20 20 = -1.2 °= -1.2 °

([α]([α] DD 2020 : 20 ℃, D line of sodium spectrum (589 nm), 1% solution): 20 ℃, D line of sodium spectrum (589 nm), 1% solution)

실시예 6: 터트-부틸 (S)-3-메틸-4-옥소피페리딘-1-카르복실레이트 (화학식 IV의 화합물)의 제조Example 6: Preparation of Tert-Butyl (S) -3-methyl-4-oxopiperidine-1-carboxylate (Compound of Formula IV)

수소반응기에 아세트산에틸 7.7 kg, 실시예 4에서 제조된 (S)-1-벤질-3-메틸피페리딘-4-온 1.2 kg을 투입하고 교반하여 완전히 용해하였다. 디-터트-부틸 디카보네이트 1.6 kg, 10% 팔라듐/탄소 0.06 kg을 투입하고 교반하였다. 25±2 ℃, 수소 50 psi (3.7±0.2 atm)로 조절하여 24 시간 동안 교반하였다. 반응이 완결되면 팔라듐/탄소를 여과하고 40 ℃에서 진공농축하였다. n-헵탄 1.7 kg 투입 후 0±5 ℃로 냉각하여 결정화하였다. 여과하고, 실온에서 진공건조하여 표제 화합물 (1.0 kg, 78%, 99.2% ee)을 수득하였다. In a hydrogen reactor, 7.7 kg of ethyl acetate and 1.2 kg of (S) -1-benzyl-3-methylpiperidin-4-one prepared in Example 4 were added and stirred to dissolve completely. 1.6 kg of di-tert-butyl dicarbonate and 0.06 kg of 10% palladium / carbon were added and stirred. The mixture was adjusted to 25 ± 2 ° C. and 50 psi of hydrogen (3.7 ± 0.2 atm) and stirred for 24 hours. Upon completion of the reaction, the palladium / carbon was filtered off and concentrated in vacuo at 40 ° C. 1.7 kg of n-heptane was charged and then cooled to 0 ± 5 ° C. to crystallize. Filtration and vacuum drying at room temperature gave the title compound (1.0 kg, 78%, 99.2% ee).

1H-NMR (400MHz, CDCl3): δ = 1.02 (d, 3H), 1.47 (s, 9H), 2.34-2.56 (m, 3H), 2.70-2.89 (m, 1H), 3.22 (t, 1H), 4.16-4.19 (m, 2H) 1 H-NMR (400 MHz, CDCl 3 ): δ = 1.02 (d, 3H), 1.47 (s, 9H), 2.34-2.56 (m, 3H), 2.70-2.89 (m, 1H), 3.22 (t, 1H ), 4.16-4.19 (m, 2H)

실시예 7: 화학식 Example 7: Formula entent -II 및 화학식 II로부터 라세미화를 통한 1-벤질-3-메틸피페리딘-4-온-Benzyl-3-methylpiperidin-4-one via racemization from -II and Formula II (화학식 I의 화합물)의 제조 (recycle)Preparation of (Compound of Formula I)

반응기에 화학식 II의 화합물 (실시예 1)를 제조하고 남은 여액을 투입하고, 45 ℃에서 진공 농축하였다. 0 내지 5 ℃로 냉각하고, 10% NaOH 수용액 83 L를 서서히 투입하였다. 35 내지 40 ℃로 승온하여 6 시간 동안 교반하였다. 디클로로메탄 221.9 kg을 투입하고 30분 교반 후 유기층을 분리하였다. 수층에 디클로로메탄 133.4 kg을 투입하고 30분 교반 후 유기층을 분리하였다. 유기층에 무수황산마그네슘 59 kg을 투입하고 30분 교반 후 여과하였다. 40 ℃에서 진공 농축하여 표제 화합물 (23.6 kg, 80%)을 수득하였다. The compound of formula II (Example 1) was prepared in the reactor, and the remaining filtrate was added thereto and concentrated in vacuo at 45 ° C. It cooled to 0-5 degreeC, and 83 L of 10% NaOH aqueous solution was slowly added. It heated up at 35-40 degreeC and stirred for 6 hours. 221.9 kg of dichloromethane was added thereto, stirred for 30 minutes, and the organic layer was separated. 133.4 kg of dichloromethane was added to the aqueous layer, and the organic layer was separated after stirring for 30 minutes. 59 kg of anhydrous magnesium sulfate was put into the organic layer, and it stirred for 30 minutes, and filtered. Concentration in vacuo at 40 ° C. gave the title compound (23.6 kg, 80%).

