KR101709543B1 - Novel voriconazole intermediate and synthesis of voriconazole - Google Patents

Novel voriconazole intermediate and synthesis of voriconazole Download PDF

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KR101709543B1
KR101709543B1 KR1020140176067A KR20140176067A KR101709543B1 KR 101709543 B1 KR101709543 B1 KR 101709543B1 KR 1020140176067 A KR1020140176067 A KR 1020140176067A KR 20140176067 A KR20140176067 A KR 20140176067A KR 101709543 B1 KR101709543 B1 KR 101709543B1
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구영삼
김정태
윤도배
이병우
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(주) 에프엔지리서치
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Abstract

본 발명은 1) 하기 화학식 4의 화합물과 하기 화학식 5의 화합물을 리포마스키 유형 커플링 반응시켜 하기 화학식 3의 화합물을 합성하는 단계; 2) 상기 화학식 3의 화합물에서 치환기인 티올기 및 클로로기를 제거하여 하기 화학식 2의 라세메이트 보리코나졸을 수득하는 단계; 및 3) 상기 화학식 2의 라세메이트 화합물을 광학적 활성산을 이용하여 광학분리하는 단계를 포함하는, 하기 화학식 1의 보리코나졸의 제조 방법을 제공한다.

Figure 112014119784717-pat00025

(상기 화학식들에서,
R은 페닐, 피리딘, 피리미딘, 티아졸, 벤조티아졸, 벤조옥사졸, 이미다졸, 1-메틸이미다졸, C1~C4 알킬 또는 이들 화합물의 치환체이고, 상기 치환체의 치환기는 각각 독립적으로 할로, 니트로 및 메톡시 중에서 선택된 1종 이상이다.)The present invention relates to a process for preparing a compound represented by the following general formula (1): (1) synthesizing a compound represented by the following general formula (3) by reacting a compound represented by the following general formula (4) 2) removing the thiol group and the chloro group which are substituents in the compound of Formula 3 to obtain racemate boricconazole of Formula 2; And 3) optically separating the racemic compound of formula (2) using an optically active acid.
Figure 112014119784717-pat00025

(In the above formulas,
R is phenyl, pyridine, pyrimidine, thiazole, benzothiazole, benzoxazole, imidazole, 1-methylimidazole, C 1 -C 4 alkyl or substituents of these compounds, And is at least one selected from halo, nitro and methoxy.

Description

신규한 보리코나졸 중간체 및 이를 이용한 보리코나졸의 제조 방법{Novel voriconazole intermediate and synthesis of voriconazole}Novel voriconazole intermediate and synthesis of voriconazole, a novel voriconazole intermediate,

본 발명은 보리코나졸(Voriconazole)의 중간체 및 이를 이용한 보리코나졸의 제조 방법에 관한 것이다.
The present invention relates to an intermediate of Voriconazole, and a process for the preparation of boriconazole using the intermediate.

보리코나졸(Voriconazole)은 하기 화학식 1로 표시되며 (2R,3S)-2-(2,4-디플루오로페닐)-3-(5-플루오로피리미딘-4-일)-1-(1H-1,2,4-트리아졸-1-일)부탄-2-올[2R,3S-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol]의 일반명을 가진다.Voriconazole is represented by the following formula (1) and is represented by the following formula (1): (2R, 3S) -2- (2,4-difluorophenyl) -3- (5-fluoropyrimidin- 2, 4-difluorophenyl) -3- (5-fluoropyrimidin-4-yl) -1- 1H-1,2,4-triazol-1-yl) butan-2-ol].

[화학식 1][Chemical Formula 1]

Figure 112014119784717-pat00001
Figure 112014119784717-pat00001

보리코나졸은 항진균제로 잘 알려져 있으며, 화이자사(Pfizer)에서 상품명 "Vfend"로 시판되고 있다. 보리코나졸은 미생물 중 칸디다(candida), 트리코피톤(Trichophyton), 마이크로스포룸(microspourum), 에피더모피톤(Epidemophyton) 종에 의해 유발된 인간의 국소적 진균성 감염 또는 칸디다 알비칸스(candida albicans)에 의해 유발된 점막을 치료하는 데 유용한 것으로 알려져 있다.Voriconazole is well known as an antifungal agent and is commercially available from Pfizer under the trade designation "Vfend ". Voriconazole is a topical fungal infection of humans induced by Candida, Trichophyton, Microspourum, Epidemophyton species in microorganisms or Candida albicans ), ≪ / RTI >

상기 화학식 1에서와 같이, 보리코나졸은 중심에 인접한 2개의 비대칭 탄소를 가지므로, 이론적으로는 총 4가지의 입체이성질체가 생성될 수 있다. 따라서, 의약품의 광학적 특징상 2개의 비대칭 탄소가 형성되는 반응에서의 입체 선택성의 증가와 원하는 입체이성질체의 효과적인 분리공정이 요구된다.As shown in the above formula (1), since the voriconazole has two asymmetric carbons adjacent to the center, theoretically, four kinds of stereoisomers can be produced in total. Therefore, an increase in stereoselectivity in a reaction in which two asymmetric carbons are formed due to the optical characteristics of a drug, and an effective separation process of a desired stereoisomer are required.

보리코나졸의 최초 합성 방법은 유럽특허 제0440372호[패밀리 특허: 미국특허 제5,278,175호, 대한민국 특허공보 제10-1993-0011039호]에 하기 반응식 1과 같은 방법으로 개시되어 있다.The first method of synthesizing boricone sol is disclosed in European Patent No. 0440372 (Family Patent: US Patent No. 5,278,175, Korean Patent Publication No. 10-1993-0011039) as shown in the following Reaction Scheme 1.

[반응식 1][Reaction Scheme 1]

Figure 112014119784717-pat00002
Figure 112014119784717-pat00002

상기 특허는 -70℃ ~ -50℃ 조건 하에서 4-클로로-6-에틸-5-플루오로피리미딘의 유기 리튬 유도체를 1-(2,4-디플루오로페닐)-2-(1H-1,2,4-트리아졸-1-일)에탄온에 첨가하여 커플링 반응시켜 얻어진 거울상 이성질체를 컬럼 크로마토그래피로 분리하여 보리코나졸(2R,3S)을 제조하는 방법을 개시하고 있다. 그러나 상기 특허에 따르면 (2R,3S/2S,3R):(2R,3R/2S,3S)의 비율이 1.1:1 몰비로 입체 선택성이 낮을 뿐 아니라, (2R,3S/2S,3R) 거울상 입체이성질체의 쌍 분리후 수율이 12~25%로 매우 낮아 대량 생산하기에 적합하지 않다.The patent discloses that an organolithium derivative of 4-chloro-6-ethyl-5-fluoropyrimidine is reacted with 1- (2,4-difluorophenyl) -2- (1H- , 2,4-triazol-1-yl) ethanone and subjected to a coupling reaction, thereby separating the obtained enantiomer by column chromatography to prepare a solution of boricone sol (2R, 3S). However, according to the patent, the ratio of (2R, 3S / 2S, 3R): (2R, 3R / 2S, 3S) is 1.1: 1, The yield after isomer separation is as low as 12 ~ 25%, which is not suitable for mass production.

유럽특허 제0871625호[패밀리 특허: 미국특허 제6,586,594호, 대한민국 특허공개 제10-1999-0036174호]는 하기 반응식 2에 보이는 바와 같이 리포마스키 유형 반응(Reformatsky-type reaction)을 이용함으로써 거울상 입체이성질체의 입체 선택성을 (2R,3S/2S,3R):(2R,3R/2S,3S) = 9:1 몰비로 높이고 반응 수율도 향상시켰으나, 수율은 66%로 여전히 낮으며, 출발 물질로 사용되는 피리미딘 유도체가 액상이므로 미반응물을 정제하기가 어렵고, 순도가 낮아 반응이 완결되지 않는 문제점이 있다.European Patent No. 0871625 [Family Patent: U.S. Patent No. 6,586,594, Korean Patent Laid-Open No. 10-1999-0036174] discloses a method for producing an enantiomeric enantiomer by using a Reformatsky-type reaction as shown in Reaction Scheme 2 below. (2R, 3S / 2S, 3R): (2R, 3R / 2S, 3S) = 9: 1 molar ratio and the reaction yield was improved, but the yield was still low as 66% , The unreacted product is difficult to purify and the purity is low, so that the reaction is not completed.

[반응식 2][Reaction Scheme 2]

Figure 112014119784717-pat00003
Figure 112014119784717-pat00003

대한민국 특허공개 제10-2009-0014468호는 피리미딘 유도체의 순도를 높이기 위하여 하기 반응식 3의 방법으로 피리미딘 유도체에 티올기를 도입하여 치환된 티오 피리미딘 유도체를 합성하였다.Korean Patent Laid-Open No. 10-2009-0014468 discloses a thiopyrimidine derivative substituted by introducing a thiol group into a pyrimidine derivative by the method of Reaction Scheme 3 below to increase the purity of the pyrimidine derivative.

[반응식 3][Reaction Scheme 3]

Figure 112014119784717-pat00004
Figure 112014119784717-pat00004

대한민국 특허등록 제10-0971371호는 피리미딘 유도체의 순도를 높이기 위하여 하기 반응식 4의 방법으로 피리미딘 유도체에 설폰기를 도입하여 치환된 피리미딘 설포네이트를 이용하여 보리코나졸을 합성하였다.Korean Patent Registration No. 10-0971371 discloses a method of synthesizing boricone sol by using a substituted pyrimidine sulfonate by introducing a sulfone group into a pyrimidine derivative by the method of Reaction 4 to increase the purity of the pyrimidine derivative.

