KR102213991B1 - An Improved manufacturing method of Zabofloxacin - Google Patents
An Improved manufacturing method of Zabofloxacin Download PDFInfo
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- KR102213991B1 KR102213991B1 KR1020140060112A KR20140060112A KR102213991B1 KR 102213991 B1 KR102213991 B1 KR 102213991B1 KR 1020140060112 A KR1020140060112 A KR 1020140060112A KR 20140060112 A KR20140060112 A KR 20140060112A KR 102213991 B1 KR102213991 B1 KR 102213991B1
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- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/10—Spiro-condensed systems
Abstract
본 발명은 자보플록사신 D-아스파르트산염의 개선된 제조방법에 관한 것이다.
본 발명은 자보플록사신 D-아스파르트산염을 제조하기 위하여 사용하는 출발물질인 8-메톡시이미노-2,6-디아자-스피로[3,4]옥탄-2-카르복실산 t-부틸에스테르 숙신산염(TBDCS) 또는 2-(2,2,2-트리플루오로-아세틸)-2,6-디아자-스피로[3.4]옥탄-8-온 O-메틸옥심 메탄설폰산염(TDMOS)의 신규한 제조방법을 제공한다.
본 발명에 따른 제조방법은 상기 출발물질을 높은 수율과 높은 품질(HPLC 순도; 99.5% 이상)로 제조할 수 있어, 대량생산에 적합하며, 치환반응시 TBDCS나 TDMOS를 1.0~1.1 당량을 사용하여 획기적으로 생산단가를 절감할 수 방법을 제공하기 때문에 자보플록사신 D-아스파르트산염의 대량생산에 유용하게 이용될 수 있다.The present invention relates to an improved method for preparing zabofloxacin D-aspartate.
The present invention is a starting material used to prepare zabofloxacin D-aspartate, 8-methoxyimino-2,6-diaza-spiro[3,4]octane-2-carboxylic acid t-butyl ester succinic acid Salt (TBDCS) or 2-(2,2,2-trifluoro-acetyl)-2,6-diaza-spiro[3.4]octane-8-one O -methyloxime methanesulfonate (TDMOS) Provides a manufacturing method.
The manufacturing method according to the present invention can prepare the starting material in high yield and high quality (HPLC purity; 99.5% or more), so it is suitable for mass production, and when the substitution reaction is performed, 1.0 to 1.1 equivalents of TBDCS or TDMOS are used. It can be usefully used in mass production of zabofloxacin D-aspartate because it provides a method to dramatically reduce production cost.
Description
본 발명은 자보플록사신 D-아스파르트산염의 개선된 제조방법에 관한 것이다.
The present invention relates to an improved method for preparing zabofloxacin D-aspartate.
자보플록사신은 그램 음성균 뿐만 아니라 그램 양성균에도 우수한 항균력을 나타내며, 특히 기존의 퀴놀론 내성균주 및 메티실린 내성균에도 탁월한 효과를 발휘하는 퀴놀론카르복실산 항균제로서, 그 화학명은 1-시클로프로필-6-플루오로-7-(8-메톡시이미노-2,6-디아자-스피로[3,4]옥트-6-일)-4-옥소-1,4-디히드로-[1,8]나프티리딘-3-카르복실산이고, 미국특허공보 제6,313,299호에 상기 화합물과 그의 제조방법이 개시되어 있다.
Zabofloxacin is a quinolone carboxylic acid antibacterial agent that exhibits excellent antibacterial activity against not only gram-negative bacteria but also gram-positive bacteria, and is particularly effective against existing quinolones-resistant bacteria and methicillin-resistant bacteria.The chemical name is 1-cyclopropyl-6-fluoro. Rho-7-(8-methoxyimino-2,6-diaza-spiro[3,4]oct-6-yl)-4-oxo-1,4-dihydro-[1,8]naphthyridine- It is a 3-carboxylic acid, and U.S. Patent Publication No. 6,313,299 discloses the compound and its preparation method.
또한, 미국특허공보 제8,324,238호에는 하기 화학식 1로 표시되는 자보플록사신 D-아스파르트산염이 개시되어 있는데, 하기 자보플록사신 D-아스파르트산염은 통상적으로 제조될 수 있는 인산염, 염산염 등에 비해 용해도가 현저히 뛰어날 뿐만 아니라, 안정성 등의 물리화학적 성질도 우수하고, 독성이 거의 없는 것으로 알려져 있다.In addition, U.S. Patent Publication No. 8,324,238 discloses zabofloxacin D-aspartate represented by the following formula (1), and the following zabofloxacin D-aspartate has a significantly higher solubility than phosphate, hydrochloride, etc. In addition to being excellent, it is known to be excellent in physicochemical properties such as stability and almost no toxicity.
<화학식 1><Formula 1>
상기 미국특허공보 제6,313,299호 및 제8,324,238호에는 하기 화학식 3 화합물인 7-클로로-1-시클로프로필-6-플루오로-4-옥소-1,4-디히드로[1,8]나프티리딘-3- 카르복실산의 염소 위치에서 치환반응 시켜 자보플록사신을 제조하는 방법이 개시되어 있다.In the US Patent Publication Nos. 6,313,299 and 8,324,238, 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro[1,8]naphthyridine-3, which is a compound of Formula 3 -A method of producing zabofloxacin by carrying out a substitution reaction at the chlorine position of a carboxylic acid is disclosed.
<화학식 3><Formula 3>
상기 미국특허공보에는 상기 화학식 3 화합물의 염소 위치에 치환되는 물질의 제조방법이 개시되어 있는데, 그 반응식을 도시하면 하기 <반응식 1>과 같다.The US Patent Publication discloses a method of preparing a substance substituted at the chlorine position of the compound of Formula 3, and the reaction scheme is shown in <Reaction Scheme 1> below.
<반응식 1><Reaction Scheme 1>
상기 반응식 1에서 화합물 8인 1-벤질-4-에톡시카르보닐-피롤리딘-3-온 화합물을 사용하여 화합물 9인 t-부틸-8-(메톡시이미노)-2,6-디아자스피로[3.4]옥탄-2-카르복실레이트(TBDC)를 제조하는 것인데, 상기 반응식 1은 아자이드기를 환원반응 하기 위하여 라니니켈과 수소 압력하에서 반응을 진행하여야 하며, 벤질 보호기를 제거하기 위하여 팔라듐과 수소 압력하에서 반응시켜야 하기 때문에, 반응 공정이 길며, 두 단계의 공정에서 고가의 라니니켈과 팔라듐을 사용하고 수소압력 하에서 반응을 진행하기 때문에 상업적으로 생산하는데 위험성이 있고 적절치 않다. 또한 상기 반응식 1에서 제조되는 화합물 9는 액체상태로 안정하지 않아 취급 및 보관시 어려움이 있으며, 상기 화학식 3 화합물과 염소 위치에서 치환반응시에 2.3 당량 사용하여야 하는데, 매우 고가라는 점이 단점이다.
Compound 9 t-butyl-8-(methoxyimino)-2,6-diazas using compound 8, 1-benzyl-4-ethoxycarbonyl-pyrrolidin-3-one compound in Scheme 1 To prepare pyro[3.4]octane-2-carboxylate (TBDC), in Scheme 1, the reaction must be carried out with Ranickel under hydrogen pressure to reduce the azide group, and palladium and palladium must be used to remove the benzyl protecting group. Since the reaction must be carried out under hydrogen pressure, the reaction process is long, and because expensive Ranickel and palladium are used in the two-stage process, and the reaction proceeds under hydrogen pressure, there is a risk for commercial production and is not appropriate. In addition, compound 9 prepared in Reaction Scheme 1 is not stable in a liquid state, so it is difficult to handle and store, and it must be used in an amount of 2.3 equivalents in the substitution reaction at the chlorine position with the compound of Chemical Formula 3, which is very expensive.
본 발명자들은 자보플록사신 D-아스파르트산염의 제조방법을 연구한 끝에 종래 출발물질로 사용된 화학식 9 화합물 대신 신규의 출발물질로부터 상기 화학식 3 화합물의 염소 위치를 치환시켜 목적 화합물을 높은 수율과 높은 품질(HPLC 순도; 99.5% 이상)로 상업적으로 생산할 수 있는 제조방법을 발견하고 연구한 끝에 본 발명을 완성하였다.
After studying the method for preparing zabofloxacin D-aspartate, the present inventors substituted the chlorine position of the compound of Formula 3 from the novel starting material instead of the compound of Formula 9 used as the conventional starting material to obtain the target compound in high yield and high quality. (HPLC purity; 99.5% or more), the present invention was completed after discovering and researching a method that can be commercially produced.
본 발명은 7-클로로-1-시클로프로필-6-플루오로-4-옥소-1,4-디히드로[1,8]나프티리딘-3-카르복실산(화학식 3 화합물)의 염소 위치를 치환시켜 목적화합물인 자보플록사신 D-아스파르트산염을 높은 수율과 높은 품질(HPLC 순도; 99.5% 이상)로 상업적으로 생산할 수 있는 신규의 출발물질을 제공하고자 한다.
The present invention replaces the chlorine position of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxylic acid (chemical formula 3 compound) Thus, it is intended to provide a novel starting material that can commercially produce the target compound, zabofloxacin D-aspartate, in high yield and high quality (HPLC purity; 99.5% or more).
또한, 본 발명은 상기 출발물질의 신규한 제조방법을 이용한 자보플록사신 또는 자보플록사신 D-아스파르트산염의 제조방법을 제공하고자 한다.
In addition, the present invention is to provide a method for preparing zabofloxacin or zabofloxacin D-aspartate using the novel method for preparing the starting material.
상기 목적을 달성하기 위하여 본 발명은 자보플록사신 D-아스파르트산염을 제조하기 위하여 사용되는 하기 화학식 6 화합물인 8-메톡시이미노-2,6-디아자-스피로 [3,4]옥탄-2-카르복실산 t-부틸에스테르 숙신산염(TBDCS) 및 이의 신규한 제조방법을 제공한다.In order to achieve the above object, the present invention is an 8-methoxyimino-2,6-diaza-spiro [3,4]octane-2- which is a compound of the following formula 6 used to prepare zabofloxacin D-aspartate. It provides a carboxylic acid t-butyl ester succinate (TBDCS) and a novel method for preparing the same.
<화학식 6><Formula 6>
상기 본 발명에 따른 화학식 6 화합물을 상기 화학식 3 화합물의 염소 위치를 치환시키는데 사용하는 경우, 상기 화학식 6 화합물은 고체상태로 안정하고 취급 및 보관이 용이할 뿐만 아니라, 목적화합물인 자보플록사신 D-아스파르트산염을 높은 수율과 높은 품질(HPLC 순도; 99.5% 이상)로 상업적으로 생산할 수 있다.
When the compound of Formula 6 according to the present invention is used to replace the chlorine position of the compound of Formula 3, the compound of Formula 6 is stable in a solid state and easy to handle and store, as well as the target compound, zabofloxacin D- Aspartate can be produced commercially in high yield and high quality (HPLC purity; 99.5% or more).
상기 본 발명에 따른 화학식 6 화합물의 신규한 제조방법을 도식화하면 하기 <반응식 2>로 표시할 수 있다.Schematic of the novel method for preparing the compound of Formula 6 according to the present invention can be represented by the following <Scheme 2>.