1H-NMR (400MHz, CDCl3): δ = 0.85 (d, 3H), 2.02 (t, 1H), 2.16(d, 1H), 2.32 (t, 1H), 2.50-2.67 (m, 2H), 2.98-3.23 (m, 2H), 3.58 (s, 2H), 7.23-7.36 (m, 5H) 1 H-NMR (400 MHz, CDCl 3 ): δ = 0.85 (d, 3H), 2.02 (t, 1H), 2.16 (d, 1H), 2.32 (t, 1H), 2.50-2.67 (m, 2H), 2.98-3.23 (m, 2H), 3.58 (s, 2H), 7.23-7.36 (m, 5H)

실시예 8: 화학식 Example 8: Formula entent -II 및 화학식 II로부터 라세미화를 통한 1-벤질-3-메틸피페리딘-4-온-Benzyl-3-methylpiperidin-4-one via racemization from -II and Formula II (화학식 I의 화합물)의 제조 (recycle)Preparation of (Compound of Formula I)

반응기에 화학식 II의 화합물 (실시예 2)를 제조하고 남은 여액을 투입하고, 45 ℃에서 진공 농축하였다. 0 내지 5 ℃로 냉각하고, 10% NaOH 수용액 4.8 L를 서서히 투입하였다. 35 내지 40 ℃로 승온하여 6 시간 동안 교반하였다. 디클로로메탄 12.8 kg을 투입하고 30분 교반 후 유기층을 분리하였다. 수층에 디클로로메탄 7.7 kg을 투입하고 30분 교반 후 유기층을 분리하였다. 유기층에 무수황산마그네슘 3.4 kg을 투입하고 30분 교반 후 여과하였다. 40 ℃에서 진공 농축하여 표제 화합물 (1.3 kg, 75%)을 수득하였다. The compound of formula II (Example 2) was prepared in the reactor, and the remaining filtrate was added thereto and concentrated in vacuo at 45 ° C. It cooled to 0-5 degreeC, and added 4.8 L of 10% NaOH aqueous solution gradually. It heated up at 35-40 degreeC and stirred for 6 hours. 12.8 kg of dichloromethane was added thereto, and the organic layer was separated after stirring for 30 minutes. 7.7 kg of dichloromethane was added to the aqueous layer, and the organic layer was separated after stirring for 30 minutes. 3.4 kg of anhydrous magnesium sulfate was put into the organic layer, and it stirred for 30 minutes, and filtered. Concentration in vacuo at 40 ° C. gave the title compound (1.3 kg, 75%).

1H-NMR (400MHz, CDCl3): δ = 0.85 (d, 3H), 2.02 (t, 1H), 2.16(d, 1H), 2.32 (t, 1H), 2.50-2.67 (m, 2H), 2.98-3.23 (m, 2H), 3.58 (s, 2H), 7.23-7.36 (m, 5H) 1 H-NMR (400 MHz, CDCl 3 ): δ = 0.85 (d, 3H), 2.02 (t, 1H), 2.16 (d, 1H), 2.32 (t, 1H), 2.50-2.67 (m, 2H), 2.98-3.23 (m, 2H), 3.58 (s, 2H), 7.23-7.36 (m, 5H)

Claims (19)

하기 화학식 II의 화합물:
[화학식 II]
Figure pat00014
A compound of formula II:
[Formula II]
Figure pat00014
 제 1 항에 있어서, 상기 화학식 II의 화합물은,
(R)-1-벤질-3-메틸피페리딘-4-온 (2S,3S)-2,3-비스((4-메틸벤조일)옥시)숙신산 염; 또는
(S)-1-벤질-3-메틸피페리딘-4-온 (2R,3R)-2,3-비스((4-메틸벤조일)옥시)숙신산 염;
인 화합물.The compound of claim 1, wherein
(R) -1-benzyl-3-methylpiperidin-4-one (2S, 3S) -2,3-bis ((4-methylbenzoyl) oxy) succinic acid salt; or
(S) -1-benzyl-3-methylpiperidin-4-one (2R, 3R) -2,3-bis ((4-methylbenzoyl) oxy) succinic acid salt;
Phosphorus compounds. 하기 화학식 I의 화합물을 광학분할시키는 단계를 포함하는, 하기 화학식 II의 화합물을 제조하는 방법:
[화학식 I]
Figure pat00015

[화학식 II]
Figure pat00016
A process for preparing a compound of formula II comprising optically splitting a compound of formula I:
[Formula I]
Figure pat00015