[반응식 4][Reaction Scheme 4]

Figure 112014119784717-pat00005
Figure 112014119784717-pat00005

상기 반응식 3 및 4는 모두 6-에틸-5-플루오로-4-히드록시피리미딘을 출발물질로 이용하는 데, 상기 6-에틸-5-플루오로-4-히드록시피리미딘은 하기 반응식 5과 같이 a) 또는 b)의 방법으로 합성된다. 방법 a)는 수소화 팔라듐 촉매반응을 이용하므로 생산비가 많이 소요되고, 방법 b)는 출발물질인 2-플루오로-3-옥소펜탄산 에틸 에스테르가 고가이므로 경제성이 떨어지는 단점이 있다.In the above reaction schemes 3 and 4, 6-ethyl-5-fluoro-4-hydroxypyrimidine is used as a starting material. Are synthesized by the methods of a) or b). The process a) requires a large production cost because it utilizes a palladium hydrogenation catalyst, and the process b) has a disadvantage in that the starting material, 2-fluoro-3-oxopentanoic acid ethyl ester, is expensive and therefore economical.

[반응식 5][Reaction Scheme 5]

Figure 112014119784717-pat00006

Figure 112014119784717-pat00006

본 발명은 종래 기술에 비해 저가의 출발물질을 이용하면서도, 합성 공정이 개선되는 한편, 고수율의 보리코나졸를 제조하는 방법을 제공하는 데 그 목적이 있다.
It is an object of the present invention to provide a method for producing a high yield of boricone sol while using an inexpensive starting material as compared with the prior art, while improving the synthesis process.

상기 목적을 달성하기 위하여 본 발명은, According to an aspect of the present invention,

1) 하기 화학식 4의 화합물과 하기 화학식 5의 화합물을 리포마스키 유형 커플링 반응시켜 하기 화학식 3의 화합물을 합성하는 단계; 1) synthesizing a compound represented by the following formula (3) by subjecting a compound represented by the following formula (4) and a compound represented by the following formula (5) to lipomaski type coupling reaction;

2) 상기 화학식 3의 화합물로부터 티올기 및 클로로기를 제거하여 하기 화학식 2의 라세메이트 보리코나졸을 수득하는 단계; 및 2) removing the thiol group and the chloro group from the compound of Formula 3 to obtain racemate boricconazole of Formula 2; And

3) 상기 화학식 2의 라세메이트 화합물을 광학적 활성산을 이용하여 광학분리하는 단계를 포함하는 하기 화학식 1의 보리코나졸의 제조 방법을 제공한다.3) optically separating the racemate compound of Formula 2 with an optically active acid.

Figure 112014119784717-pat00007
Figure 112014119784717-pat00007

(상기 화학식들에서(In the above formulas

R은 페닐, 피리딘, 피리미딘, 티아졸, 벤조티아졸, 벤조옥사졸, 이미다졸, 1-메틸이미다졸, C1~C4 알킬 또는 이들 화합물의 치환체이고, 상기 치환체의 치환기는 각각 독립적으로 할로, 니트로 및 메톡시 중에서 선택된 1종 이상이다.)R is phenyl, pyridine, pyrimidine, thiazole, benzothiazole, benzoxazole, imidazole, 1-methylimidazole, C 1 -C 4 alkyl or substituents of these compounds, And is at least one selected from halo, nitro and methoxy.

상기 단계 1)의 화학식 5의 신규 보리코나졸 중간체는,The novel boricone sol intermediate of formula (5) in step 1)

하기 화학식 10의 화합물 또는 화학식 11의 화합물을 옥시염화인(POCl3)과 반응시켜 하기 화학식 9의 화합물을 합성하는 단계; 상기 화학식 9의 화합물과 할로에탄 화합물과 반응시켜 하기 화학식 8의 화합물을 합성하는 단계; 상기 화학식 8의 화합물을 하기 화학식 8의 티올 화합물과 반응시켜 하기 화학식 6의 화합물을 합성하는 단계; 및 상기 화학식 6의 화합물을 할로겐 공여체(halogen donor)과 반응시켜 상기 화학식 6의 화합물의 에틸기의 1번 위치를 할로기로 치환시키는 단계를 포함하여 합성될 수 있다.Reacting a compound of formula (10) or a compound of formula (11) with phosphorus oxychloride (POCl 3 ) to synthesize a compound of formula (9); Reacting the compound of Formula 9 with a haloethane compound to synthesize a compound of Formula 8; Reacting the compound of Formula 8 with a thiol compound of Formula 8 to synthesize a compound of Formula 6; And reacting the compound of Formula 6 with a halogen donor to replace the 1-position of the ethyl group of the compound of Formula 6 with a halo group.

Figure 112014119784717-pat00008
Figure 112014119784717-pat00008

(상기 화학식들에서(In the above formulas

R은 페닐, 피리딘, 피리미딘, 티아졸, 벤조티아졸, 벤조옥사졸, 이미다졸, 1-메틸이미다졸, C1~C4 알킬 또는 이들 화합물의 치환체이고, 상기 치환체의 치환기는 각각 독립적으로 할로, 니트로 및 메톡시 중에서 선택된 1종 이상이다.)
R is phenyl, pyridine, pyrimidine, thiazole, benzothiazole, benzoxazole, imidazole, 1-methylimidazole, C 1 -C 4 alkyl or substituents of these compounds, And is at least one selected from halo, nitro and methoxy.

본 발명에 따른 보리코나졸 제조 방법은 고순도 및 고수율로 대량 생산에 유리하다. 또한, 저가의 우라실 유도체를 이용하고, 종래 기술에 비해 반응 공정수가 줄어들어 생산 비용, 생산 시간 면에서 유리한 효과가 있다.
The production method of the boriconazole according to the present invention is advantageous for mass production with high purity and high yield. In addition, the use of low-cost uracil derivatives reduces the number of reaction steps compared to the prior art, which is advantageous in terms of production cost and production time.

본 발명자들은 하기 반응식에 보이는 바와 같이 우라실(Uracil) 초기 유도체인 5-플루오로우라실(화학식 10) 또는 5-플루오르피리미딘-2,4-디올(화학식 11)을 이용하여 일련의 공정을 거쳐 신규 보리코나졸 중간체(화학식 5)를 합성한 다음, 상기 신규 보리코나졸 중간체(화학식 5)로부터 공지의 방법으로 보리코나졸(화학식 1)을 합성하여 본 발명을 완성하였다.As shown in the following reaction formula, the present inventors conducted a series of processes using a 5-fluorouracil ( Formula 10 ) or 5-fluoropyrimidine-2,4-diol ( Formula 11 ), which is an early derivative of Uracil, voriconazole intermediate synthesize (formula 5), and then, the voriconazole (I) by known methods from the novel voriconazole intermediates (formula V) and completed the present invention by synthesis.

Figure 112014119784717-pat00009
Figure 112014119784717-pat00009

(상기 화학식들에서(In the above formulas

R은 페닐, 피리딘, 피리미딘, 티아졸, 벤조티아졸, 벤조옥사졸, 이미다졸, 1-메틸이미다졸, C1~C4 알킬 또는 이들 화합물의 치환체이고, 상기 치환체의 치환기는 각각 독립적으로 할로, 니트로 및 메톡시 중에서 선택된 1종 이상이다.)R is phenyl, pyridine, pyrimidine, thiazole, benzothiazole, benzoxazole, imidazole, 1-methylimidazole, C 1 -C 4 alkyl or substituents of these compounds, And is at least one selected from halo, nitro and methoxy.

본 발명의 주요 특징은 상기 화학식 5로 표시되는 바와 같이 티올기가 유도된 신규 보리코나졸 중간체를 이용하는 데 있다. 티올기가 도입된 보리코나졸 중간체는 배경기술에서 설명한 바와 같이 대한민국 특허공개 제10-2009-0014468호에 하기 반응식 3으로 공지되어 있는 데, 상기 특허는 피리민딘 2번 위치에 클로로기가 없는 반면, 본 발명은 피리민딘 2번 위치에 클로로기가 있는 피리미딘 중간체를 보리코나졸 합성에 이용하는 데 특징이 있다.The main feature of the present invention is to use a novel boronicazole intermediate in which a thiol group is derived as shown in the above formula (5). As described in the Background of the Invention, a boriconeazole intermediate to which a thiol group is introduced is known from Korean Patent Laid-Open No. 10-2009-0014468 by the following Reaction Scheme 3, and the patent does not have a chloro group at the position 2 of pyrimidine, The invention is characterized by the use of pyrimidine intermediates having a chloro group at position 2 of pyrimidine in the synthesis of boriconazole.

[반응식 3][Reaction Scheme 3]

Figure 112014119784717-pat00010
Figure 112014119784717-pat00010

특허공개 제10-2009-0014468호는 상기 반응식 3에 보이는 바와 같이 6-에틸-5-플루오로-4-히드록시피리미딘의 하드록시기를 클로로기로 치환한 다음 티올기를 도입하는 데, 중국특허등록 CN102190628B는 피리미딘 2번 위치에 하이드록시기가 제거된 6-에틸-5-플루오로-4-히드록시피리미딘를 합성하기 위하여 하기 반응식 8과 같이 매우 복잡한 공정을 거친다.Patent Publication No. 10-2009-0014468 discloses a method in which a thiol group is introduced by substituting chloro group for a 6-ethyl-5-fluoro-4-hydroxypyrimidine with a hydroxy group as shown in Reaction Scheme 3, CN102190628B is subjected to a very complicated process as shown in the following Reaction Scheme 8 to synthesize 6-ethyl-5-fluoro-4-hydroxypyrimidine in which the hydroxy group is removed at the position 2 of pyrimidine.