<반응식 2><Reaction Scheme 2>
상기 반응식 2에서 Cbz-는 벤질옥시카르보닐기, Boc-는 t-부틸옥시카르보닐기, Ms-는 메탄설포닐기를 나타낸다.
In Scheme 2, Cbz- represents a benzyloxycarbonyl group, Boc- represents a t-butyloxycarbonyl group, and Ms- represents a methanesulfonyl group.
상기 반응식 2를 구체적으로 설명하면 하기와 같다.The detailed description of Scheme 2 is as follows.
ⅰ) 하기 화학식 12 화합물인 3-시아노-4-옥소-피롤리딘-1-카르복실산 벤질에스테르 화합물을 사용하여 메톡시아민염산염과 반응 후 중간체를 분리하지 않고 동일한 반응기 내에서 포름알데히드수용액과 반응하여 하기 화학식 13 화합물인 3-시아노-3-히드록시메틸-4-메톡시이미노-피롤리딘-1-카르복실산벤질에스테르 화합물을 제조한다.I) Aqueous formaldehyde solution in the same reactor without separating the intermediate after reaction with methoxyamine hydrochloride using a 3-cyano-4-oxo-pyrrolidine-1-carboxylic acid benzyl ester compound of the following formula 12 And to prepare a 3-cyano-3-hydroxymethyl-4-methoxyimino-pyrrolidine-1-carboxylic acid benzyl ester compound of the following formula (13).
<화학식 12><Formula 12>
<화학식 13><Formula 13>
ⅱ) 상기 화학식 13 화합물을 메탄설포닐클로라이드를 사용하여 메실화반응을 진행하여 하기 화학식 14 화합물인 3-시아노-3-메탄설포닐옥시메틸-4-메톡시이미노-피롤리딘-1-카르복실산벤질에스테르 화합물을 제조한 후 소디움보로하이드라이드와 리튬클로라이드를 사용하여 질소기류하에서 니트릴기를 환원반응하여 하기 화학식 15 화합물인 3-아미노메틸-3-메탄설포닐옥시메틸-4-메톡시이미노-피롤리딘-1-카르복실산벤질에스테르 화합물을 제조한다.Ii) The mesylation reaction of the compound of Formula 13 was carried out using methanesulfonyl chloride, and the compound of the following Formula 14, 3-cyano-3-methanesulfonyloxymethyl-4-methoxyimino-pyrrolidine-1- After preparing the benzyl carboxylic acid compound, sodium borohydride and lithium chloride were used to reduce the nitrile group under nitrogen flow, and the following formula 15 compound 3-aminomethyl-3-methanesulfonyloxymethyl-4-me Toxiimino-pyrrolidine-1-carboxylic acid benzyl ester compound is prepared.
<화학식 14><Formula 14>
<화학식 15><Formula 15>
이 때, 니트릴기를 환원시키기 위한 환원제로는 소디움보로하이드라이드-리튬클로라이드 혼합체(NaBH4-LiCl), 소디움보로하이드라이드-코발트클로라이드 혼합체(NaBH4-CoCl2), 소디움보로하이드라이드-니켈클로라이드 혼합체(NaBH4-NiCl2)를 사용할 수 있으며, 바람직하게는 소디움보로하이드라이드-리튬클로라이드 혼합체(NaBH4-LiCl)를 사용하여 질소기류 하에서 반응할 때 비교적 높은 수율로 제조할 수 있다.
At this time, as a reducing agent for reducing the nitrile group, sodium borohydride-lithium chloride mixture (NaBH 4 -LiCl), sodium borohydride-cobalt chloride mixture (NaBH 4 -CoCl 2 ), sodium borohydride- Nickel chloride mixture (NaBH 4 -NiCl 2 ) can be used, preferably sodium borohydride-lithium chloride mixture (NaBH 4 -LiCl) can be prepared in a relatively high yield when reacted under a nitrogen stream. .
ⅲ) 상기 화학식 15 화합물을 에탄올에서 가열하여 고리화 반응을 진행 후 프탈산을 사용하여 하기 화학식 16 화합물인 8-메톡시이미노-2,6-디아자-스피로[3.4]옥탄-6-카르복실산벤질에스테르프탈산을 제조한다.Iii) 8-methoxyimino-2,6-diaza-spiro[3.4]octane-6-carboxylic acid, which is a compound of the following formula 16, using phthalic acid after heating the compound of Formula 15 in ethanol to perform a cyclization reaction. Benzylesterphthalic acid is prepared.
<화학식 16><Formula 16>
ⅳ) 상기 화학식 16 화합물의 자유염기에 인산, 황산 등의 무기산과 메탄설폰산, p-톨루엔설폰산, 옥살산, 말레인산, 타르타르산, 푸마르산, 만데르산, 벤조산, 프탈산 등의 유기산을 사용하여 염을 제조할 수 있으며, 특히 프탈산이 안정한 상태로 양호한 결과를 얻을 수 있다.
Iv) In the free base of the compound of Formula 16, inorganic acids such as phosphoric acid and sulfuric acid and organic acids such as methanesulfonic acid, p -toluenesulfonic acid, oxalic acid, maleic acid, tartaric acid, fumaric acid, manderic acid, benzoic acid, and phthalic acid are used to prepare a salt. It can be produced, and in particular, good results can be obtained in a stable state of phthalic acid.
상기 화학식 16 화합물에 Di-t-부틸디카보네이트를 사용하여 아제티딘고리의 아민기를 t-부톡시카르보닐기로 보호한 후 벤질옥시카르보닐기는 팔라듐-활성탄을 사용하여 수소 압력하에서 반응하여 탈보호 반응을 시킨 다음 숙신산을 사용하여 상기 화학식 6 화합물인 8-메톡시이미노-2,6-디아자-스피로[3.4]옥탄-2-카르복실산 t-부틸에스테르 숙신산염(TBDCS)을 얻을 수 있다.
After protecting the amine group of the azetidine ring with t-butoxycarbonyl group using Di-t-butyldicarbonate in the compound of Formula 16, the benzyloxycarbonyl group was reacted under hydrogen pressure using palladium-activated carbon for deprotection reaction. The following succinic acid may be used to obtain 8-methoxyimino-2,6-diaza-spiro[3.4]octane-2-carboxylic acid t-butyl ester succinate (TBDCS), which is the compound of Formula 6 above.
또한, 화학식 6 화합물은 자유염기 형태로 제조될 수 있으며, 또는 메탄설폰산, p-톨루엔설폰산, 아세트산, 시트르산, 말레인산, 숙신산, 옥살산, 벤조산, 타르타르산, 푸마르산, 글루쿠론산의 유기산과 반응하여 유기산염의 형태로 제조될 수 있는데, 특히 화학식 6 화합물인 숙신산염이 안정한 상태로 양호한 결과를 얻을 수 있다.
In addition, the compound of Formula 6 may be prepared in the form of a free base, or reacted with organic acids such as methanesulfonic acid, p -toluenesulfonic acid, acetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, and glucuronic acid. It can be prepared in the form of an organic acid salt, in particular, the succinate of the formula 6 compound can obtain good results in a stable state.
상기와 같이, 신규한 방법에 의해 제조된 화학식 6 화합물(TBDCS)은 하기 화학식 3 화합물인 7-클로로-1-시클로프로필-6-플루오로-4-옥소-1,4-디히드로[1,8]나프티리딘-3-카르복실산과 반응을 진행하여 최종 목적 화합물인 화학식 1의 자보플록사신 D-아스파르트산염을 제조할 수 있다.As described above, the compound of Formula 6 (TBDCS) prepared by the novel method is 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro[1, 8] The reaction with naphthyridine-3-carboxylic acid can be carried out to prepare the final target compound, zabofloxacin D-aspartate of the formula (1).
<화학식 1><Formula 1>
<화학식 3><Formula 3>
상기 화학식 6 화합물과 화학식 3 화합물을 반응시켜 목적화합물인 자보플록사신 D-아스파르트산염을 제조하는 반응도식을 <반응식 3>으로 나타내었다.The reaction scheme for preparing the target compound, zabofloxacin D-aspartate, by reacting the compound of Formula 6 with the compound of Formula 3 is shown in <Scheme 3>.
<반응식 3><Reaction Scheme 3>
ⅴ) 상기 ⅳ) 단계에서 제조된 화학식 6 화합물인 8-메톡시이미노-2,6-디아자-스피로[3.4]옥탄-2-카르복실산 t-부틸에스테르 숙신산(TBDCS)과 상기 화학식 3화합물인 7-클로로-1-시클로프로필-6-플루오로-4-옥소-1,4-디히드로[1,8]나프티리딘-3-카르복실산을 사용하여 치환반응 시켜 화학식 7 화합물인 7-(2-t-부톡시카르보닐-8-메톡시이미노-2,6-디아자-스피로[3,4]옥트-6-일)-1-시클로프로필-6-플루오로-4-옥소-1,4-디히드로[1,8]나프티리딘-3-카르복실산을 제조하고, 이 화합물을 트리플루오로아세트산을 사용하여 t-부틸옥시카르보닐기를 탈보호 반응시킨 후 염산염으로 치환하여 자보플록사신 염산염인 화학식 23 화합물을 제조한 다음 수산화나트륨, 탄산나트륨, 탄산수소나트륨, 탄산칼륨, 탄산수소칼륨, 수산화칼륨, 수산화리튬과 같은 무기염기를 사용하여 중화반응 시켜 화학식 2 화합물인 1-시클로프로필-6-플루오로-7-(8-메톡시이미노-2,6-디아자-스피로[3,4]옥트-6-일)-4-옥소-1,4-디히드로-[1,8]나프티리딘-3-카르복실산(자보플록사신)을 제조하고, D-아스파르트산을 사용하여 최종 목적 화합물인 화학식 1 화합물을 제조할 수 있다.
V) 8-methoxyimino-2,6-diaza-spiro[3.4]octane-2-carboxylic acid t-butyl ester succinic acid (TBDCS) and the compound of Formula 3, which is the compound of Formula 6 prepared in step iv) Phosphorous 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxylic acid was used to perform a substitution reaction to obtain the compound 7- (2-t-Butoxycarbonyl-8-methoxyimino-2,6-diaza-spiro[3,4]oct-6-yl)-1-cyclopropyl-6-fluoro-4-oxo- 1,4-dihydro[1,8]naphthyridine-3-carboxylic acid was prepared, and this compound was subjected to a deprotection reaction of the t-butyloxycarbonyl group using trifluoroacetic acid, and then substituted with hydrochloride to zabofloc. After preparing the compound of Formula 23, which is sashin hydrochloride, it is neutralized using an inorganic base such as sodium hydroxide, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, potassium hydroxide, and lithium hydroxide to form 1-cyclopropyl- 6-Fluoro-7-(8-methoxyimino-2,6-diaza-spiro[3,4]oct-6-yl)-4-oxo-1,4-dihydro-[1,8] Naphthyridine-3-carboxylic acid (zabofloxacin) is prepared, and D-aspartic acid can be used to prepare the final target compound, the compound of Formula 1.