[Formula II]
Figure pat00016
 하기 화학식 III의 화합물:
[화학식 III]
Figure pat00017
A compound of formula III:
[Formula III]
Figure pat00017
 제 4 항에 있어서, 상기 화학식 III의 화합물은,
(R)-1-벤질-3-메틸피페리딘-4-온; 또는
(S)-1-벤질-3-메틸피페리딘-4-온;
인 화합물.The compound of claim 4, wherein
(R) -1-benzyl-3-methylpiperidin-4-one; or
(S) -1-benzyl-3-methylpiperidin-4-one;
Phosphorus compounds. 제1항에 따른 화학식 II의 화합물과 염기를 반응시키는 단계를 포함하는, 하기 화학식 III의 화합물을 제조하는 방법:
[화학식 III]
Figure pat00018
A process for preparing a compound of formula III comprising reacting a compound of formula II according to claim 1 with a base:
[Formula III]
Figure pat00018
 하기 화학식 I의 화합물을 광학분할시켜 하기 화학식 II의 화합물을 제조하는 단계 (단계 1)를 포함하는, 하기 화학식 IV의 화합물의 제조방법:
[화학식 I]
Figure pat00019

[화학식 II]
Figure pat00020

[화학식 IV]
Figure pat00021
A process for preparing a compound of formula (IV) comprising the step (step 1) of preparing a compound of formula (II) by optically splitting a compound of formula (I):
[Formula I]
Figure pat00019

[Formula II]
Figure pat00020

[Formula IV]
Figure pat00021
 제 7 항에 있어서, 상기 화학식 II의 화합물과 염기를 반응시켜 하기 화학식 III의 화합물을 제조하는 단계 (단계 2)를 더 포함하는 제조방법:
[화학식 III]
Figure pat00022
The method of claim 7, further comprising the step of preparing a compound of formula III by reacting the compound of formula II with a base (step 2):
[Formula III]
Figure pat00022
 제 8 항에 있어서, 상기 화학식 III의 화합물과 디-터트-부틸-디카보네이트를 반응시켜 상기 화학식 IV의 화합물을 제조하는 단계 (단계 3)를 더 포함하는 제조방법.The method of claim 8, further comprising the step (step 3) of preparing the compound of Formula IV by reacting the compound of Formula III with di-tert-butyl-dicarbonate. 제 8 항에 있어서, 상기 단계 1에서 화학식 II의 화합물을 제조한 후 반대의 광학이성질체에 염기를 가하여 라세미화시켜 상기 화학식 I의 화합물을 다시 제조하고 이를 단계 1에서 재사용하는 단계 (단계 4)를 더 포함하는 제조방법.The method according to claim 8, wherein the compound of formula II is prepared in step 1, and then racemized by adding a base to the opposite optical isomer to prepare a compound of formula I and reuse it in step 1 (step 4) Further comprising the manufacturing method. 제 7 항에 있어서, 상기 단계 1은 화학식 I의 화합물을 하기 화학식 V-1 또는 V-2의 화합물과 결합시키는 것인 제조방법:
[화학식 V-1]
Figure pat00023

[화학식 V-2]
Figure pat00024
The method of claim 7, wherein the step 1 combines a compound of Formula I with a compound of Formula V-1 or V-2:
[Formula V-1]
Figure pat00023