[반응식 8][Reaction Scheme 8]

Figure 112014119784717-pat00011
Figure 112014119784717-pat00011

이에 반해, 본 발명은 6-에틸-5-플루오로-4-히드록시피리미딘 과정을 거칠 필요없이 상기 화학식 8의 화합물로부터 곧바로 티올기를 도입하여 보리코나졸을 합성할 수 있음을 확인하였다. 본 발명의 제조 방법은 상기 특허공개 제10-2009-0014468호에 비해 3개 공정을 줄이는 잇점이 있다.
On the other hand, it was confirmed that the present invention can introduce the thiol group directly from the compound of the formula (8) without the need for the 6-ethyl-5-fluoro-4-hydroxypyrimidine process to synthesize the boricone. The manufacturing method of the present invention has the advantage of reducing the number of processes by 3 compared to the above-mentioned Patent Publication No. 10-2009-0014468.

이하, 본 발명을 반응단계 별로 설명한다.Hereinafter, the present invention will be described in terms of reaction steps.

본 발명의 하기 화학식 1의 보리코나졸 제조 방법은 하기 반응식 7에 도시된 바와 같이, The process for preparing a boricone sol of the present invention represented by the following formula (1)

1) 하기 화학식 4의 화합물과 하기 화학식 5의 화합물을 리포마스키 유형 커플링 반응시켜 하기 화학식 3의 화합물을 합성하는 단계; 1) synthesizing a compound represented by the following formula (3) by subjecting a compound represented by the following formula (4) and a compound represented by the following formula (5) to lipomaski type coupling reaction;

2) 상기 화학식 3의 화합물로부터 티올기 및 클로로기를 제거하여 하기 화학식 2의 라세메이트 보리코나졸을 수득하는 단계; 및 2) removing the thiol group and the chloro group from the compound of Formula 3 to obtain racemate boricconazole of Formula 2; And

3) 상기 화학식 2의 라세메이트 화합물을 광학적 활성산을 이용하여 광학분리하는 단계를 포함하여 이루어진다.3) optically separating the racemate compound of Formula 2 with an optically active acid.

[반응식 7][Reaction Scheme 7]

Figure 112014119784717-pat00012
Figure 112014119784717-pat00012

(상기 반응식에서,(In the above scheme,

R은 페닐, 피리딘, 피리미딘, 티아졸, 벤조티아졸, 벤조옥사졸, 이미다졸, 1-메틸이미다졸, C1~C4 알킬 또는 이들 화합물의 치환체이고, 상기 치환체의 치환기는 각각 독립적으로 할로, 니트로 및 메톡시 중에서 선택된 1종 이상이다.)R is phenyl, pyridine, pyrimidine, thiazole, benzothiazole, benzoxazole, imidazole, 1-methylimidazole, C 1 -C 4 alkyl or substituents of these compounds, And is at least one selected from halo, nitro and methoxy.

상기 단계 1)에서 화학식 4와 화학식 5의 신규 화합물을 이용하여 공지의 반응 조건인 리포마스키 유형 커플링 반응을 이용하여 반응시킨다. 반응온도는 바람직하게는 -15 내지 0℃에서 실시되며, 생성되는 거울상 이성질체 쌍 (2R,3S/2S,3R:2R,3R/2S,3S)의 비율은 약 10:1로 생성된다. 이러한 (2R,3S/2S,3R)거울상 이성질체 쌍은 IPA와 같은 유기 용매에서의 결정화를 통해 쉽게 분리가 가능하고 순도 99%이상, 수율 80% 이상의 고순도와 고수율의 화학식 3의 화합물이 제조될 수 있다.In the above step 1), the novel compounds of the formulas (4) and (5) are reacted using the lipomasquivalent coupling reaction known in the art. The reaction temperature is preferably from -15 to 0 캜, and the ratio of the resulting enantiomeric pair (2R, 3S / 2S, 3R: 2R, 3R / 2S, 3S) is about 10: 1. Such (2R, 3S / 2S, 3R) enantiomer pairs can be easily separated through crystallization in an organic solvent such as IPA, and a compound of formula (3) with a purity of 99% or higher and a yield of 80% .

상기 단계 2)는 Pd/C, 라니니켈 또는 아연을 촉매로 사용하고 수소 공여체로 수소기체 또는 암모늄 포름산을 이용하여 피리미딘의 설포닐기 뿐 만 아니라 클로로기도 동시에 완전히 제거되면서 화학식 2의 (2R,3S/2S,3R)라세메이트 보리코나졸이 수득된다. 상기 반응의 경우 불순물이 거의 생성되지 않아 순도는 99% 이상, 수율은 90% 이상으로 합성된다.The above step 2) can be carried out by using Pd / C, Raney nickel, or zinc as a catalyst, and using hydrogen gas or ammonium formic acid as a hydrogen donor, not only the sulfonyl group of pyrimidine but also chloro- / 2S, 3R) racemate boricone sol is obtained. In the case of the reaction, almost no impurities are generated, and the purity is 99% or more and the yield is 90% or more.

상기 단계 3)의 경우 화학식 2의 화합물을 적당한 광학 활성산, 바람직하게는 R-(-)-10-캠포설폰산과 반응시켜 (2R,3S)이성질체를 결정화시킨 다음, 불순물 제거 공정을 거치면 최종적으로 고체의 보리코나졸이 수득된다.In step 3), the compound of formula 2 is reacted with a suitable optically active acid, preferably R - (-) - 10-camphorsulfonic acid to crystallize the (2R, 3S) isomer, To give a solid boricone sol.

본 발명의 제조 방법은 순도 99.95% 이상, 고수율의 보리코나졸을 제공한다.The preparation method of the present invention provides a high yield of the boricone sol having a purity of 99.95% or more.

상술한 상기 화학식 5의 보리코나졸 중간체 화합물은 우라실(화학식 10) 또는 우라실의 초기 유도체(화학식 11)로부터 하기 반응식 8의 합성법을 통해 제조될 수 있다.The above-mentioned boricone sol intermediate compound of formula (5) can be prepared from uracil (10) or an early derivative of uracil (11) by the synthesis of the following reaction formula (8).

[반응식 8][Reaction Scheme 8]

Figure 112014119784717-pat00013
Figure 112014119784717-pat00013

(상기 반응식에서(In the above reaction formula

R은 페닐, 피리딘, 피리미딘, 티아졸, 벤조티아졸, 벤조옥사졸, 이미다졸, 1-메틸이미다졸, C1~C4 알킬 또는 이들 화합물의 치환체이고, 상기 치환체의 치환기는 각각 독립적으로 할로, 니트로 및 메톡시 중에서 선택된 1종 이상이다.)
R is phenyl, pyridine, pyrimidine, thiazole, benzothiazole, benzoxazole, imidazole, 1-methylimidazole, C 1 -C 4 alkyl or substituents of these compounds, And is at least one selected from halo, nitro and methoxy.

이하, 실시예를 통하여 본 발명의 제조 방법을 더욱 상세히 설명한다. 하기 실시예는 본 발명의 예시하기 위한 것일 뿐, 본 발명의 범위가 실시예에 한정되는 것은 아니다.Hereinafter, the production method of the present invention will be described in more detail with reference to Examples. The following examples are illustrative of the present invention, but the scope of the present invention is not limited to these examples.

[실시예 1][Example 1]

Figure 112014119784717-pat00014
Figure 112014119784717-pat00014

(A) 2,4-디클로로-5-플루오로피리미딘 (화학식 9)의 합성(A) Synthesis of 2,4-dichloro-5-fluoropyrimidine (9)

반응기에 5-플루오로우라실(화학식 10) 11.1g(85.3m㏖)과 옥시염화인(POCl3) 39.4g(257.0m㏖)을 투입하고 95℃로 승온한 후 N,N-디메틸아민(DMA) 20.7g을 1시간 동안 적가하고 120℃로 승온하여 3시간 동안 교반하였다. 온도를 0℃로 냉각하고 3N HCl 수용액 1500ml를 10℃ 이하에서 적가하였다. 적가 완료 후 10℃에서 3시간 교반 후 여과하고 건조하여 2,4-디클로로-5-플루오로피리미딘(화학식 9) 13.4g(80.3m㏖)을 얻었다.(수율:94%)11.1 g (85.3 mmol) of 5-fluorouracil ( Formula 10 ) and 39.4 g (257.0 mmol) of phosphorus oxychloride (POCl 3 ) were added to the reactor, and the temperature was raised to 95 ° C. N, N-Dimethylamine ) Was added dropwise for 1 hour, the temperature was raised to 120 ° C and the mixture was stirred for 3 hours. The temperature was cooled to 0 占 폚 and 1500 ml of 3N HCl aqueous solution was added dropwise at 10 占 폚 or lower. After completion of the dropwise addition, the mixture was stirred at 10 캜 for 3 hours, filtered and dried to obtain 13.4 g (80.3 mmol) of 2,4-dichloro-5-fluoropyrimidine 9 (yield: 94%

1H NMR(400MHz, CDCl3) δ 8.5(1H) ppm 1 H NMR (400MHz, CDCl 3 ) δ 8.5 (1H) ppm

(B) 2,4-디클로로-6-에틸-5-플루오로피리미딘 (화학식 8)의 합성(B) Synthesis of 2,4-dichloro-6-ethyl-5-fluoropyrimidine 8