또한, 본 발명은 자보플록사신 D-아스파르트산염을 제조하기 위하여 사용되는 다른 형태의 출발물질로 하기 화학식 4 화합물인 2-(2,2,2-트리플루오로-아세틸)-2,6-디아자-스피로[3.4]옥탄-8-온 O-메틸옥심 메탄설폰산염(TDMOS) 화합물 및 이의 제조방법을 제공한다.In addition, the present invention is another type of starting material used to prepare zabofloxacin D-aspartate, 2-(2,2,2-trifluoro-acetyl)-2,6-dia Ja-spiro[3.4]octane-8-one O -methyloxime methanesulfonate (TDMOS) compound and a method for preparing the same are provided.
<화학식 4><Formula 4>
상기 본 발명에 따른 화학식 4 화합물을 사용하여 상기 화학식 3 화합물의 염소 위치를 치환시켜 목적화합물인 자보플록사신 D-아스파르트산염을 제조하는 경우, 높은 수율과 높은 품질(HPLC 순도; 99.5% 이상)로 제조할 수 있으며, 대량생산에 적합하다.
In the case where the target compound, zabofloxacin D-aspartate, is prepared by substituting the chlorine position of the compound of Formula 3 using the compound of Formula 4 according to the present invention, high yield and high quality (HPLC purity; 99.5% or more) are achieved. It can be manufactured and is suitable for mass production.
상기 본 발명에 따른 화학식 4 화합물의 신규한 제조방법을 도식화하면 하기 <반응식 4>로 표시할 수 있다.Schematic of the novel method for preparing the compound of Formula 4 according to the present invention can be represented by the following <Scheme 4>.
<반응식 4> <Reaction Scheme 4>
상기 반응식 4에서 Boc-는 t-부틸옥시카르보닐기, Ms-는 메탄설포닐기를 나타낸다.
In Scheme 4, Boc- represents t-butyloxycarbonyl group, and Ms- represents methanesulfonyl group.
상기 반응식 4를 구체적으로 설명하면 하기와 같다.The detailed description of Scheme 4 is as follows.
ⅰ) 하기 화학식 17 화합물인 3-시아노-4-옥소-피롤리딘-1-카르복실산 t-부틸에스테르 화합물을 사용하여 메톡시아민염산염과 반응 후 중간체를 분리하지 않고 동일한 반응기내에서 포름알데히드수용액과 반응하여 하기 화학식 18 화합물인 3-시아노-3-히드록시메틸-4-메톡시이미노-피롤리딘-1-카르복실산 t-부틸에스테르 화합물을 제조한다.Ⅰ) After reaction with methoxyamine hydrochloride using a 3-cyano-4-oxo-pyrrolidine-1-carboxylic acid t-butyl ester compound, which is a compound of the following formula 17, form in the same reactor without separating the intermediate. By reacting with an aqueous aldehyde solution, a 3-cyano-3-hydroxymethyl-4-methoxyimino-pyrrolidine-1-carboxylic acid t-butyl ester compound, which is a compound of the following formula (18), is prepared.
<화학식 17> <Formula 17>
<화학식 18> <Formula 18>
ⅱ) 상기 화학식 18 화합물을 메탄설포닐클로라이드를 사용하여 메실화 반응을 진행하여 하기 화학식 19 화합물인 3-시아노-3-메탄설포닐옥시메틸-4-메톡시이미노-피롤리딘-1-카르복실산 t-부틸에스테르 화합물을 제조한 후, 소디움보로하이드라이드와 리튬클로라이드를 사용하여 질소기류하에서 니트릴기를 환원반응하여 하기 화학식 20 화합물인 3-아미노메틸-3-메탄설포닐옥시메틸-4-메톡시이미노-피롤리딘-1-카르복실산 t-부틸에스테르 화합물을 제조한다.Ii) The mesylation reaction of the compound of Formula 18 was performed using methanesulfonyl chloride, and the compound of Formula 19, 3-cyano-3-methanesulfonyloxymethyl-4-methoxyimino-pyrrolidine-1- After preparing a carboxylic acid t-butyl ester compound, sodium borohydride and lithium chloride were used to reduce the nitrile group under a nitrogen stream to obtain 3-aminomethyl-3-methanesulfonyloxymethyl- A 4-methoxyimino-pyrrolidine-1-carboxylic acid t-butyl ester compound is prepared.
<화학식 19><Formula 19>
<화학식 20><Formula 20>
이 때, 니트릴기를 환원시키기 위한 환원제로는 소디움보로하이드라이드-리튬클로라이드 혼합체(NaBH4-LiCl), 소디움보로하이드라이드-코발트클로라이드 혼합체(NaBH4-CoCl2), 소디움보로하이드라이드-니켈클로라이드 혼합체(NaBH4-NiCl2)를 사용할 수 있으며, 바람직하게는 소디움보로하이드라이드-리튬클로라이드 혼합체(NaBH4-LiCl)를 사용하여 질소기류 하에서 반응할 때 비교적 높은 수율로 제조할 수 있다.
At this time, as a reducing agent for reducing the nitrile group, sodium borohydride-lithium chloride mixture (NaBH 4 -LiCl), sodium borohydride-cobalt chloride mixture (NaBH 4 -CoCl 2 ), sodium borohydride- Nickel chloride mixture (NaBH 4 -NiCl 2 ) can be used, preferably sodium borohydride-lithium chloride mixture (NaBH 4 -LiCl) can be prepared in a relatively high yield when reacted under a nitrogen stream. .
ⅲ) 상기 화학식 20 화합물을 에탄올에서 가열하여 고리화 반응을 진행하여 하기 화학식 21 화합물인 8-메톡시이미노-2,6-디아자-스피로[3.4]옥탄-6-카르복실산 t-부틸 에스테르 메탄설폰산염을 제조한 다음 화학식 21 화합물을 아제티딘 고리의 아민기에 트리플루오로아세트산무수물을 사용하여 트리플루오로아세틸기로 차폐시켜 하기 화학식 22 화합물인 8-메톡시이미노-2-(2,2,2-트리플루오로-아세틸)-2,6- 디아자-스피로[3.4]옥탄-6-카르복실산 t-부틸에스테르 화합물을 제조한다.Iii) 8-methoxyimino-2,6-diaza-spiro[3.4]octane-6-carboxylic acid t-butyl ester, which is the compound of Formula 21, by heating the compound of Formula 20 in ethanol to undergo a cyclization reaction After preparing methanesulfonate, the compound of Formula 21 was shielded with a trifluoroacetyl group using trifluoroacetic anhydride in the amine group of the azetidine ring, and the compound of Formula 22, 8-methoxyimino-2-(2,2, A 2-trifluoro-acetyl)-2,6-diaza-spiro[3.4]octane-6-carboxylic acid t-butyl ester compound is prepared.
<화학식 21><Formula 21>
<화학식 22><Formula 22>
ⅳ) 상기 화학식 22 화합물을 메탄설폰산을 사용하여 t-부틸옥시카르보닐기를 탈보호 반응을 진행하여 상기 화학식 4 화합물인 2-(2,2,2-트리플루오로-아세틸)-2,6-디아자-스피로[3.4]옥탄-8-온 O-메틸옥심 메탄설폰산염(TDMOS)을 제조할 수 있다.
Iv) Deprotection of the t-butyloxycarbonyl group of the compound of Formula 22 using methanesulfonic acid, and the compound of Formula 4, 2-(2,2,2-trifluoro-acetyl)-2,6- Diaza-spiro[3.4]octane-8-one O -methyloxime methanesulfonate (TDMOS) can be prepared.
화학식 4 화합물은 자유염기 형태로 제조될 수 있으며, 또는 메탄설폰산, p-톨루엔설폰산, 아세트산, 시트르산, 말레인산, 숙신산, 옥살산, 벤조산, 타르타르산, 푸마르산, 글루쿠론산의 유기산과 반응하여 유기산염의 형태로 제조될 수 있는데, 특히 화학식 4 화합물인 메탄설폰산염이 안정한 상태로 양호한 결과를 얻을 수 있다.
The compound of Formula 4 may be prepared in the form of a free base, or by reacting with organic acids of methanesulfonic acid, p -toluenesulfonic acid, acetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, and glucuronic acid. It can be prepared in the form, in particular, the methanesulfonate of the formula 4 compound can obtain good results in a stable state.
상기와 같이, 신규한 방법에 의해 제조된 화학식 4 화합물(TDMOS)은 하기 화학식 3 화합물인 7-클로로-1-시클로프로필-6-플루오로-4-옥소-1,4-디히드로[1,8]나프티리딘-3-카르복실산과 반응을 진행하여 최종 목적 화합물인 화학식 1의 자보플록사신 D-아스파르트산염을 제조할 수 있다.As described above, the compound of Formula 4 (TDMOS) prepared by the novel method is 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro[1, 8] The reaction with naphthyridine-3-carboxylic acid can be carried out to prepare the final target compound, zabofloxacin D-aspartate of the formula (1).
<화학식 1><Formula 1>
상기 화학식 4 화합물과 화학식 3 화합물을 반응시켜 목적화합물인 자보플록사신 D-아스파르트산염의 제조방법을 <반응식 5>로 나타내었다.A method of preparing the target compound, zabofloxacin D-aspartate, by reacting the compound of Formula 4 with the compound of Formula 3 is shown in <Scheme 5>.
<반응식 5> <Reaction Scheme 5>
ⅴ) 상기 ⅳ) 단계에서 제조된 상기 화학식 4 화합물인 2-(2,2,2-트리플루오로-아세틸)-2,6-디아자-스피로[3.4]옥탄-8-온 O-메틸옥심 메탄설폰산염(TDMOS)과 화학식 3 화합물인 7-클로로-1-시클로프로필-6-플루오로-4-옥소-1,4-디히드로[1,8]나프티리딘-3-카르복실산을 사용하여 치환반응 시켜 화학식 5 화합물인 1-시클로프로필-6-플루오로-7-[8-메톡시이미노-2-(2,2,2-트리플루오로-아세틸)-2,6-디아자-스피로[3.4]옥트-6-일]-4-옥소-1,4-디히드로-[1,8]나프티리딘-3-카르복실산을 제조한 다음 화학식 5 화합물의 트리플루오로아세틸기를 탈보호하기 위해 수산화나트륨, 탄산나트륨, 탄산수소나트륨, 탄산칼륨, 탄산수소칼륨, 수산화칼륨, 수산화리튬 등과 같은 무기염기를 사용하여 탈보호 반응 후 중화반응 시켜 화학식 2 화합물인 1-시클로프로필-6-플루오로-7-(8-메톡시이미노-2,6-디아자-스피로[3,4]옥트-6-일)-4-옥소-1,4-디히드로-[1,8]나프티리딘-3-카르복실산(자보플록사신)을 제조하고, D-아스파르트산을 사용하여 최종 목적 화합물인 자보플록사신 D-아스파르트산염을 제조할 수 있다.
V) 2-(2,2,2-trifluoro-acetyl)-2,6-diaza-spiro[3.4]octane-8-one O -methyloxime, which is the compound of Formula 4 prepared in step iv) Using methanesulfonate (TDMOS) and the compound of Formula 3, 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxylic acid And a substitution reaction, which is a compound of formula 5, 1-cyclopropyl-6-fluoro-7-[8-methoxyimino-2-(2,2,2-trifluoro-acetyl)-2,6-diaza- Prepare spiro[3.4]oct-6-yl]-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid, and then deprotect the trifluoroacetyl group of the compound of formula (5). To do this, an inorganic base such as sodium hydroxide, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, potassium hydroxide, lithium hydroxide, etc. is used to neutralize the compound by deprotection and then neutralize 1-cyclopropyl-6-fluoro. -7-(8-methoxyimino-2,6-diaza-spiro[3,4]oct-6-yl)-4-oxo-1,4-dihydro-[1,8]naphthyridine-3 -Carboxylic acid (zabofloxacin) can be prepared, and the final target compound, zabofloxacin D-aspartate, can be prepared using D-aspartic acid.