[Formula V-2]
Figure pat00024
 제 7 항에 있어서, 상기 단계 1은 메탄올, 에탄올, 이소프로판올, 아세톤, 아세토니트릴, 에틸아세테이트, 디클로로메탄, 테트라히드로푸란 또는 이의 혼합용매에서 수행되는 것인 제조방법.The method of claim 7, wherein step 1 is performed in methanol, ethanol, isopropanol, acetone, acetonitrile, ethyl acetate, dichloromethane, tetrahydrofuran or a mixed solvent thereof. 제 7 항에 있어서, 상기 단계 1은 0 내지 50 ℃에서 수행되는 것인 제조방법.The method of claim 7, wherein step 1 is carried out at 0 to 50 ℃. 제 8 항에 있어서, 상기 단계 2의 염기는 수산화암모늄, 수산화나트륨, 수산화칼륨 또는 수산화리튬인 제조방법. The method of claim 8, wherein the base of step 2 is ammonium hydroxide, sodium hydroxide, potassium hydroxide or lithium hydroxide. 제 8 항에 있어서, 상기 단계 2에서 pH 9.8 내지 10.5 로 조절하는 것인 제조방법. The method of claim 8, wherein the step 2 is adjusted to pH 9.8 to 10.5. 제 9 항에 있어서, 상기 단계 3은 팔라듐 촉매를 사용하는 것인 제조방법.10. The process according to claim 9, wherein step 3 uses a palladium catalyst. 제 16 항에 있어서, 상기 팔라듐 촉매는 Pd/C, Pd(OH)2 또는 Pd(OH)2/C 인 제조방법 The method of claim 16, wherein the palladium catalyst is Pd / C, Pd (OH) 2 or Pd (OH) 2 / C. 제 9 항에 있어서, 상기 단계 3은 메탄올, 에탄올, 에틸아세테이트, 테트라히드로푸란 및 이들의 혼합물로 이루어진 군에서 선택되는 어느 하나의 용매 하에서 수행되는 제조방법.The method of claim 9, wherein step 3 is performed under any one solvent selected from the group consisting of methanol, ethanol, ethyl acetate, tetrahydrofuran and mixtures thereof. 제 10 항에 있어서, 상기 단계 4의 염기는 수산화나트륨, 수산화암모늄, 수산화칼륨 또는 수산화리튬인 제조방법.The method of claim 10, wherein the base of step 4 is sodium hydroxide, ammonium hydroxide, potassium hydroxide or lithium hydroxide.
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Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004041777A2 (en) 2002-10-30 2004-05-21 Merck & Co., Inc. Heteroarylpiperidine modulators of chemokine receptor activity
WO2004058709A1 (en) 2002-12-23 2004-07-15 Millennium Pharmaceuticals, Inc. Ccr8 inhibitors
WO2005040169A2 (en) 2003-09-17 2005-05-06 Janssen Pharmaceutica, N.V. Fused heterocyclic compounds as serotonin receptor modulators
WO2008119718A1 (en) 2007-03-29 2008-10-09 Glaxo Group Limited Compounds which have activity at m1 receptor and their uses in medicine
WO2009106534A1 (en) 2008-02-26 2009-09-03 H. Lundbeck A/S Novel heterocyclic carboxamides as m1 agonists
WO2010051374A1 (en) 2008-10-31 2010-05-06 Pain Therapeutics, Inc. Analgesic that binds filamin a
WO2013021052A1 (en) 2011-08-10 2013-02-14 Janssen R&D Ireland Antibacterial piperidinyl substituted 3,4-dihydro-1h-[1,8]naphthyridinones
WO2013181579A2 (en) 2012-05-31 2013-12-05 Eisai R & D Management Co., Ltd. Tetrahydropyrazolopyrimidine compounds
WO2014023815A1 (en) 2012-08-10 2014-02-13 Janssen R&D Ireland New antibacterial compounds
WO2016120850A1 (en) 2015-01-30 2016-08-04 Pfizer Inc. Sulfonamide-subsituted indole modulators of rorc2 and methods of use thereof
WO2016120849A1 (en) 2015-01-30 2016-08-04 Pfizer Inc. Methoxy-substituted pyrrolopyridine modulators of rorc2 and methods of use thereof

Patent Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004041777A2 (en) 2002-10-30 2004-05-21 Merck & Co., Inc. Heteroarylpiperidine modulators of chemokine receptor activity
WO2004058709A1 (en) 2002-12-23 2004-07-15 Millennium Pharmaceuticals, Inc. Ccr8 inhibitors
WO2005040169A2 (en) 2003-09-17 2005-05-06 Janssen Pharmaceutica, N.V. Fused heterocyclic compounds as serotonin receptor modulators
WO2008119718A1 (en) 2007-03-29 2008-10-09 Glaxo Group Limited Compounds which have activity at m1 receptor and their uses in medicine
WO2009106534A1 (en) 2008-02-26 2009-09-03 H. Lundbeck A/S Novel heterocyclic carboxamides as m1 agonists
WO2010051374A1 (en) 2008-10-31 2010-05-06 Pain Therapeutics, Inc. Analgesic that binds filamin a
WO2013021052A1 (en) 2011-08-10 2013-02-14 Janssen R&D Ireland Antibacterial piperidinyl substituted 3,4-dihydro-1h-[1,8]naphthyridinones
WO2013181579A2 (en) 2012-05-31 2013-12-05 Eisai R & D Management Co., Ltd. Tetrahydropyrazolopyrimidine compounds
WO2014023815A1 (en) 2012-08-10 2014-02-13 Janssen R&D Ireland New antibacterial compounds
WO2016120850A1 (en) 2015-01-30 2016-08-04 Pfizer Inc. Sulfonamide-subsituted indole modulators of rorc2 and methods of use thereof
WO2016120849A1 (en) 2015-01-30 2016-08-04 Pfizer Inc. Methoxy-substituted pyrrolopyridine modulators of rorc2 and methods of use thereof

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