반응기에 마그네슘 분말 16.3g과 테트라하이드로퓨란(THF) 280ml를 투입하고 40℃이하에서 브로모에탄 72.9g(669.0m㏖)을 서서히 적가하였다. 적가 완료 후 4시간 교반한 다음 0℃로 냉각하고 상기 수득된 2,4-디클로로-5-플루오로피리미딘(화학식 9) 56.0g(335.4m㏖)을 테트라하이드로퓨란 150ml에 용해하여 10℃이하에서 적가하였다. 15℃에서 2시간 교반 후 다시 0℃로 냉각하고 트리에틸아민(TEA) 33.9g을 테트라하이드로퓨란 56ml로 희석하여 5℃이하에서 1시간동안 적가하였다. 요오드 분말 85.1g을 테트라하이드로퓨란 56ml에 용해하여 1시간 동안 적가하고 2시간 교반하였다. 정제수 1000ml를 투입 후 5N HCl 수용액으로 pH를 1로 맞춘 후 톨루엔 600ml로 추출하였다. 추출한 유기층은 2% NaHSO3 600ml로 세척하고 유기층에 남아 았는 물은 MgSO4 처리 제거 후 여과하고 진공 농축하여 2,4-디클로로-6-에틸-5-플루오로피리미딘(화학식 8) 58.2g(298.4m㏖)을 얻었다.(수율: 89%)16.3 g of magnesium powder and 280 ml of tetrahydrofuran (THF) were charged into the reactor, and 72.9 g (669.0 mmol) of bromoethane was slowly added dropwise at 40 占 폚 or lower. After the addition was complete, stirring for 4 hours and then cooled to 0 ℃ was dissolved pyrimidine (chemical formula 9) 56.0g (335.4m㏖) to the obtained 2,4-dichloro-5-fluoro tetrahydrofuran 150ml below 10 ℃ Lt; / RTI > After stirring at 15 DEG C for 2 hours, the reaction mixture was cooled to 0 DEG C, and 33.9 g of triethylamine (TEA) was diluted with 56 mL of tetrahydrofuran and added dropwise at 5 DEG C or lower for 1 hour. 85.1 g of iodine powder was dissolved in 56 ml of tetrahydrofuran, and the mixture was added dropwise for 1 hour and stirred for 2 hours. After adding 1000 ml of purified water, the pH was adjusted to 1 with 5N HCl aqueous solution, and then extracted with 600 ml of toluene. The extracted organic layer was washed with 600ml 2% NaHSO 3, and the remaining organic layer is MgSO 4 atneun water treatment was removed by filtration and pyrimidine (Formula 8), 2,4-dichloro-6-ethyl-5-fluoro concentrated in vacuo and then 58.2g ( 298.4 mmol). (Yield: 89%).

1H NMR(400MHz, CDCl3) δ 1.3(3H) 2.9(2H) ppm 1 H NMR (400 MHz, CDCl 3 )? 1.3 (3H) 2.9 (2H) ppm

(C) 2-클로로-4-에틸-5-플루오로-6-(페닐티오)피리미딘 (화학식 6a)의 합성(C) Synthesis of 2-chloro-4-ethyl-5-fluoro-6- (phenylthio) pyrimidine (6a)

상기 수득된 2,4-디클로로-6-에틸-5-플루오로피리미딘(화학식 8) 58.2g(298.4m㏖)를 아세토니트릴(CH3CN) 600ml에 투입하여 용해하고 N,N'-디이소프로필에틸아민(DIPEA) 42.9g을 투입하고 0℃로 냉각하였다. 티오페놀(화학식 7a) 36.1g(327.6m㏖)을 5℃이하에서 1시간 동안 적가하고 실온으로 승온하여 3시간 교반하였다. 40℃에서 진공 농축하여 아세토니트릴을 제거하고 정제수 500ml 투입 교반하고 에틸아민(EA) 500ml로 추출하였다. 유기층에 남아 았는 물은 MgSO4 처리 제거 후 여과 하고 진공 농축하여 2-클로로-4-에틸-5-플루오로-6-(페닐티오)피리미딘(화학식 6a) 78.6g(292.5m㏖)을 얻었다.(수율: 98%)58.2 g (298.4 mmol) of the obtained 2,4-dichloro-6-ethyl-5-fluoropyrimidine 8 was dissolved in 600 ml of acetonitrile (CH 3 CN) to dissolve N, N'-di 42.9 g of isopropylethylamine (DIPEA) was added and cooled to 0 占 폚. 36.1 g (327.6 mmol) of thiophenol ( Formula 7a ) was added dropwise at 5 DEG C or lower for 1 hour, the temperature was raised to room temperature, and the mixture was stirred for 3 hours. The mixture was concentrated in vacuo at 40 캜 to remove acetonitrile, 500 ml of purified water was added thereto, stirred and extracted with 500 ml of ethylamine (EA). Atneun remain in the organic layer is MgSO 4 water process then filtered off and concentrated in vacuo to give 2-chloro-4-ethyl-5-fluoro-6- (phenylthio) pyrimidine to give the (formula 6a) 78.6g (292.5m㏖) . (Yield: 98%).

1H NMR(400MHz, CDCl3) δ 1.2~1.3(3H) 2.7(2H) 7.4~7.5(5H) ppm 1 H NMR (400 MHz, CDCl 3 )? 1.2-1.3 (3H) 2.7 (2H) 7.4-7.5 (5H) ppm

(D) 4-(1-브로모에틸)-2-클로로-5-플루오로-6-(페닐티오)피리미딘 (화학식 5a) 의 합성(D) Synthesis of 4- (1-bromoethyl) -2-chloro-5-fluoro-6- (phenylthio) pyrimidine

상기 수득된 2-클로로-4-에틸-5-플루오로-6-(페닐티오)피리미딘(화학식 6a) 78.6g(292.5m㏖)을 메틸렌클로라이드(MC) 700ml에 용해하고 N-브로모숙신이미드(NBS) 62.4g(350.6m㏖)과 아조비스이소부티로니트릴(AIBN) 5.0g을 투입하고 40℃로 승온하여 24시간 교반한 후 실온으로 냉각하고 정제수 800ml를 투입하고 층분리하였다. 유기층은 4% NaHSO3 수용액 600ml로 세척하고 다시 7% NaHCO3수용액으로 세척하였다. 유기층에 남아 았는 물은 MgSO4 처리 제거 후 여과하고 진공 농축하고 Hx?? 250ml 투입하고 실온에서 1시간 교반후 0℃로 냉각하여 2시간 교반후 여과하고 진공 건조하여 4-(1-브로모에틸)-2-클로로-5-플루오로-6-(페닐티오)피리미딘(화학식 5a) 99.6g(286.5m㏖)을 얻었다.(수율: 98%)78.6 g (292.5 mmol) of the obtained 2-chloro-4-ethyl-5-fluoro-6- (phenylthio) pyrimidine 6a was dissolved in 700 ml of methylene chloride (MC) 62.4 g (350.6 mmol) of imide (NBS) and 5.0 g of azobisisobutyronitrile (AIBN) were charged, and the mixture was heated to 40 DEG C, stirred for 24 hours, cooled to room temperature, and 800 ml of purified water was added thereto. The organic layer was washed with 600 ml of 4% NaHSO 3 aqueous solution and again with 7% aqueous NaHCO 3 solution. The organic layer was washed with MgSO 4 , filtered and concentrated in vacuo. And the mixture was stirred at room temperature for 1 hour, cooled to 0 deg. C and stirred for 2 hours, followed by filtration and vacuum drying to obtain 4- (1-bromoethyl) -2-chloro-5-fluoro-6- (phenylthio) (Yield: 98%) of 99.6 g (286.5 mmol) of ( Formula 5a ).

1H NMR(400MHz, CDCl3) δ 2.0(3H) 5.2(1H) 7.4~7.5(5H) ppm 1 H NMR (400 MHz, CDCl 3 )? 2.0 (3H) 5.2 (1H) 7.4-7.5 (5H) ppm

(E) 3-(2-클로로-5-플루오로-6-(페닐티오)피리미딘-4-일)-2-(2,4-디플루오로페닐)-1-(1H-1,2,4-트리아졸-1-일)부탄-2-올 (화학식 3a)의 합성(E) 3- (2-Chloro-5-fluoro-6- (phenylthio) pyrimidin-4-yl) -2- (2,4- difluorophenyl) , 4-triazol-1-yl) butan-2-ol (formula 3a)

질소 대기하에서 아연 분말 14.1g, 납 분말 0.7g을 무수 테트라하이드로퓨란 70ml를 투입 교반하고 요오드 분말 29.5g을 무수 테트라하이드로퓨란 100ml에 용해하여 50℃이하에서 적가하였다. 적가 완료 후 1시간 교반하고 -15℃이하로 냉각하였다. 상기 수득된 4-(1-브로모에틸)-2-클로로-5-플루오로-6-(페닐티오)피리미딘(화학식 5a) 17.9g(51.5m㏖), 1-(2,4-디플루오로페닐)-2-(1H-1,2,4-트리아졸-1-일)에탄온(화학식 4) 9.59g(43.0m㏖), 요오드 분말 3.7g을 무수 테트라하이드로퓨란 100ml에 용해하여 -5℃이하에서 1시간 동안 적가하고 적가 완료 후 1시간 추가 교반하였다. 반응이 종결된 후 정제수 400ml을 투입하고 실온에서 1시간 교반하였다. 고체 잔류물은 여과하여 제거 후 메틸렌클로라이드 350ml 투입하여 추출하였다. 유기층은 10% HCl 수용액 200ml로 세척하고 다시 4% NaHSO3 수용액 200ml로 세척하고 7% NaHCO3 수용액 300ml로 세척하고 다시 2% 에틸렌다이아민테트라아세트산(EDTA) 수용액으로 세척하였다. 유기층에 남아 았는 물은 MgSO4 처리 제거 후 여과 하고 진공 농축하고 이소프로필에테르(IPE) 100ml을 투입하고 실온에서 1시간 교반 후 0℃로 냉각하여 2시간 교반후 여과하고 진공 건조하여 3-(2-클로로-5-플루오로-6-(페닐티오)피리미딘-4-일)-2-(2,4-디플루오로페닐)-1-(1H-1,2,4-트리아졸-1-일)부탄-2-올(화학식 3a) 14.8g(30.1m㏖)을 얻었다.(수율: 70%)Under a nitrogen atmosphere, 14.1 g of zinc powder and 0.7 g of lead powder were mixed with 70 ml of anhydrous tetrahydrofuran, and 29.5 g of iodine powder was dissolved in 100 ml of anhydrous tetrahydrofuran. After completion of dropwise addition, the mixture was stirred for 1 hour and cooled to -15 캜 or lower. The resultant 4- (1-bromoethyl) -2-chloro-5-fluoro-6- (phenylthio) pyrimidine (formula 5a) 17.9g (51.5m㏖), l- (2,4- di 9.59 g (43.0 mmol) of iodine ( Formula 4 ) and 3.7 g of iodine powder were dissolved in 100 ml of anhydrous tetrahydrofuran, The mixture was added dropwise at -5 [deg.] C or lower for 1 hour, and further stirred for 1 hour after completion of dropwise addition. After completion of the reaction, 400 ml of purified water was added thereto, followed by stirring at room temperature for 1 hour. The solid residue was filtered off and extracted with 350 ml of methylene chloride. The organic layer was washed with 10% HCl aqueous solution and 200ml again washed with 4% NaHSO 3 solution 200ml, and washed with 7% NaHCO 3 solution and washed 300ml of 2% ethylene diamine tetraacetic acid (EDTA) solution back to. Atneun to remain in the organic layer with water is filtered to remove MgSO 4 and concentrated in vacuo and treated with isopropyl ether added (IPE) 100ml and cooled to 0 ℃ After stirring at room temperature for 1 hour and then stirred for 2 hours, filtered and dried under vacuum 3- (2 (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) Yl) butan-2-ol ( formula 3a ) (yield: 70%).