본 발명은 자보플록사신 D-아스파르트산염을 제조하기 위해 사용되는 출발물질인 8-메톡시이미노-2,6-디아자-스피로[3,4]옥탄-2-카르복실산 t-부틸에스테르 숙신산염(TBDCS)을 신규한 제조방법에 의해서 높은 수율과 높은 품질(HPLC 순도; 99.5% 이상)로 대량생산에 적합한 방법으로 제조할 수 있다.
The present invention is a starting material used to prepare zabofloxacin D-aspartate, 8-methoxyimino-2,6-diaza-spiro[3,4]octane-2-carboxylic acid t-butyl ester succinic acid Salt (TBDCS) can be prepared in a method suitable for mass production with high yield and high quality (HPLC purity; 99.5% or more) by a novel manufacturing method.
또한, 본 발명은 자보플록사신 D-아스파르트산염을 제조하기 위해 사용하는 다른 형태의 출발물질인 2-(2,2,2-트리플루오로-아세틸)-2,6-디아자-스피로[3.4]옥탄-8-온 O-메틸옥심 메탄설폰산염(TDMOS)을 신규한 제조방법에 의해서 높은 수율과 높은 품질(HPLC 순도; 99.5% 이상)로 대량생산에 적합한 방법으로 제조할 수 있다.
In addition, the present invention is another type of starting material used to prepare zabofloxacin D-aspartate, 2-(2,2,2-trifluoro-acetyl)-2,6-diaza-spiro[3.4 ]Octan-8-one O -methyloxime methanesulfonate (TDMOS) can be prepared in a method suitable for mass production with high yield and high quality (HPLC purity; 99.5% or more) by a novel manufacturing method.
특히, 본 발명은 치환반응시 TBDCS나 TDMOS를 1.0~1.1 당량을 사용하여 획기적으로 생산단가를 절감할 수 방법을 제공하기 때문에 자보플록사신 D-아스파르트산염의 대량생산에 유용하게 이용될 수 있다.
In particular, the present invention can be usefully used in mass production of zabofloxacin D-aspartate because it provides a method that can significantly reduce production cost by using 1.0 to 1.1 equivalents of TBDCS or TDMOS during the substitution reaction.
상기한 바와 같은 본 발명의 제조방법은 다음의 실시예에 의거하여 더욱 상세히 설명하는 바, 본 발명이 이에 한정되는 것은 아니다.
The manufacturing method of the present invention as described above will be described in more detail based on the following examples, but the present invention is not limited thereto.
<실시예 1><Example 1> 3-시아노-3-히드록시메틸-4-메톡시이미노-피롤리딘-1-카르복실산 벤질에스테르(화학식 13)의 제조Preparation of 3-cyano-3-hydroxymethyl-4-methoxyimino-pyrrolidine-1-carboxylic acid benzyl ester (Chemical Formula 13)
메탄올 14L에 메톡시아민염산염 1.44kg과 피리딘 1.16L을 넣고 23~28℃에서 30분 동안 교반하였다. 여기에 메탄올 3.5L에 3-시아노-4-옥소- 피롤리딘-1-카르복실산 벤질에스테르 3.5kg을 녹인 용액을 천천히 첨가하여 23~28℃에서 18시간 동안 교반하였다. 반응혼합물을 10~15℃로 냉각한 후 탄산칼륨수용액(정제수 7L에 탄산칼륨 1.98kg을 녹인 수용액)을 첨가하였다. 이 반응혼합물에 35% 포름알데히드수용액 1.84kg을 넣고 23~28℃에서 2시간 교반한 후 10~15℃로 냉각하였다. 4N 염산을 사용하여 상기 용액을 pH 7 정도로 조절 후 감압농축하였다. 잔사에 에틸아세테이트 17.5L와 정제수 17.5L를 첨가하여 10~15℃로 냉각하였다. 20% 염산을 사용하여 상기 용액을 pH 4 정도로 조절 후 층 분리하여 수층을 제거하였다. 유기층(에틸아세테이트층)에 정제수 17.5L를 첨가한 후 교반하면서 pH 4 정도로 조절 후 층 분리하여 수층을 제거하였다. 유기층에 정제수 17.5L를 첨가한 후 중탄산나트륨수용액을 사용하여 pH 7 정도로 조절하여 수층을 제거하였다. 유기층을 무수황산나트륨을 사용하여 건조 후 감압농축하여 상기 표제화합물 3.91kg을 얻었다(수율: 90%).1.44kg of methoxyamine hydrochloride and 1.16L of pyridine were added to 14L of methanol, and stirred at 23~28℃ for 30 minutes. A solution obtained by dissolving 3.5 kg of 3-cyano-4-oxo-pyrrolidine-1-carboxylic acid benzyl ester in 3.5 L of methanol was slowly added thereto, followed by stirring at 23 to 28° C. for 18 hours. After the reaction mixture was cooled to 10 to 15°C, an aqueous potassium carbonate solution (an aqueous solution obtained by dissolving 1.98 kg of potassium carbonate in 7 L of purified water) was added. 1.84 kg of 35% aqueous formaldehyde solution was added to the reaction mixture, stirred at 23 to 28°C for 2 hours, and then cooled to 10 to 15°C. The solution was adjusted to pH 7 using 4N hydrochloric acid and then concentrated under reduced pressure. 17.5L of ethyl acetate and 17.5L of purified water were added to the residue, and the mixture was cooled to 10~15℃. The solution was adjusted to about pH 4 using 20% hydrochloric acid, and the layers were separated to remove the aqueous layer. After 17.5 L of purified water was added to the organic layer (ethyl acetate layer), the pH was adjusted to about 4 while stirring, and the layers were separated to remove the aqueous layer. After adding 17.5 L of purified water to the organic layer, the aqueous layer was removed by adjusting the pH to about 7 using an aqueous sodium bicarbonate solution. The organic layer was dried using anhydrous sodium sulfate and then concentrated under reduced pressure to obtain 3.91 kg of the title compound (yield: 90%).
1H-NMR(CDCl3, ppm) : 3.73~3.75(m, 1H), 3.85~3.88(m, 2H), 3.91(s, 3H), 3.98~4.03(m, 1H), 4.19(bs, 2H), 5.11(s, 2H), 7.33~7.34(m, 5H)
1 H-NMR(CDCl3, ppm): 3.73~3.75(m, 1H), 3.85~3.88(m, 2H), 3.91(s, 3H), 3.98~4.03(m, 1H), 4.19(bs, 2H) , 5.11(s, 2H), 7.33~7.34(m, 5H)
<실시예 2><Example 2> 3-시아노-3-메탄설포닐옥시메틸-4-메톡시이미노-피롤리딘-1-카르복실 산 벤질에스테르(화학식 14)의 제조Preparation of 3-cyano-3-methanesulfonyloxymethyl-4-methoxyimino-pyrrolidine-1-carboxylic acid benzyl ester (Formula 14)
디클로로메탄 20L에 3-시아노-3-히드록시메틸-4-메톡시이미노-피롤리딘-1-카르복실산 벤질에스테르 3.91kg을 가하여 0~5℃로 냉각하였다. 이 용액에 트리에틸아민 1.83kg과 메탄설포닐클로라이드 1.62kg을 0~10℃에서 천천히 첨가하여 20~25℃에서 18시간 동안 교반하며 반응시켰다. 이 반응혼합물에 정제수 20L를 첨가하여 교반 후 수층을 제거한 다음 유기층에 중탄산나트륨 수용액을 사용하여 pH 9 정도로 조절 후 수층을 제거하였다. 유기층을 무수황산나트륨으로 건조 후 감압농축하여 상기 표제화합물 4.5kg을 얻었다(수율: 90.9%). 3.91 kg of 3-cyano-3-hydroxymethyl-4-methoxyimino-pyrrolidine-1-carboxylic acid benzyl ester was added to 20 L of dichloromethane, followed by cooling to 0-5°C. To this solution, 1.83 kg of triethylamine and 1.62 kg of methanesulfonyl chloride were slowly added at 0 to 10°C, followed by stirring at 20 to 25°C for 18 hours. 20L of purified water was added to the reaction mixture, and after stirring, the aqueous layer was removed, and the pH was adjusted to about 9 using sodium bicarbonate aqueous solution in the organic layer, and the aqueous layer was removed. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain 4.5 kg of the title compound (yield: 90.9%).
1H-NMR(CDCl3, ppm) : 3.09(3H, s), 3.93~3.99(m, 4H), 4.03~4.05(d, 1H, J=11.75Hz), 4.24(d, 2H, J=8.6Hz), 4.29(d, 1H, J=10.3Hz), 4.48(d, 1H, J=10.6Hz), 5.15(s, 2H), 7.35~7.36(m, 5H)
1 H-NMR(CDCl3, ppm): 3.09(3H, s), 3.93~3.99(m, 4H), 4.03~4.05(d, 1H, J=11.75Hz), 4.24(d, 2H, J=8.6Hz ), 4.29(d, 1H, J=10.3Hz), 4.48(d, 1H, J=10.6Hz), 5.15(s, 2H), 7.35~7.36(m, 5H)
<실시예 3><Example 3> 3-아미노메틸-3-메탄설포닐옥시메틸-4-메톡시이미노-피롤리딘-1-카르복실산 벤질에스테르(화학식 15)의 제조Preparation of 3-Aminomethyl-3-methanesulfonyloxymethyl-4-methoxyimino-pyrrolidine-1-carboxylic acid benzyl ester (Chemical Formula 15)
3-아미노메틸-3-메탄설포닐옥시메틸-4-메톡시이미노-피롤리딘-1-카르복실산 벤질에스테르 4.5kg에 에틸아세테이트 11.3L와 무수에탄올 11.3L를 가하여 질소기류하에서 0~5℃로 냉각하여 리튬클로라이드 50g과 소디움보로하이드라이드 0.98kg을 첨가하고, 0~5℃에서 30분 동안 교반한 후 20~25℃에서 18시간 동안 교반하였다. 반응혼합물을 0~10℃로 냉각하여 에틸아세테이트 18L와 정제수 18L를 첨가한 후 20% 염산을 사용하여 pH 3.5로 조절하였다. 층 분리한 후 유기층으로부터 정제수를 사용하여 추가로 추출한 다음 수층을 합하여 디클로로메탄 22.5L를 첨가하였다. 중탄산나트륨수용액을 사용하여 pH 7.3으로 조절 후 층 분리하여 무수황산나트륨으로 건조한 다음 감압농축하여 상기 표제화합물 3.74kg을 얻었다(수율: 82.3%).