1H NMR(400MHz, CDCl3) δ 1.0~1.1(3H) 3.9~4.0(1H) 4.3~4.7(2H) 5.8(1H) 6.7~6.8(2H) 7.4~7.6(7H) 7.9(1H) ppm 1 H NMR (400 MHz, CDCl 3 )? 1.0-1.1 (3H) 3.9-4.0 (1H) 4.3-4.7 (2H) 5.8 (1H) 6.7-6.8 (2H) 7.4-7.6 (7H) 7.9

(F) 2-(2,4-디플루오로페닐)-3-(5-플루오로피리미딘-4-일)-1-(1H-1,2,4-트리아졸-1-일)부탄-2-올 (화학식 2)의 합성(F) Synthesis of 2- (2,4-difluorophenyl) -3- (5-fluoropyrimidin-4-yl) Ol (Formula 2)

상기 수득된 3-(2-클로로-5-플루오로-6-(페닐티오)피리미딘-4-일)-2-(2,4-디플루오로페닐)-1-(1H-1,2,4-트리아졸-1-일)부탄-2-올(화학식 3a) 9.3g(18.9m㏖)을 테트라하이드로퓨란 100ml 투입 교반 용해하고 아연 분말 8.8g을 투입하고 50℃로 승온한 후 포름산암모늄(NH4HCO2) 11.3g을 정제수 55ml에 용해하여 1시간 동안 적가하였다. 적가 완료 후 승온하여 8시간 환류 교반하였다. 실온으로 냉각하고 여과하여 고체 잔류물을 제거하 후 에틸아민 60ml로 추출하였다. 7% NaHCO3 수용액 100ml로 세척하고 유기층은 진공 농축하였다. 농축액에 에탄올 126ml 투입 용해하고 소듐 아세테이트 3.8g, 10% Pd/C 3.1g을 투입하고 수소가스를 5kgf/cm2을 채우고 45℃로 승온하여 12시간 교반하였다. 실온으로 냉각하고 여과하여 고체 잔류물을 제거하고 진공 농축하였다. 정제수 100ml, 메틸렌클로라이드 100ml을 투입 교반하여 추출하고 유기층은 정제수 80ml로 다시 세척하였다. 유기층에 남아 았는 물은 MgSO4 처리 제거 후 여과하고 진공 농축하고 이소프로필알코올 35ml을 투입한 후 승온하여 용해시키고 정제수 160ml를 서서히 적가하여 결정화시켰다. 적가 완료 후 실온에서 1시간 교반한 후 0℃로 냉각하여 2시간 더 교반하여 여과하고 진공 건조하여 2-(2,4-디플루오로페닐)-3-(5-플루오로피리미딘-4-일)-1-(1H-1,2,4-트리아졸-1-일)부탄-2-올(화학식 2) 5.7g(16.3m㏖)을 얻었다.(수율: 86%)The obtained 3- (2-chloro-5-fluoro-6- (phenylthio) pyrimidin-4-yl) -2- (2,4-difluorophenyl) , 9.3 g (18.9 mmol) of 4-triazol-1-yl) butan-2-ol ( formula 3a ) were dissolved in 100 ml of tetrahydrofuran, and 8.8 g of zinc powder was added thereto. (NH 4 HCO 2) was added dropwise 11.3g was dissolved in purified water for 1 hour, 55ml. After the dropwise addition, the mixture was heated to reflux and stirred for 8 hours. Cooled to room temperature and filtered to remove the solid residue and then extracted with 60 ml of ethylamine. Washed with 7% NaHCO 3 aqueous solution and 100ml organic layer was concentrated in vacuo. To the concentrate, 126 ml of ethanol was added and dissolved, and 3.8 g of sodium acetate and 3.1 g of 10% Pd / C were charged. The hydrogen gas was charged to 5 kgf / cm 2 and the temperature was raised to 45 캜 and stirred for 12 hours. Cooled to room temperature and filtered to remove the solid residue and concentrate in vacuo. 100 ml of purified water and 100 ml of methylene chloride were added and extracted by stirring, and the organic layer was washed again with 80 ml of purified water. The water remaining in the organic layer was removed by treatment with MgSO 4 , filtered and concentrated in vacuo. 35 ml of isopropyl alcohol was added, and the mixture was heated to dissolve and 160 ml of purified water was gradually added dropwise to crystallize. After completion of dropwise addition, the mixture was stirred at room temperature for 1 hour, cooled to 0 ° C, stirred for 2 hours, filtered and vacuum dried to obtain 2- (2,4-difluorophenyl) -3- yl) -1- (1H-1,2,4- triazol-1-yl) butane-2-ol (formula II) was obtained 5.7g (16.3m㏖) (yield: 86%)

1H NMR(400MHz, CDCl3) δ 1.0~1.1(3H) 4.1(1H) 4.2~4.7(2H) 6.4(1H) 6.7~6.8(2H) 7.5(1H) 7.5~7.6(1H) 7.9(1H) 8.6(1H) 8.9(1H) ppm 1 H NMR (400 MHz, CDCl 3 )? 1.0-1.1 (3H) 4.1 (1H) 4.2-4.7 (2H) 6.4 (1H) 6.7-6.8 (2H) 8.6 (1H) 8.9 (1H) ppm

(G) (2R,3S)-2-(2,4-디플루오로페닐)-3-(5-플루오로피리미딘-4-일)-1-(1H-1,2,4-트리아졸-1-일)부탄-2-올 (화학식 1: 보리코나졸)의 합성(G) Synthesis of (2R, 3S) -2- (2,4-difluorophenyl) -3- (5-fluoropyrimidin- -1-yl) butan-2-ol (formula 1: boriconeazole)

상기 수득한 2-(2,4-디플루오로페닐)-3-(5-플루오로피리미딘-4-일)-1-(1H-1,2,4-트리아졸-1-일)부탄-2-올(화학식 2) 5.7g(16.3m㏖)을 아세톤 80ml에 투입 교반 용해시키고 (1R)-(-)-10-캠포설폰산 3.8g을 메탄올 30ml에 용해하여 1시간 동안 적가하였다. 적가 완료 후 승온하여 1시간 환류 교반하고 서서히 0℃냉각한 후 2시간 교반하여 여과하였다. 여과 고체를 메틸렌클로라이드 30ml, 정제수 30ml, NaHCO3 1.9g 투입하고 1시간 교반 후 정치하여 층분리하였다. 유기층은 7% NaHCO3 수용액 30ml로 세척하고 다시 정제수 30ml로 세척하였다. 유기층에 남아 았는 물은 MgSO4 처리 제거 후 여과하고 진공 농축하고 이소프로필알코올 8ml 투입한 후 승온하여 용해시키고 정제수 50ml를 서서히 적가하여 결정화시켰다. 적가 완료 후 실온에서 1시간 교반한 후 0℃로 냉각하여 2시간 더 교반하여 여과하고 진공 건조하여 보리코나졸(화학식 1) 2.3g(6.6m㏖)을 얻었다.(수율: 41%, 광학순도 99.95% 이상)The resulting 2- (2,4-difluorophenyl) -3- (5-fluoropyrimidin-4-yl) -1- (1H- 2-ol and (II) the stirring 5.7g (16.3m㏖) in 80ml of acetone was dissolved (1R) - (-) - 10-camphorsulfonic acid 3.8g was dissolved in 30ml of methanol was added dropwise over 1 hour. After completion of dropwise addition, the temperature was raised, and the mixture was refluxed for 1 hour, cooled slowly at 0 ° C, and then stirred for 2 hours for filtration. 30 ml of methylene chloride, 30 ml of purified water and 1.9 g of NaHCO 3 were added to the filtrate, followed by stirring for 1 hour, followed by layer separation. The organic layer was washed with water and washed with 30ml of purified water back to 7% NaHCO 3 aqueous solution 30ml. The water remaining in the organic layer was filtered off with MgSO 4 , filtered and concentrated in vacuo. 8 ml of isopropyl alcohol was added, and the mixture was heated to dissolve and 50 ml of purified water was gradually added dropwise to crystallize. After the addition was complete after stirring for 1 hour at room temperature, filtered and stirred for additional 2 hours and cooled to 0 ℃ and vacuum dried to give the voriconazole (Formula 1) 2.3g (6.6m㏖) (yield: 41%, optical purity 99.95% or more)

1H NMR(400MHz, CDCl3) δ 1.0~1.1(3H) 4.1(1H) 4.2~4.7(2H) 6.4(1H) 6.7~6.8(2H) 7.5(1H) 7.5~7.6(1H) 7.9(1H) 8.6(1H) 8.9(1H) ppm
1 H NMR (400 MHz, CDCl 3 )? 1.0-1.1 (3H) 4.1 (1H) 4.2-4.7 (2H) 6.4 (1H) 6.7-6.8 (2H) 8.6 (1H) 8.9 (1H) ppm

[실시예 2][Example 2]

Figure 112014119784717-pat00015
Figure 112014119784717-pat00015

(A) 2,4-디클로로-5-플루오로피리미딘 (화학식 9)의 합성(A) Synthesis of 2,4-dichloro-5-fluoropyrimidine (9)

반응기에 5-플루오로피리미딘-2,4-디올(화학식 11) 11.2g(86.1m㏖)과 옥시염화인(POCl3) 38.9g(253.8m㏖)을 투입하고 95℃로 승온한 후 N,N-디메틸아민(DMA) 20.7g을 1시간 동안 적가하고 120℃로 승온하여 3시간 동안 교반하였다. 온도를 0℃로 냉각하고 3N HCl 수용액 1500ml를 10℃ 이하에서 적가하였다. 적가 완료 후 10℃에서 3시간 교반 후 여과하고 건조하여 2,4-디클로로-5-플루오로피리미딘(화학식 9) 13.2g(79.1m㏖)을 얻었다.(수율:92%)11.2 g (86.1 mmol) of 5-fluoropyrimidine-2,4-diol ( Formula 11 ) and 38.9 g (253.8 mmol) of phosphorus oxychloride (POCl 3 ) were charged into the reactor, And 20.7 g of N-dimethylamine (DMA) were added dropwise for 1 hour, the temperature was raised to 120 ° C and the mixture was stirred for 3 hours. The temperature was cooled to 0 占 폚 and 1500 ml of 3N HCl aqueous solution was added dropwise at 10 占 폚 or lower. After completion of the dropwise addition, the mixture was stirred at 10 캜 for 3 hours, filtered and dried to obtain 13.2 g (79.1 mmol) of 2,4-dichloro-5-fluoropyrimidine 9 (yield: 92%

1H NMR(400MHz, CDCl3) δ 8.5(1H) ppm 1 H NMR (400MHz, CDCl 3 ) δ 8.5 (1H) ppm

(B) 2,4-디클로로-6-에틸-5-플루오로피리미딘 (화학식 8)의 합성(B) Synthesis of 2,4-dichloro-6-ethyl-5-fluoropyrimidine 8

반응기에 마그네슘 분말 16.3g과 테트라하이드로퓨란 280ml를 투입하고 40℃이하에서 브로모에탄 73.1g(670.8m㏖)을 서서히 적가하였다. 적가 완료 후 4시간 교반한 다음 0℃로 냉각하고 상기 수득된 2,4-디클로로-5-플루오로피리미딘(화학식 9) 56.0g(335.4m㏖)을 테트라하이드로퓨란 150ml에 용해하여 10℃이하에서 적가하였다. 15℃에서 2시간 교반 후 다시 0℃로 냉각하고 트리에틸아민(TEA) 33.9g을 테트라하이드로퓨란 56ml로 희석하여 5℃이하에서 1시간동안 적가하였다. 요오드 분말 85.1g을 테트라하이드로퓨란 56ml에 용해하여 1시간 동안 적가하고 2시간 교반하였다. 정제수 1000ml를 투입 후 5N HCl 수용액으로 pH를 1로 맞춘 후 톨루엔 600ml로 추출하였다. 추출한 유기층은 2% NaHSO3 600ml로 세척하고 유기층에 남아 았는 물은 MgSO4 처리 제거 후 여과하고 진공 농축하여 2,4-디클로로-6-에틸-5-플루오로피리미딘(화학식 8) 58.1g(297.9m㏖)을 얻었다.(수율: 89%)16.3 g of magnesium powder and 280 ml of tetrahydrofuran were added to the reactor, and 73.1 g (670.8 mmol) of bromoethane was gradually added dropwise at 40 ° C or lower. After the addition was complete, stirring for 4 hours and then cooled to 0 ℃ was dissolved pyrimidine (chemical formula 9) 56.0g (335.4m㏖) to the obtained 2,4-dichloro-5-fluoro tetrahydrofuran 150ml below 10 ℃ Lt; / RTI > After stirring at 15 DEG C for 2 hours, the reaction mixture was cooled to 0 DEG C, and 33.9 g of triethylamine (TEA) was diluted with 56 mL of tetrahydrofuran and added dropwise at 5 DEG C or lower for 1 hour. 85.1 g of iodine powder was dissolved in 56 ml of tetrahydrofuran, and the mixture was added dropwise for 1 hour and stirred for 2 hours. After adding 1000 ml of purified water, the pH was adjusted to 1 with 5N HCl aqueous solution, and then extracted with 600 ml of toluene. The extracted organic layer was washed with 600ml 2% NaHSO 3, and the remaining organic layer is MgSO 4 atneun water treatment was removed by filtration and pyrimidine (Formula 8), 2,4-dichloro-6-ethyl-5-fluoro concentrated in vacuo and then 58.1g ( 297.9 mmol). (Yield: 89%).

1H NMR(400MHz, CDCl3) δ 1.3(3H) 2.9(2H) ppm 1 H NMR (400 MHz, CDCl 3 )? 1.3 (3H) 2.9 (2H) ppm

(C) 2-클로로-4-에틸-5-플루오로-6-[(벤조티아졸)티오]피리미딘 (화학식 6b)의 합성(C) Synthesis of 2-chloro-4-ethyl-5-fluoro-6 - [(benzothiazole) thio] pyrimidine 6b

상기 수득된 2,4-디클로로-6-에틸-5-플루오로피리미딘(화학식 8) 58.1g(297.9m㏖)를 아세토니트릴(CH3CN) 600ml에 투입하여 용해하고 N,N'-디이소프로필에틸아민 43.0g을 투입하고 0℃로 냉각하였다. 벤조티아졸-2-티올(화학식 7b) 55.5g(331.8m㏖)을 5℃이하에서 1시간 동안 적가하고 실온으로 승온하여 3시간 교반하였다. 40℃에서 진공 농축하여 아세토니트릴을 제거하고 정제수 500ml 투입 교반하고 에틸아민 500ml로 추출하였다. 유기층에 남아 았는 물은 MgSO4 처리 제거 후 여과 하고 진공 농축하여 2-클로로-4-에틸-5-플루오로-6-[(벤조티아졸)티오]피리미딘(화학식 6b) 93.3g(286.4m㏖)을 얻었다.(수율: 96%)58.1 g (297.9 mmol) of the obtained 2,4-dichloro-6-ethyl-5-fluoropyrimidine (8 ) was dissolved in 600 ml of acetonitrile (CH 3 CN) to dissolve N, N'-di 43.0 g of isopropylethylamine was added and cooled to 0 占 폚. 55.5 g (331.8 mmol) of benzothiazole-2-thiol ( Formula 7b ) was added dropwise at 5 ° C or lower for 1 hour, the temperature was raised to room temperature, and the mixture was stirred for 3 hours. The mixture was concentrated in vacuo at 40 캜 to remove acetonitrile, 500 ml of purified water was added thereto, stirred and extracted with 500 ml of ethylamine. Remaining in the organic layer is MgSO atneun water 2-chloro-4-ethyl-5-fluoro and 4 after the removal process, filtered and concentrated in vacuo to give 6 - [(benzothiazole) thio] pyrimidine (formula 6b) 93.3g (286.4m ㏖) (yield: 96%).

1H NMR(400MHz, CDCl3) δ 1.2~1.3(3H) 2.7(2H) 7.5(2H) 8.1~8.2(2H) ppm 1 H NMR (400 MHz, CDCl 3 )? 1.2-1.3 (3H) 2.7 (2H) 7.5 (2H) 8.1-8.2 (2H) ppm

(D) 4-(1-브로모에틸)-2-클로로-5-플루오로-6-[(벤조티아졸)티오]피리미딘 (화학식 5b) 의 합성(D) Synthesis of 4- (1-bromoethyl) -2-chloro-5-fluoro-6 - [(benzothiazole) thio] pyrimidine 5b

상기 수득된 2-클로로-4-에틸-5-플루오로-6-[(벤조티아졸)티오]피리미딘(화학식 6b) 93.3g(286.4m㏖)을 메틸렌클로라이드 700ml에 용해하고 N-브로모숙신이미드(NBS) 62.2g(349.5m㏖)과 아조비스이소부티로니트릴(AIBN) 5.0g을 투입하고 40℃로 승온하여 24시간 교반한 후 실온으로 냉각하고 정제수 800ml를 투입하고 층분리하였다. 유기층은 4% NaHSO3 수용액 600ml로 세척하고 다시 7% NaHCO3수용액으로 세척하였다. 유기층에 남아 았는 물은 MgSO4 처리 제거 후 여과하고 진공 농축하고 Hx?? 250ml 투입하고 실온에서 1시간 교반후 0℃로 냉각하여 2시간 교반후 여과하고 진공 건조하여 4-(1-브로모에틸)-2-클로로-5-플루오로-6-[(벤조티아졸)티오]피리미딘(화학식 5b) 114.1g(281.9m㏖)을 얻었다.(수율: 98%)93.3 g (286.4 mmol) of the obtained 2-chloro-4-ethyl-5-fluoro-6 - [(benzothiazole) thio] pyrimidine ( Formula 6b ) were dissolved in 700 ml of methylene chloride, 62.2 g (349.5 mmol) of succinimide (NBS) and 5.0 g of azobisisobutyronitrile (AIBN) were added, and the mixture was heated to 40 DEG C, stirred for 24 hours, cooled to room temperature, 800 ml of purified water was added, . The organic layer was washed with 600 ml of 4% NaHSO 3 aqueous solution and again with 7% aqueous NaHCO 3 solution. The organic layer was washed with MgSO 4 , filtered and concentrated in vacuo. The mixture was stirred at room temperature for 1 hour, cooled to 0 ° C and stirred for 2 hours, followed by filtration and vacuum drying to give 4- (1-bromoethyl) -2-chloro-5-fluoro-6 - [(benzothiazole) Thio] pyrimidine ( 5b ) (yield: 98%).