To 4.5 kg of 3-aminomethyl-3-methanesulfonyloxymethyl-4-methoxyimino-pyrrolidine-1-carboxylic acid benzyl ester, 11.3 L of ethyl acetate and 11.3 L of anhydrous ethanol were added to 0-5 under a nitrogen stream. After cooling to °C, 50 g of lithium chloride and 0.98 kg of sodium borohydride were added, followed by stirring at 0 to 5°C for 30 minutes, followed by stirring at 20 to 25°C for 18 hours. The reaction mixture was cooled to 0-10°C, 18L of ethyl acetate and 18L of purified water were added, and the pH was adjusted to 3.5 using 20% hydrochloric acid. After the layers were separated, the organic layer was further extracted with purified water, and then the aqueous layers were combined and 22.5 L of dichloromethane was added. After adjusting the pH to 7.3 using an aqueous sodium bicarbonate solution, the layers were separated, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain 3.74 kg of the title compound (yield: 82.3%).
<실시예 4><Example 4> 8-메톡시이미노-2,6-디아자-스피로[3.4]옥탄-6-카르복실산 벤질에스테르 프탈산염(화학식 16)의 제조Preparation of 8-methoxyimino-2,6-diaza-spiro[3.4]octane-6-carboxylic acid benzyl ester phthalate (Chemical Formula 16)
3-아미노메틸-3-메탄설포닐옥시메틸-4-메톡시이미노-피롤리딘-1-카르복실산 벤질에스테르 2.7kg에 무수에탄올 5.4L를 첨가하여 75~78℃에서 4시간 동안 가열 후 냉각한 다음 감압농축하였다. 잔사에 에틸아세테이트 13.5L와 정제수 13.5L를 첨가하여 층 분리하였다. 수층(product층)에 10% 수산화나트륨수용액을 사용하여 pH 10.2로 조절 후 수층에 디클로로메탄 13.5L를 첨가하였다. 층 분리 후 유기층을 무수황산나트륨으로 건조 후 감압농축하여 잔사를 얻었고, 이 잔사는 에탄올에 녹여 용액 A를 제조한 후 메탄올 7.9L에 프탈산 0.77kg을 녹인 용액에 천천히 첨가하였다. 20~25℃에서 2시간 동안 교반 후 여과, 세척(무수에탄올 3L) 및 건조하여 상기 표제화합물 2.69kg(수율: 84.3%)을 얻었다.After adding 5.4 L of anhydrous ethanol to 2.7 kg of 3-aminomethyl-3-methanesulfonyloxymethyl-4-methoxyimino-pyrrolidine-1-carboxylic acid benzyl ester, heating at 75-78°C for 4 hours After cooling, it was concentrated under reduced pressure. The layers were separated by adding 13.5L of ethyl acetate and 13.5L of purified water to the residue. After adjusting the pH to 10.2 using 10% aqueous sodium hydroxide solution to the aqueous layer (product layer), 13.5 L of dichloromethane was added to the aqueous layer. After layer separation, the organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain a residue. This residue was dissolved in ethanol to prepare Solution A, and then slowly added to a solution of 0.77 kg of phthalic acid in 7.9 L of methanol. After stirring for 2 hours at 20 ~ 25 ℃ filtered, washed (3L anhydrous ethanol) and dried to give the title compound 2.69kg (yield: 84.3%).
1H-NMR(DMSO-d6, ppm) : 3.85~3.91(m, 5H), 4.00~4.04(m, 4H), 4.08~4.11(m, 2H), 5.04(s, 2H), 7.27~7.31(m, 1H), 7.34(d, 4H, J=5.0Hz), 7.46~7.49(m, 2H), 8.13~8.16(m, 2H)
1 H-NMR(DMSO-d6, ppm): 3.85~3.91(m, 5H), 4.00~4.04(m, 4H), 4.08~4.11(m, 2H), 5.04(s, 2H), 7.27~7.31( m, 1H), 7.34(d, 4H, J=5.0Hz), 7.46~7.49(m, 2H), 8.13~8.16(m, 2H)
<실시예 5><Example 5> 8-메톡시이미노-2,6-디아자-스피로[3.4]옥탄-2-카르복실산 t-부틸 에스테르 숙신산염(화학식 6, TBDCS)의 제조Preparation of 8-methoxyimino-2,6-diaza-spiro[3.4]octane-2-carboxylic acid t-butyl ester succinate (Chemical Formula 6, TBDCS)
에틸아세테이트 2.44L에 8-메톡시이미노-2,6-디아자-스피로[3.4]옥탄-6- 카르복실산 벤질에스테르 프탈산염 0.61kg과 정제수 2.44L를 넣고 0~5℃로 냉각하였다. 0~10℃에서 수산화나트륨 0.11kg과 Di-t-부틸디카보네이트 0.29kg을 첨가하여 20~25℃에서 2시간 동안 교반하였다. 수층을 제거한 후 유기층에 정제수 2.4L를 첨가한 다음 교반하여 수층을 제거하였다. 유기층을 무수황산나트륨을 사용하여 건조한 후 감압농축하여 잔사 A를 얻었다. 잔사 A에 메탄올 3.05L, 10% 팔라듐/활성탄 24.4g 첨가하여 수소가스 압력하에서 20~30℃의 온도에서 4시간 동안 교반한 후 여액을 감압농축하여 잔사 B를 얻었다. 반응조에 메탄올 996ml와 숙신산 158.16g을 넣고 교반하면서 이소프로판올 1.49L에 잔사 B를 녹인 용액을 첨가하여 20~25℃에서 2시간 동안 교반한 후 0~5℃에서 2시간 동안 교반한 다음 여과 및 세척(이소프로판올 0.43L), 건조하여 상기 표제화합물 462g(수율: 92.4%)을 얻었다. To 2.44 L of ethyl acetate, 0.61 kg of 8-methoxyimino-2,6-diaza-spiro[3.4]octane-6-carboxylic acid benzyl ester phthalate and 2.44 L of purified water were added and cooled to 0-5°C. 0.11 kg of sodium hydroxide and 0.29 kg of Di-t-butyldicarbonate were added at 0 to 10°C, followed by stirring at 20 to 25°C for 2 hours. After removing the aqueous layer, 2.4L of purified water was added to the organic layer, followed by stirring to remove the aqueous layer. The organic layer was dried using anhydrous sodium sulfate and then concentrated under reduced pressure to obtain a residue A. To the residue A, 3.05 L of methanol and 24.4 g of 10% palladium/activated carbon were added and stirred for 4 hours at a temperature of 20 to 30° C. under hydrogen gas pressure, and the filtrate was concentrated under reduced pressure to obtain a residue B. 996 ml of methanol and 158.16 g of succinic acid were added to the reactor, and a solution of the residue B was added to 1.49 L of isopropanol while stirring, stirred at 20 to 25°C for 2 hours, stirred at 0 to 5°C for 2 hours, followed by filtration and washing ( Isopropanol 0.43L) and dried to obtain 462g (yield: 92.4%) of the title compound.
1HNMR(D2O,ppm):1.34(s,9H),2.42(s,4H),3.74(s,2H),3.86(s,3H),4.03(m,2H),4.06(s,4H)
1 HNMR(D 2 O,ppm):1.34(s,9H),2.42(s,4H),3.74(s,2H),3.86(s,3H),4.03(m,2H),4.06(s,4H) )
<실시예 6><Example 6> 3-시아노-3-히드록시메틸-4-메톡시이미노-피롤리딘-1-카르복실산 t-부틸에스테르(화학식 18)의 제조Preparation of 3-cyano-3-hydroxymethyl-4-methoxyimino-pyrrolidine-1-carboxylic acid t-butyl ester (Chemical Formula 18)
메탄올 21.8L에 3-시아노-4-옥소-피롤리딘-1-카르복실산 t-부틸에스테르 4.36kg, 염산메톡시아민 2.08kg과 피리딘 1.64kg을 가한 후 20~30℃에서 5시간 동안 교반하였다. 반응 혼합액을 10~15℃로 냉각하고 무수탄산칼륨 3.15kg과 정제수 8.72L 및 35% 포름알데히드 2.67kg을 가한 후 20~30℃에서 1시간 동안 교반하였다. 반응 혼합액을 감압농축한 후 정제수 30.5L를 가하여 20~30℃에서 1시간 동안 교반한 다음 석출된 고체를 여과 및 건조하여 상기 표제화합물 4.99kg을 얻었다(수율: 89.3%).To 21.8 L of methanol, 4.36 kg of 3-cyano-4-oxo-pyrrolidine-1-carboxylic acid t-butyl ester, 2.08 kg of methoxyamine hydrochloride and 1.64 kg of pyridine were added, and then at 20 to 30°C for 5 hours. Stirred. The reaction mixture was cooled to 10~15℃, 3.15kg of anhydrous potassium carbonate, 8.72L of purified water, and 2.67kg of 35% formaldehyde were added, followed by stirring at 20~30℃ for 1 hour. After the reaction mixture was concentrated under reduced pressure, 30.5 L of purified water was added, stirred at 20 to 30° C. for 1 hour, and then the precipitated solid was filtered and dried to obtain 4.99 kg of the title compound (yield: 89.3%).
1H-NMR(DMSO-d6,ppm): 1.38(s, 9H), 3.59(d, 2H, J=4.87Hz), 3.64~3.72(m, 1H) 3.81~3.87(m, 1H), 3.85(s, 3H), 3.98~4.09(m, 2H), 5.93(t, 1H, J=5.88Hz)
1 H-NMR(DMSO-d 6 ,ppm): 1.38(s, 9H), 3.59(d, 2H, J=4.87Hz), 3.64~3.72(m, 1H) 3.81~3.87(m, 1H), 3.85 (s, 3H), 3.98~4.09(m, 2H), 5.93(t, 1H, J=5.88Hz)
<실시예 7><Example 7> 3-시아노-3-메탄설포닐옥시메틸-4-메톡시이미노-피롤리딘-1- 카르복실산 t-부틸에스테르(화학식 19)의 제조Preparation of 3-cyano-3-methanesulfonyloxymethyl-4-methoxyimino-pyrrolidine-1-carboxylic acid t-butyl ester (Chemical Formula 19)
디클로로메탄 21.6L에 3-시아노-3-히드록시메틸-4-메톡시이미노-피롤리딘 -1-카르복실산 t-부틸에스테르 4.31kg, 트리에틸아민 3.12L를 넣고 0℃로 냉각한 다음 메탄설포닐클로라이드 1.36L을 서서히 가한 후 20~25℃에서 1시간 동안 교반하였다. 반응혼합액에 정제수 21.6L를 넣고 중탄산나트륨수용액으로 pH 9.0~9.5로 조절한 후 유기층을 추출한 다음 무수황산나트륨으로 건조한 후 여과 및 감압농축하여 상기 표제화합물 5.56kg을 얻었다(수율: 100%).
4.31 kg of 3-cyano-3-hydroxymethyl-4-methoxyimino-pyrrolidine-1-carboxylic acid t-butyl ester and 3.12 L of triethylamine were added to 21.6 L of dichloromethane and cooled to 0°C. Then, 1.36L of methanesulfonyl chloride was slowly added, followed by stirring at 20-25°C for 1 hour. 21.6 L of purified water was added to the reaction mixture, the pH was adjusted to 9.0 to 9.5 with sodium bicarbonate aqueous solution, the organic layer was extracted, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain 5.56 kg of the title compound (yield: 100%).
<실시예 8><Example 8> 3-아미노메틸-3-메탄설포닐옥시메틸-4-메톡시이미노-피롤리딘-1- 카르복실산 t-부틸에스테르(화학식 20)의 제조Preparation of 3-Aminomethyl-3-methanesulfonyloxymethyl-4-methoxyimino-pyrrolidine-1-carboxylic acid t-butyl ester (Formula 20)
에틸아세테이트 13.9L와 에탄올 13.9L에 3-시아노-3-메탄설포닐옥시 메틸-4-메톡시이미노-피롤리딘-1-카르복실산 t-부틸에스테르 5.56kg을 첨가한 후 질소기류하에서 5~10℃로 냉각하여 리튬클로라이드 70g과 소디움보로 하이드라이드 1.21kg을 가한 다음 25~30℃에서 17시간 동안 교반하였다. 반응혼합액에 에틸아세테이트 22.24L와 정제수 22.24L를 넣고 20% 염산으로 pH 3.5~4.5로 조절한 후 교반하여 층 분리하였다. 유기층에 남아있는 목적화합물은 추가로 정제수를 사용하여 추출하였다. 얻어진 수층은 중탄산나트륨수용액으로 pH 7.0~7.5로 조절하고 디클로로메탄 22.24L로 추출한 다음 무수황산나트륨으로 건조한 후 여과 및 감압농축하여 상기 표제화합물 4.67kg을 얻었다(수율: 83.1%).
After adding 5.56 kg of 3-cyano-3-methanesulfonyloxy methyl-4-methoxyimino-pyrrolidine-1-carboxylic acid t-butyl ester to 13.9 L of ethyl acetate and 13.9 L of ethanol, under a nitrogen stream After cooling to 5 to 10°C, 70 g of lithium chloride and 1.21 kg of sodium borohydride were added, followed by stirring at 25 to 30°C for 17 hours. To the reaction mixture, 22.24L of ethyl acetate and 22.24L of purified water were added, and the pH was adjusted to 3.5-4.5 with 20% hydrochloric acid, followed by stirring to separate layers. The target compound remaining in the organic layer was further extracted using purified water. The obtained aqueous layer was adjusted to pH 7.0-7.5 with sodium bicarbonate aqueous solution, extracted with 22.24 L of dichloromethane, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain 4.67 kg of the title compound (yield: 83.1%).
<실시예 9><Example 9> 8-메톡시이미노-2,6-디아자-스피로[3.4]옥탄-6-카르복실산 t-부틸 에스테르 메탄설폰산염(화학식 21)의 제조Preparation of 8-methoxyimino-2,6-diaza-spiro[3.4]octane-6-carboxylic acid t-butyl ester methanesulfonate (Chemical Formula 21)
3-아미노메틸-3-메탄설포닐옥시메틸-4-메톡시이미노-피롤리딘-1-카르복실산 t-부틸에스테르 4.65kg에 에탄올 9.3L를 가하여 75~78℃에서 4시간 동안 교반 하였다. 반응혼합액을 20~25℃로 냉각하고 n-헥산 18.6L를 가한 후 0~5℃에서 2시간 동안 교반한 다음 생성된 고체를 여과, 세척 및 건조하여 상기 표제화합물 3.92kg을 얻었다(수율: 84.3%).9.3 L of ethanol was added to 4.65 kg of 3-aminomethyl-3-methanesulfonyloxymethyl-4-methoxyimino-pyrrolidine-1-carboxylic acid t-butyl ester and stirred at 75-78°C for 4 hours. . The reaction mixture was cooled to 20~25℃, 18.6L of n-hexane was added, stirred at 0~5℃ for 2 hours, and the resulting solid was filtered, washed and dried to obtain 3.92kg of the title compound (yield: 84.3 %).
1H-NMR(DMSO-d6,ppm): 1.37(s, 9H), 2.37(s, 3H), 3.78(s, 2H), 3.86(s, 3H), 3.91 (s, 2H), 4.00(d, 2H, J=11.17Hz), 4.08(d, 2H, J=11.46Hz), 8.89(bs, 1H)
1 H-NMR (DMSO-d 6 ,ppm): 1.37 (s, 9H), 2.37 (s, 3H), 3.78 (s, 2H), 3.86 (s, 3H), 3.91 (s, 2H), 4.00 ( d, 2H, J=11.17Hz), 4.08 (d, 2H, J=11.46Hz), 8.89 (bs, 1H)
<실시예 10><Example 10> 8-메톡시이미노-2-(2,2,2-트리플루오로-아세틸)-2,6-디아자-8-methoxyimino-2-(2,2,2-trifluoro-acetyl)-2,6-diaza-
스피로 [3.4]옥탄-6-카르복실산 t-부틸에스테르(화학식 22)의 제조Preparation of spiro [3.4]octane-6-carboxylic acid t-butyl ester (Chemical Formula 22)
디클로로메탄 8.8L에 8-메톡시이미노-2,6-디아자-스피로[3.4]옥탄-6- 카르복실산 t-부틸에스테르 메탄설폰산 1.76kg과 트리에틸아민 1.54L를 넣고 0℃로 냉각한 후 트리플루오로아세트산무수물 0.84L를 서서히 가한 다음 15~20℃에서 2시간 동안 교반하였다. 반응혼합액에 정제수 8.8L를 넣고 유기층을 분리 한 후 정제수 8.8L로 한번 더 세척한 다음 감압농축하였다. 잔사에 에탄올을 넣고 교반하면서 정제수를 14.08L를 넣고 10~15℃에서 2시간 동안 교반한 후 생성된 고체를 여과 및 건조하여 상기 표제화합물 1.66kg을 얻었다(수율: 94.5%). To 8.8L of dichloromethane, add 1.76kg of 8-methoxyimino-2,6-diaza-spiro[3.4]octane-6-carboxylic acid t-butyl ester methanesulfonic acid and 1.54L of triethylamine, and then cool to 0℃. After that, 0.84 L of trifluoroacetic anhydride was slowly added, followed by stirring at 15 to 20°C for 2 hours. After 8.8L of purified water was added to the reaction mixture, the organic layer was separated, washed once more with 8.8L of purified water, and then concentrated under reduced pressure. Ethanol was added to the residue, and 14.08 L of purified water was added while stirring, followed by stirring at 10 to 15° C. for 2 hours, and the resulting solid was filtered and dried to obtain 1.66 kg of the title compound (yield: 94.5%).
1H―NMR(DMSO―d6,ppm):1.37(s,9H),3.76(s,2H),3.83(s,3H),3.96(s,2H),4.10(d,1H,J=10.31Hz),4.16(d,1H,J=10.31Hz), 4.41(d, 1H, J=9.45Hz), 4.52(d, 1H, J=9.74Hz)
1 H-NMR(DMSO-d 6 ,ppm):1.37(s,9H),3.76(s,2H),3.83(s,3H),3.96(s,2H),4.10(d,1H,J=10.31 Hz),4.16(d,1H,J=10.31Hz), 4.41(d, 1H, J=9.45Hz), 4.52(d, 1H, J=9.74Hz)
<실시예 11><Example 11> 2-(2,2,2-트리플루오로-아세틸)-2,6-디아자-스피로[3.4]옥탄-8-2-(2,2,2-trifluoro-acetyl)-2,6-diaza-spiro[3.4]octane-8-
온 On OO - 메틸-옥심 메탄설폰산염(화학식 4, TDMOS)의 제조-Preparation of methyl-oxime methanesulfonate (Chemical Formula 4, TDMOS)
에틸아세테이트 5.3L에 8-메톡시이미노-2-(2,2,2-트리플루오로-아세틸)- 2,6-디아자-스피로[3.4]옥탄-6-카르복실산 t-부틸에스테르 1.06kg을 가하여 교반하면서 메탄설폰산 0.22L를 서서히 가한 후 40~45℃에서 8시간 동안 교반하였다. 반응혼합물을 20~25℃로 냉각하여 0.5시간 교반한 다음 침전된 고체를 여과, 세척 및 건조하여 상기 표제화합물 979g을 얻었다(수율: 93.4%).Ethyl acetate 5.3L to 8-methoxyimino-2-(2,2,2-trifluoro-acetyl)-2,6-diaza-spiro[3.4]octane-6-carboxylic acid t-butyl ester 1.06 While adding kg and stirring, 0.22L of methanesulfonic acid was slowly added, followed by stirring at 40-45°C for 8 hours. The reaction mixture was cooled to 20-25° C., stirred for 0.5 hours, and then the precipitated solid was filtered, washed and dried to obtain 979 g of the title compound (yield: 93.4%).
1H―NMR(DMSO―d6,ppm):2.38(s,3H),3.75(s,2H),3.87(s,3H),3.95(s,2H),4.06(d,1H,J=10.60Hz),4.23(d,1H,J=10.60Hz),4.37(d,1H,J=10.02Hz),4.58(d,1H,J=9.74Hz),9.28(bs,1H)
1 H-NMR(DMSO-d 6 ,ppm):2.38(s,3H),3.75(s,2H),3.87(s,3H),3.95(s,2H),4.06(d,1H,J=10.60 Hz),4.23(d,1H,J=10.60Hz),4.37(d,1H,J=10.02Hz),4.58(d,1H,J=9.74Hz),9.28(bs,1H)
<실시예 12><Example 12> 7-(2-t-부톡시카르보닐-8-메톡시이미노-2,6-디아자-스피로[3,4]옥트- 6-일)-1-시클로프로필-6-플루오로-4-옥소-1,4-디히드로[1,8]나프티리딘-3-카르복실산(화학식 7)의 제조7-(2-t-butoxycarbonyl-8-methoxyimino-2,6-diaza-spiro[3,4]oct-6-yl)-1-cyclopropyl-6-fluoro-4- Preparation of oxo-1,4-dihydro[1,8]naphthyridine-3-carboxylic acid (Chemical Formula 7)
반응조에 질소기류하에서 아세토니트릴 134.0kg, 7-클로로-1-시클로프로필 -6-플루오로-4-옥소-1,4-디히드로[1,8]나프티리딘-3-카르복실산 13.2kg, 트리 에틸아민 11.8kg과 8-메톡시이미노-2,6-디아자-스피로[3,4]옥탄-2-카르복실산 t-부틸에스테르 숙신산염 19.2kg을 첨가하고 내부온도를 55~60℃까지 가열한 후 5시간 동안 교반하였다. 반응 완결 후 반응물을 내부온도 20~25℃로 냉각하여 무수에탄올 105.1kg을 첨가하고 20~25℃에서 1시간 동안 교반한 후 생성된 고체를 여과, 세척 및 건조하여 상기 표제화합물 22.2kg를 얻었다(수율: 94.8%).134.0 kg of acetonitrile, 13.2 kg of 7-chloro-1-cyclopropyl -6-fluoro-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxylic acid in a reactor under a nitrogen stream, Triethylamine 11.8kg and 8-methoxyimino-2,6-diaza-spiro[3,4]octane-2-carboxylic acid t-butyl ester succinate 19.2kg were added and the internal temperature was 55~60℃. After heating to, the mixture was stirred for 5 hours. After completion of the reaction, the reaction product was cooled to an internal temperature of 20 to 25°C, 105.1 kg of anhydrous ethanol was added, stirred at 20 to 25°C for 1 hour, and the resulting solid was filtered, washed and dried to obtain 22.2 kg of the title compound ( Yield: 94.8%).