1H NMR(400MHz, CDCl3) δ 2.0(3H) 5.2(1H) 7.5(2H) 8.1~8.2(2H) ppm 1 H NMR (400 MHz, CDCl 3 )? 2.0 (3H) 5.2 (1H) 7.5 (2H) 8.1-8.2 (2H) ppm

(E) 3-(2-클로로-5-플루오로-6-[(벤조티아졸)티오]피리미딘-4-일)-2-(2,4-디플루오로페닐)-1-(1H-1,2,4-트리아졸-1-일)부탄-2-올 (화학식 3b)의 합성(E) 3- (2-chloro-5-fluoro-6 - [(benzothiazole) thio] pyrimidin- -1,2,4-triazol-1-yl) butan-2-ol (Formula 3b)

질소 대기하에서 아연 분말 14.1g, 납 분말 0.7g을 무수 테트라하이드로퓨란 70ml를 투입 교반하고 요오드 분말 29.5g을 무수 테트라하이드로퓨란 100ml에 용해하여 50℃이하에서 적가하였다. 적가 완료 후 1시간 교반하고 -15℃이하로 냉각하였다. 상기 수득된 4-(1-브로모에틸)-2-클로로-5-플루오로-6-[(벤조티아졸)티오]피리미딘(화학식 5b) 21.5g(53.1m㏖), 1-(2,4-디플루오로페닐)-2-(1H-1,2,4-트리아졸-1-일)에탄온(화학식 4) 9.60g(43.0m㏖), 요오드 분말 3.7g을 무수 테트라하이드로퓨란 100ml에 용해하여 -5℃이하에서 1시간 동안 적가하고 적가 완료 후 1시간 추가 교반하였다. 반응이 종결된 후 정제수 400ml을 투입하고 실온에서 1시간 교반하였다. 고체 잔류물은 여과하여 제거 후 메틸렌클로라이드 350ml 투입하여 추출하였다. 유기층은 10% HCl 수용액 200ml로 세척하고 다시 4% NaHSO3 수용액 200ml로 세척하고 7% NaHCO3 수용액 300ml로 세척하고 다시 2% 에틸렌다이아민테트라아세트산 수용액으로 세척하였다. 유기층에 남아 았는 물은 MgSO4 처리 제거 후 여과 하고 진공 농축하고 이소프로필에테르 100ml을 투입하고 실온에서 1시간 교반 후 0℃로 냉각하여 2시간 교반후 여과하고 진공 건조하여 3-(2-클로로-5-플루오로-6-[(벤조티아졸)티오]피리미딘-4-일)-2-(2,4-디플루오로페닐)-1-(1H-1,2,4-트리아졸-1-일)부탄-2-올(화학식 3b) 15.9g(29.0m㏖)을 얻었다.(수율: 68%)Under a nitrogen atmosphere, 14.1 g of zinc powder and 0.7 g of lead powder were mixed with 70 ml of anhydrous tetrahydrofuran, and 29.5 g of iodine powder was dissolved in 100 ml of anhydrous tetrahydrofuran. After completion of dropwise addition, the mixture was stirred for 1 hour and cooled to -15 캜 or lower. Thus obtained 4- (1-bromoethyl) -2-chloro-5-fluoro-6 - [(benzothiazole) thio] pyrimidine (Formula 5b) 21.5g (53.1m㏖), 1 (2 , 9.60 g (43.0 mmol) of iodine powder ( Formula 4 ) and 3.7 g of iodine powder were dissolved in anhydrous tetrahydrofuran And the mixture was added dropwise at -5 ° C or lower for 1 hour. After completion of dropwise addition, the mixture was further stirred for 1 hour. After completion of the reaction, 400 ml of purified water was added thereto, followed by stirring at room temperature for 1 hour. The solid residue was filtered off and extracted with 350 ml of methylene chloride. The organic layer was washed with 10% HCl aqueous solution and 200ml again washed with 4% NaHSO 3 solution 200ml, and washed with 7% NaHCO 3 solution and washed 300ml of 2% aqueous solution of ethylene diamine tetra acetic acid back to. The water remaining in the organic layer was filtered off with MgSO 4, concentrated in vacuo, and 100 ml of isopropyl ether was added thereto. After stirring at room temperature for 1 hour, the mixture was cooled to 0 ° C and stirred for 2 hours. After filtration and vacuum drying, 3- 2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazole-2-carboxylic acid ethyl ester) 1-yl) butan-2-ol (Formula 3b ) (yield: 68%).

1H NMR(400MHz, CDCl3) δ 1.0~1.1(3H) 3.9~4.0(1H) 4.3~4.7(2H) 5.8(1H) 6.7~6.8(2H) 7.4~7.6(4H) 7.9(1H) 8.1~8.2(2H) ppm 1 H NMR (400 MHz, CDCl 3 )? 1.0-1.1 (3H) 3.9-4.0 (1H) 4.3-4.7 (2H) 5.8 (1H) 6.7-6.8 (2H) 7.4-7.6 (4H) 7.9 8.2 (2H) ppm

(F) 2-(2,4-디플루오로페닐)-3-(5-플루오로피리미딘-4-일)-1-(1H-1,2,4-트리아졸-1-일)부탄-2-올 (화학식 2)의 합성(F) Synthesis of 2- (2,4-difluorophenyl) -3- (5-fluoropyrimidin-4-yl) Ol (Formula 2)

상기 수득된 3-(2-클로로-5-플루오로-6-[(벤조티아졸)티오]피리미딘-4-일)-2-(2,4-디플루오로페닐)-1-(1H-1,2,4-트리아졸-1-일)부탄-2-올(화학식 3b) 11.1g(20.2m㏖)을 테트라하이드로퓨란 100ml 투입 교반 용해하고 아연 분말 8.8g을 투입하고 50℃로 승온한 후 포름산암모늄(NH4HCO2) 11.6g을 정제수 55ml에 용해하여 1시간 동안 적가하였다. 적가 완료 후 승온하여 8시간 환류 교반하였다. 실온으로 냉각하고 여과하여 고체 잔류물을 제거하 후 에틸아민 60ml로 추출하였다. 7% NaHCO3 수용액 100ml로 세척하고 유기층은 진공 농축하였다. 농축액에 에탄올 126ml 투입 용해하고 소듐 아세테이트 3.8g, 10% Pd/C 3.1g을 투입하고 수소가스를 5kgf/cm2을 채우고 45℃로 승온하여 12시간 교반하였다. 실온으로 냉각하고 여과하여 고체 잔류물을 제거하고 진공 농축하였다. 정제수 100ml, 메틸렌클로라이드 100ml을 투입 교반하여 추출하고 유기층은 정제수 80ml로 다시 세척하였다. 유기층에 남아 았는 물은 MgSO4 처리 제거 후 여과하고 진공 농축하고 이소프로필알코올 35ml을 투입한 후 승온하여 용해시키고 정제수 160ml를 서서히 적가하여 결정화시켰다. 적가 완료 후 실온에서 1시간 교반한 후 0℃로 냉각하여 2시간 더 교반하여 여과하고 진공 건조하여 2-(2,4-디플루오로페닐)-3-(5-플루오로피리미딘-4-일)-1-(1H-1,2,4-트리아졸-1-일)부탄-2-올(화학식 2) 5.8g(16.6m㏖)을 얻었다.(수율: 82%)The resulting 3- (2-chloro-5-fluoro-6 - [(benzothiazol) thio] pyrimidin- 1,2,4-triazol-1-yl) butane-2-ol (melting formula 3b) 11.1g (20.2m㏖) in 100ml of tetrahydrofuran was stirred and added zinc powder 8.8g, and the temperature was raised to 50 ℃ After that, 11.6 g of ammonium formate (NH 4 HCO 2 ) was dissolved in 55 ml of purified water and added dropwise for 1 hour. After the dropwise addition, the mixture was heated to reflux and stirred for 8 hours. Cooled to room temperature and filtered to remove the solid residue and then extracted with 60 ml of ethylamine. Washed with 7% NaHCO 3 aqueous solution and 100ml organic layer was concentrated in vacuo. To the concentrate, 126 ml of ethanol was added and dissolved, and 3.8 g of sodium acetate and 3.1 g of 10% Pd / C were charged. The hydrogen gas was charged to 5 kgf / cm 2 and the temperature was raised to 45 캜 and stirred for 12 hours. Cooled to room temperature and filtered to remove the solid residue and concentrate in vacuo. 100 ml of purified water and 100 ml of methylene chloride were added and extracted by stirring, and the organic layer was washed again with 80 ml of purified water. The water remaining in the organic layer was removed by treatment with MgSO 4 , filtered and concentrated in vacuo. 35 ml of isopropyl alcohol was added, and the mixture was heated to dissolve and 160 ml of purified water was gradually added dropwise to crystallize. After completion of dropwise addition, the mixture was stirred at room temperature for 1 hour, cooled to 0 ° C, stirred for 2 hours, filtered and vacuum dried to obtain 2- (2,4-difluorophenyl) -3- yl) -1- (1H-1,2,4- triazol-1-yl) butane-2-ol (formula II) was obtained 5.8g (16.6m㏖) (yield: 82%)