1H―NMR(CDCl3,ppm):1.07(m,2H),1.29(m,2H),1.46(s,9H),3.65(m,1H),3.98(m,4H),3.99(s,1H),4.27(m,4H),4.58(s,2H),8.05(d,1H,J=9.6Hz),8.68(s,1H)
1 H-NMR(CDCl 3 ,ppm):1.07(m,2H),1.29(m,2H),1.46(s,9H),3.65(m,1H),3.98(m,4H),3.99(s, 1H),4.27(m,4H),4.58(s,2H),8.05(d,1H,J=9.6Hz),8.68(s,1H)
<실시예 13><Example 13> 1-시클로프로필-6-플루오로-7-(8-메톡시이미노-2,6-디아자-스피로 [3,4]옥트-6-일)-4-옥소-1,4-디히드로[1,8]나프티리딘-3-카르복실산 염산염 (화학식 23)의 제조1-cyclopropyl-6-fluoro-7-(8-methoxyimino-2,6-diaza-spiro [3,4]oct-6-yl)-4-oxo-1,4-dihydro[ 1,8] Preparation of naphthyridine-3-carboxylic acid hydrochloride (Formula 23)
반응조에 디클로로메탄 102.3kg과 7-(2-t-부톡시카르보닐-8-메톡시이미 노-2,6-디아자-스피로[3,4]옥트-6-일)-1-시클로프로필-6-플루오로-4-옥소-1,4- 디히드로[1,8]나프티리딘-3-카르복실산 22.2kg을 첨가하고 반응물에 트리플루 오로아세트산 68.1kg을 0~20℃에서 천천히 적가한 다음 0~5℃에서 5시간 동안 교반한 후 -30~-20℃로 냉각하였다(용액 A). 반응조에 무수에탄올 140.5kg을 첨가하고 -10~0℃로 냉각한 다음 아세틸클로라이드 27.8kg을 적가하여 -15~-10℃에서 교반하였다(용액 B). 용액 A에 용액 B를 -30~-15℃를 유지하면서 천천히 적가한 다음 -25~-15℃에서 에틸아세테이트 98.9kg을 첨가하였다. -15~-5℃에서 2시간 동안 교반하여 생성된 고체를 여과한 후 얻어진 습체를 반응조에 무수에탄올 122.9kg과 함께 첨가한 다음 20~25℃에서 3시간 동안 교반하였다. 반응물을 여과, 세척 및 건조하여 상기 표제화합물 18.06kg을 얻었다(수율: 93.2%).102.3 kg of dichloromethane and 7-(2-t-butoxycarbonyl-8-methoxyimino-2,6-diaza-spiro[3,4]oct-6-yl)-1-cyclopropyl in a reactor -6-Fluoro-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxylic acid 22.2kg was added, and trifluoroacetic acid 68.1kg was slowly added dropwise to the reaction at 0~20℃ Then, the mixture was stirred at 0 to 5°C for 5 hours and then cooled to -30 to -20°C (Solution A). 140.5 kg of anhydrous ethanol was added to the reaction tank, cooled to -10 to 0°C, 27.8 kg of acetyl chloride was added dropwise and stirred at -15 to -10°C (solution B). Solution B was slowly added dropwise to Solution A while maintaining -30~-15℃, and then 98.9kg of ethyl acetate was added at -25~-15℃. After filtering the resulting solid by stirring at -15 to -5°C for 2 hours, the obtained wet body was added to a reaction tank with 122.9 kg of anhydrous ethanol, followed by stirring at 20 to 25°C for 3 hours. The reaction product was filtered, washed and dried to obtain 18.06 kg of the title compound (yield: 93.2%).
1H-NMR(DMSO, ppm) : 1.1~1.11(m, 2H), 1.28~1.29(m, 2H), 3.71(dd, 1H, J=8.88, 17.60Hz), 4.09(s, 3H), 4.12~4.20(m, 4H), 4.45(s, 2H), 4.55(s, 2H), 8.05(d, 1H, J=9.48Hz), 8.58(s, 1H)
1 H-NMR(DMSO, ppm): 1.1~1.11(m, 2H), 1.28~1.29(m, 2H), 3.71(dd, 1H, J=8.88, 17.60Hz), 4.09(s, 3H), 4.12 ~4.20(m, 4H), 4.45(s, 2H), 4.55(s, 2H), 8.05(d, 1H, J=9.48Hz), 8.58(s, 1H)
<실시예 14><Example 14> 1-시클로프로필-6-플루오로-7-(8-메톡시이미노-2,6-디아자-스피로 [3,4]옥트-6-일)-4-옥소-1,4-디히드로[1,8]나프티리딘-3-카르복실산(화학식 2)의 제조1-cyclopropyl-6-fluoro-7-(8-methoxyimino-2,6-diaza-spiro [3,4]oct-6-yl)-4-oxo-1,4-dihydro[ 1,8] Preparation of naphthyridine-3-carboxylic acid (Chemical Formula 2)
반응조에 정제수 51.5kg, 무수에탄올 68.3kg 및 1-시클로프로필-6- 플루오로-7-(8-메톡시이미노-2,6-디아자-스피로[3,4]옥트-6-일)-4-옥소-1,4-디 히드로[1,8]나프티리딘-3-카르복실산 염산염 17.0kg을 첨가하고 20~25℃에서 30분 동안 교반한 후 5% 수산화나트륨수용액을 사용하여 pH 6.5~8.0으로 조절하였다. 반응물을 2시간 동안 교반한 다음 무수에탄올 47.8kg을 첨가하고 20~25℃에서 3시간 동안 교반하였다. 생성된 고체를 여과한 다음 정제수 85.3kg과 무수에탄올 13.7kg으로 세척한 후 진공 건조하여 목적화합물인 자보플록사신 15.04kg을 얻었다(수율: 96.5%).51.5 kg of purified water, 68.3 kg of anhydrous ethanol and 1-cyclopropyl-6-fluoro-7-(8-methoxyimino-2,6-diaza-spiro[3,4]oct-6-yl)- After adding 17.0 kg of 4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxylic acid hydrochloride, stirring at 20 to 25°C for 30 minutes, pH 6.5 using 5% aqueous sodium hydroxide solution It was adjusted to ~8.0. The reaction was stirred for 2 hours, and then 47.8 kg of anhydrous ethanol was added, followed by stirring at 20-25° C. for 3 hours. The resulting solid was filtered, washed with 85.3 kg of purified water and 13.7 kg of anhydrous ethanol, and dried under vacuum to obtain 15.04 kg of the target compound, zabofloxacin (yield: 96.5%).
1H-NMR(DMSO, ppm) : 1.06(m, 2H), 1.2(m, 2H), 3.67(m, 1H), 2.72(m 2H), 3.80(s, 3H), 3.99(m, 2H), 3.9(s, 2H), 4.50(bs, 2H), 7.94(dd, 1H, J=10.0Hz), 8.50(s, 1H)
1 H-NMR(DMSO, ppm): 1.06(m, 2H), 1.2(m, 2H), 3.67(m, 1H), 2.72(m 2H), 3.80(s, 3H), 3.99(m, 2H) , 3.9(s, 2H), 4.50(bs, 2H), 7.94(dd, 1H, J=10.0Hz), 8.50(s, 1H)
<실시예 15><Example 15> 1-시클로프로필-6-플루오로-7-[8-메톡시이미노-2-(2,2,2-트리플루 오로-아세틸)-2,6-디아자-스피로[3.4]옥트-6-일]-4-옥소-1,4-디히드로-[1,8]나프티리딘-3-카르복실산(화학식 5)의 제조1-cyclopropyl-6-fluoro-7-[8-methoxyimino-2-(2,2,2-trifluoro-acetyl)-2,6-diaza-spiro[3.4]oct-6- Preparation of one]-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid (Chemical Formula 5)
디메틸포름아미드 900mL에 7-클로로-1-시클로프로필-6-플루오로-4-옥소- 1,4-디히드로[1,8]나프티리딘-3-카르복실산 100.0g과 2-(2,2,2-트리플루오로- 아세틸)-2,6-디아자-스피로[3.4]옥탄-8-온 O-메틸옥심 메탄설폰산염 129.02g를 주입하고 5~10℃에서 트리에틸아민 106.0mL을 서서히 가한 후 55~60℃에서 2시간 동안 교반하였다. 반응혼합물을 20~25℃로 냉각하여 메탄올 400mL를 첨가한 후 20~25℃에서 1시간 동안 교반한 다음 여과, 세척 및 건조하여 상기 표제화합물 171.2g을 얻었다(수율: 97.3%). In 900 mL of dimethylformamide, 100.0 g of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxylic acid and 2-(2, 2,2-trifluoro-acetyl)-2,6-diaza-spiro[3.4]octane-8-one O -methyloxime methanesulfonate 129.02g was added and triethylamine 106.0mL was added at 5-10℃. After slowly adding, the mixture was stirred at 55 to 60°C for 2 hours. The reaction mixture was cooled to 20 to 25°C, 400 mL of methanol was added, stirred at 20 to 25°C for 1 hour, filtered, washed and dried to obtain 171.2 g of the title compound (yield: 97.3%).
1H-NMR (DMSO-d6, ppm) : 1.06~1.09(m,1H), 1.12~1.15(m, 2H), 1.18~1.24(2H, m), 3.68~3.73(m, 1H), 3.90(s, 3H), 4.21(d, 1H, J=10.60Hz), 4.31(d, 1H, J=10.60Hz) 4.35(m, 1H), 4.51(d, 1H, J=9.74Hz), 4.58(s, 2H), 4.66(d, 1H, J=9.45Hz), 8.05 (d, 1H, J=12.60Hz), 8.58(s,1H)
1 H-NMR (DMSO-d6, ppm): 1.06~1.09(m,1H), 1.12~1.15(m, 2H), 1.18~1.24(2H, m), 3.68~3.73(m, 1H), 3.90( s, 3H), 4.21(d, 1H, J=10.60Hz), 4.31(d, 1H, J=10.60Hz) 4.35(m, 1H), 4.51(d, 1H, J=9.74Hz), 4.58(s , 2H), 4.66(d, 1H, J=9.45Hz), 8.05 (d, 1H, J=12.60Hz), 8.58(s,1H)
<실시예 16><Example 16> 1-시클로프로필-6-플루오로-7-(8-메톡시이미노-2,6-디아자-스피로 [3.4]옥트-6-일)-4-옥소-1,4-디히드로-[1,8]나프티리딘-3-카르복실산(화학식 2)의 제조1-cyclopropyl-6-fluoro-7-(8-methoxyimino-2,6-diaza-spiro [3.4]oct-6-yl)-4-oxo-1,4-dihydro-[1 ,8] Preparation of naphthyridine-3-carboxylic acid (Chemical Formula 2)
무수에탄올 105mL와 정제수 105mL의 혼합용매에 1-시클로프로필-6- 플루오로-7-[8-메톡시이미노-2-(2,2,2-트리플루오로-아세틸)-2,6-디아자-스피로 [3.4]옥트-6-일]-4-옥소-1,4-디히드로-[1,8]나프티리딘-3-카르복실산 21.0g과 무수탄산칼륨 11.67g을 첨가한 후 40~45℃에서 1시간 동안 교반하였다. 반응혼합물을 20~25℃로 냉각하여 20% 염산을 사용하여 pH 7.0~8.0으로 조절한 후 1시간 동안 교반한 다음 석출된 고체를 여과, 세척 및 건조하여 목적화합물인 자보플록사신 16.34g을 얻었다(수율: 96.4%). 1-cyclopropyl-6-fluoro-7-[8-methoxyimino-2-(2,2,2-trifluoro-acetyl)-2,6-dia in a mixed solvent of 105 mL of anhydrous ethanol and 105 mL of purified water. After adding 21.0 g of za-spiro [3.4]oct-6-yl]-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid and 11.67 g of anhydrous potassium carbonate, 40 It was stirred at ~45 ℃ for 1 hour. The reaction mixture was cooled to 20-25°C, adjusted to pH 7.0-8.0 using 20% hydrochloric acid, stirred for 1 hour, and then the precipitated solid was filtered, washed and dried to obtain 16.34 g of the target compound, zabofloxacin. (Yield: 96.4%).
1H-NMR(DMSO, ppm) : 1.06(m, 2H), 1.2(m, 2H), 3.67(m, 1H), 2.72(m 2H), 3.80(s, 3H), 3.99(m, 2H), 3.9(s, 2H), 4.50(bs, 2H), 7.94(dd, 1H, J=10.0Hz), 8.50(s, 1H)
1 H-NMR(DMSO, ppm): 1.06(m, 2H), 1.2(m, 2H), 3.67(m, 1H), 2.72(m 2H), 3.80(s, 3H), 3.99(m, 2H) , 3.9(s, 2H), 4.50(bs, 2H), 7.94(dd, 1H, J=10.0Hz), 8.50(s, 1H)
<실시예 17><Example 17> 1-시클로프로필-6-플루오로-7-[(8Z)-8-(메톡시이미노- 2,6-디아자-스피로[3,4]옥트-6-일)]-4-옥소-1,4-디히드로-[1,8]나프티리딘-3-카르복실산 D-아스 파르트산염(화학식 1)의 제조1-cyclopropyl-6-fluoro-7-[(8Z)-8-(methoxyimino-2,6-diaza-spiro[3,4]oct-6-yl)]-4-oxo-1 Preparation of ,4-dihydro-[1,8]naphthyridine-3-carboxylic acid D-aspartate (Formula 1)
무수에탄올 406ml와 정제수 595ml에 1-시클로프로필-6-플루오로-7-(8-메톡시이미노-2,6-디아자-스피로[3,4]옥트-6일)-4-옥소-1,4-디히드로-[1,8]나프 티리딘-3-카르복실산 85g과 D-아스파르트산 32.4g을 넣고 서서히 가열하여 55~60℃에서 30분 동안 교반하였다. 반응 혼합물에 활성탄 3.8g을 넣고 55~60℃에서 30분 동안 교반 후 뜨거운 상태에서 여과하여 20~30℃로 냉각하였다. 석출된 반응 혼합물에 무수에탄올 406ml를 넣고 5~25℃에서 1~2시간 교반 후 여과, 세척(무수에탄올)한 다음 건조하여 목적화합물인 자보플록사신 D-아스파르트산염 101.1g을 얻었다(KF=4.9%).To 406 ml of anhydrous ethanol and 595 ml of purified water 1-cyclopropyl-6-fluoro-7-(8-methoxyimino-2,6-diaza-spiro[3,4]oct-6yl)-4-oxo-1 85 g of ,4-dihydro-[1,8]naphthyridine-3-carboxylic acid and 32.4 g of D-aspartic acid were added, and the mixture was slowly heated and stirred at 55 to 60° C. for 30 minutes. 3.8 g of activated carbon was added to the reaction mixture, stirred at 55 to 60°C for 30 minutes, filtered while hot, and cooled to 20 to 30°C. 406 ml of anhydrous ethanol was added to the precipitated reaction mixture, stirred at 5 to 25°C for 1 to 2 hours, filtered, washed (anhydrous ethanol), and dried to obtain 101.1 g of the target compound, zabofloxacin D-aspartate (KF=4.9 %).
녹는점(m.p.): 209.1℃(DSC)Melting point (m.p.): 209.1℃ (DSC)
1H―NMR(DMSO―d6,ppm):0.95(m,2H),1.23(m,2H),2.60(dd,1H,J=8.8Hz,J=17.7Hz),2.73(dd,1H,J=3.9Hz,17.7Hz),3.53(m,1H),3.81(dd,1H,J=3.7Hz,8.9Hz),3.97(s,3H),4.29(bs,2H),4.32~4.39(m,4H),4.45(bs,2H),7.50(d,1H,J=12.4Hz),8.44(s,1H) 1 H-NMR(DMSO-d 6 ,ppm):0.95(m,2H),1.23(m,2H),2.60(dd,1H,J=8.8Hz,J=17.7Hz),2.73(dd,1H, J=3.9Hz,17.7Hz),3.53(m,1H),3.81(dd,1H,J=3.7Hz,8.9Hz),3.97(s,3H),4.29(bs,2H),4.32~4.39(m ,4H),4.45(bs,2H),7.50(d,1H,J=12.4Hz),8.44(s,1H)
Claims (16)
화학식 5 화합물은 하기 화학식 3 화합물과 하기 화학식 4 화합물을 반응시켜 제조되는 것임을 특징으로 하는 하기 화학식 2 화합물의 제조방법.
<화학식 2>
<화학식 3>
<화학식 4>
<화학식 5>
In the preparation method of the following formula 2 compound from the following formula 5 compound,
The compound of formula 5 is a method of preparing the compound of formula 2, characterized in that it is prepared by reacting the compound of formula 3 and the compound of formula 4 below.
<Formula 2>
<Formula 3>
<Formula 4>
<Formula 5>
<화학식 22>
The method of claim 1, wherein the compound of Formula 4 is prepared by deprotecting a t-butyloxycarbonyl group using a compound of Formula 22 below using methanesulfonic acid.
<Formula 22>
<화학식 20>
<화학식 21>
The method of claim 2, wherein the compound of Formula 22 is a cyclization reaction by heating the compound of Formula 20 in ethanol to prepare the compound of Formula 21, and then the compound of Formula 21 is added to the amine group of the azetidine ring using trifluoroacetic anhydride. The method is prepared by masking with a trifluoroacetyl group.
<Formula 20>
<Formula 21>
<화학식 18>
<화학식 19>
The method of claim 3, wherein the compound of Formula 20 is prepared by a mesylation reaction of the compound of Formula 18 below using methanesulfonyl chloride to prepare the compound of Formula 19, followed by a reduction reaction of a nitrile group.
<Formula 18>
<Formula 19>
<화학식 17>
The method of claim 4, wherein the compound of Formula 18 is prepared by reacting the compound of Formula 17 with an aqueous formaldehyde solution in the same reactor without separating the intermediate produced after the reaction of the compound of Formula 17 with methoxyamine hydrochloride.
<Formula 17>
The method of claim 5, wherein the reduction reaction is performed by using sodium borohydride and lithium chloride.
The method of claim 1, wherein the compound of Formula 5 is reacted with the compound of Formula 3 according to claim 1 using 1.0 to 1.1 equivalents of the compound of Formula 4.
화학식 7 화합물은 하기 화학식 3 화합물과 하기 화학식 6 화합물을 반응시켜 제조함을 특징으로 하는 하기 화학식 2 화합물의 제조방법.
<화학식 2>
<화학식 3>
<화학식 6>
<화학식 7>
In the preparation method of the following formula 2 compound from the following formula 7 compound,
The compound of formula 7 is a method for producing a compound of formula 2, characterized in that it is prepared by reacting a compound of formula 3 and a compound of formula 6
<Formula 2>
<Formula 3>
<Formula 6>
<Formula 7>
<화학식 16>
The method of claim 8, wherein the compound of Formula 6 is prepared by protecting the amine group of the azetidine ring with t-butoxycarbonyl group in the presence of an inorganic base in the compound of Formula 16 below, and then using palladium-activated carbon. A method prepared by subjecting a benzyloxycarbonyl group to a deprotection reaction under hydrogen pressure and then reacting succinic acid.
<Formula 16>
<화학식 15>
The method of claim 9, wherein the compound of Formula 16 is prepared by using phthalic acid after performing a cyclization reaction by heating the compound of Formula 15 in an alcohol solvent.
<Formula 15>
<화학식 13>
<화학식 14>
The method of claim 10, wherein the compound of Formula 15 is prepared by mesylation reaction of the compound of Formula 13 using methanesulfonyl chloride to prepare the compound of Formula 14 and then reduction reaction of a nitrile group.
<Formula 13>
<Formula 14>
<화학식 12>
The method of claim 11, wherein the compound of Formula 13 is prepared by reacting the compound of Formula 12 with methoxyamine hydrochloride and then reacting with an aqueous formaldehyde solution in the same reactor without separating an intermediate.
<Formula 12>
The method of claim 11, wherein the reduction reaction is performed using sodium borohydride and lithium chloride.
The method of claim 8, wherein the compound of Formula 7 is prepared by reacting the compound of Formula 3 using 1.0 to 1.1 equivalents of the compound of Formula 6.
<화학식 4>
Formula 4 compound below.
<Formula 4>
<화학식 6>
<Formula 6>
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| PCT/KR2015/005009 WO2015178663A1 (en) | 2014-05-20 | 2015-05-19 | An improved manufacturing method of zabofloxacin |
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Citations (4)
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| US4822801A (en) | 1984-07-20 | 1989-04-18 | Warner-Lambert Company | 4-oxo-1,4-dihydroquinoline-3-carboxylic acid derivative as antibacterial agents |
| US5633262A (en) | 1994-06-16 | 1997-05-27 | Lg Chemical Ltd. | Quinoline carboxylic acid derivatives having 7-(4-amino-methyl-3-oxime) pyrrolidine substituent and processes for preparing thereof |
| US6313299B1 (en) | 1997-06-26 | 2001-11-06 | Dong Wha Pharmaceutical Industrial Co., Ltd. | Quinolone carboxylic acid derivatives |
| US20100184795A1 (en) | 2007-04-13 | 2010-07-22 | Dong Wha Pharmaceutical Ind. Co. Ltd | Aspartate of 1-cyclopropyl-6-fluoro-7-(8-methoxyimino-2,6-diaza-spiro[3.4]oct-6-yl)-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid, method for preparing the same, and antimicrobial pharmaceutical composition comprising the same |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4822801A (en) | 1984-07-20 | 1989-04-18 | Warner-Lambert Company | 4-oxo-1,4-dihydroquinoline-3-carboxylic acid derivative as antibacterial agents |
| US5633262A (en) | 1994-06-16 | 1997-05-27 | Lg Chemical Ltd. | Quinoline carboxylic acid derivatives having 7-(4-amino-methyl-3-oxime) pyrrolidine substituent and processes for preparing thereof |
| US6313299B1 (en) | 1997-06-26 | 2001-11-06 | Dong Wha Pharmaceutical Industrial Co., Ltd. | Quinolone carboxylic acid derivatives |
| US20100184795A1 (en) | 2007-04-13 | 2010-07-22 | Dong Wha Pharmaceutical Ind. Co. Ltd | Aspartate of 1-cyclopropyl-6-fluoro-7-(8-methoxyimino-2,6-diaza-spiro[3.4]oct-6-yl)-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid, method for preparing the same, and antimicrobial pharmaceutical composition comprising the same |
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| KR20150133433A (en) | 2015-11-30 |
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