1H NMR(400MHz, CDCl3) δ 1.0~1.1(3H) 4.1(1H) 4.2~4.7(2H) 6.4(1H) 6.7~6.8(2H) 7.5(1H) 7.5~7.6(1H) 7.9(1H) 8.6(1H) 8.9(1H) ppm 1 H NMR (400 MHz, CDCl 3 )? 1.0-1.1 (3H) 4.1 (1H) 4.2-4.7 (2H) 6.4 (1H) 6.7-6.8 (2H) 8.6 (1H) 8.9 (1H) ppm

(G) (2R,3S)-2-(2,4-디플루오로페닐)-3-(5-플루오로피리미딘-4-일)-1-(1H-1,2,4-트리아졸-1-일)부탄-2-올 (화학식 1: 보리코나졸)의 합성(G) Synthesis of (2R, 3S) -2- (2,4-difluorophenyl) -3- (5-fluoropyrimidin- -1-yl) butan-2-ol (formula 1: boriconeazole)

상기 수득한 2-(2,4-디플루오로페닐)-3-(5-플루오로피리미딘-4-일)-1-(1H-1,2,4-트리아졸-1-일)부탄-2-올(화학식 2) 5.8g(16.6m㏖)을 아세톤 80ml에 투입 교반 용해시키고 (1R)-(-)-10-캠포설폰산 3.8g을 메탄올 30ml에 용해하여 1시간 동안 적가하였다. 적가 완료 후 승온하여 1시간 환류 교반하고 서서히 0℃냉각한 후 2시간 교반하여 여과하였다. 여과 고체를 메틸렌클로라이드 30ml, 정제수 30ml, NaHCO3 1.9g 투입하고 1시간 교반 후 정치하여 층분리하였다. 유기층은 7% NaHCO3 수용액 30ml로 세척하고 다시 정제수 30ml로 세척하였다. 유기층에 남아 았는 물은 MgSO4 처리 제거 후 여과하고 진공 농축하고 이소프로필알코올 8ml 투입한 후 승온하여 용해시키고 정제수 50ml를 서서히 적가하여 결정화시켰다. 적가 완료 후 실온에서 1시간 교반한 후 0℃로 냉각하여 2시간 더 교반하여 여과하고 진공 건조하여 보리코나졸(화학식 1) 2.4g(6.9m㏖)을 얻었다.(수율: 41%, 광학순도 99.95% 이상)The resulting 2- (2,4-difluorophenyl) -3- (5-fluoropyrimidin-4-yl) -1- (1H- 2-ol and (II) the stirring 5.8g (16.6m㏖) in 80ml of acetone was dissolved (1R) - (-) - 10-camphorsulfonic acid 3.8g was dissolved in 30ml of methanol was added dropwise over 1 hour. After completion of dropwise addition, the temperature was raised, and the mixture was refluxed for 1 hour, cooled slowly at 0 ° C, and then stirred for 2 hours for filtration. 30 ml of methylene chloride, 30 ml of purified water and 1.9 g of NaHCO 3 were added to the filtrate, followed by stirring for 1 hour, followed by layer separation. The organic layer was washed with water and washed with 30ml of purified water back to 7% NaHCO 3 aqueous solution 30ml. The water remaining in the organic layer was filtered off with MgSO 4 , filtered and concentrated in vacuo. 8 ml of isopropyl alcohol was added, and the mixture was heated to dissolve and 50 ml of purified water was gradually added dropwise to crystallize. After completion of the dropwise addition, the mixture was stirred at room temperature for 1 hour, cooled to 0 캜, stirred for further 2 hours, filtered and vacuum dried to obtain 2.4 g (6.9 mmol) of boricone sol ( formula 1 ) 99.95% or more)

1H NMR(400MHz, CDCl3) δ 1.0~1.1(3H) 4.1(1H) 4.2~4.7(2H) 6.4(1H) 6.7~6.8(2H) 7.5(1H) 7.5~7.6(1H) 7.9(1H) 8.6(1H) 8.9(1H) ppm
1 H NMR (400 MHz, CDCl 3 )? 1.0-1.1 (3H) 4.1 (1H) 4.2-4.7 (2H) 6.4 (1H) 6.7-6.8 (2H) 8.6 (1H) 8.9 (1H) ppm

[실시예 3][Example 3]

Figure 112014119784717-pat00016

Figure 112014119784717-pat00016

(A) 2-클로로-4-에틸-5-플루오로-6-(피리딘-2-일-티오)피리미딘 (화학식 6c)의 합성Synthesis of 2-chloro-4-ethyl-5-fluoro-6- (pyridin-2-yl-thio) pyrimidine (6c)

2,4-디클로로-6-에틸-5-플루오로피리미딘(화학식 8) 57.8g(296.4m㏖)를 아세토니트릴 600ml에 투입하여 용해하고 N,N'-디이소프로필에틸아민 44.0g을 투입하고 0℃로 냉각하였다. 피리딘-2-티올(화학식 7c) 37.8g(340.0m㏖)을 5℃이하에서 1시간 동안 적가하고 실온으로 승온하여 3시간 교반하였다. 40℃에서 진공 농축하여 아세토니트릴을 제거하고 정제수 500ml 투입 교반하고 에틸아민 500ml로 추출하였다. 유기층에 남아 았는 물은 MgSO4 처리 제거 후 여과 하고 진공 농축하여 2-클로로-4-에틸-5-플루오로-6-(피리딘-2-일-티오)피리미딘(화학식 6c) 76.9g(285.1m㏖)을 얻었다.(수율: 96%)57.8 g (296.4 mmol) of 2,4-dichloro-6-ethyl-5-fluoropyrimidine ( Formula 8 ) was dissolved in 600 ml of acetonitrile and 44.0 g of N, N'-diisopropylethylamine 0.0 > 0 C. < / RTI > 37.8 g (340.0 mmol) of pyridine-2-thiol ( Formula 7c ) was added dropwise at 5 ° C or lower for 1 hour, the temperature was raised to room temperature, and the mixture was stirred for 3 hours. The mixture was concentrated in vacuo at 40 캜 to remove acetonitrile, 500 ml of purified water was added thereto, stirred and extracted with 500 ml of ethylamine. Atneun remain in the organic layer is MgSO water 2-chloro-4-ethyl-5-fluoro and 4 after the removal process, filtered and concentrated in vacuo to give 6- (pyridin-2-yl-thio) pyrimidine (Formula 6c) 76.9g (285.1 mmol). (Yield: 96%).

1H NMR(400MHz, CDCl3) δ 1.2~1.3(3H) 2.7(2H) 7.4~7.5(3H) 8.4(1H) ppm 1 H NMR (400 MHz, CDCl 3 )? 1.2-1.3 (3H) 2.7 (2H) 7.4-7.5 (3H) 8.4 (1H) ppm

(B) 4-(1-브로모에틸)-2-클로로-5-플루오로-6-(피리딘-2-일-티오)피리미딘 (화학식 5c) 의 합성(B) Synthesis of 4- (1-bromoethyl) -2-chloro-5-fluoro-6- (pyridin-2-yl-thio) pyrimidine 5c

상기 수득된 2-클로로-4-에틸-5-플루오로-6-(피리딘-2-일-티오)피리미딘(화학식 6c) 76.9g(285.1m㏖)을 메틸렌클로라이드 700ml에 용해하고 N-브로모숙신이미드(NBS) 61.4g(345.0m㏖)과 아조비스이소부티로니트릴(AIBN) 5.0g을 투입하고 40℃로 승온하여 24시간 교반한 후 실온으로 냉각하고 정제수 800ml를 투입하고 층분리하였다. 유기층은 4% NaHSO3 수용액 600ml로 세척하고 다시 7% NaHCO3수용액으로 세척하였다. 유기층에 남아 았는 물은 MgSO4 처리 제거 후 여과하고 진공 농축하고 Hx?? 250ml 투입하고 실온에서 1시간 교반후 0℃로 냉각하여 2시간 교반후 여과하고 진공 건조하여 4-(1-브로모에틸)-2-클로로-5-플루오로-6-(피리딘-2-일-티오)피리미딘(화학식 5c) 97.6g(279.9m㏖)을 얻었다.(수율: 98%)76.9 g (285.1 mmol) of the obtained 2-chloro-4-ethyl-5-fluoro-6- (pyridin-2-yl-thio) pyrimidine ( 6c ) was dissolved in 700 ml of methylene chloride, 61.4 g (345.0 mmol) of aminosuccinimide (NBS) and 5.0 g of azobisisobutyronitrile (AIBN) were charged, and the mixture was heated to 40 DEG C, stirred for 24 hours, cooled to room temperature, 800 ml of purified water was added, Respectively. The organic layer was washed with 600 ml of 4% NaHSO 3 aqueous solution and again with 7% aqueous NaHCO 3 solution. The organic layer was washed with MgSO 4 , filtered and concentrated in vacuo. And the mixture was stirred at room temperature for 1 hour. The mixture was cooled to 0 deg. C, stirred for 2 hours, filtered and vacuum dried to obtain 4- (1-bromoethyl) -2-chloro- -Thio) pyrimidine ( 5c ) (yield: 98%).

1H NMR(400MHz, CDCl3) δ 2.0(3H) 5.2(1H) 7.4~7.5(3H) 8.4(1H) ppm 1 H NMR (400 MHz, CDCl 3 )? 2.0 (3H) 5.2 (1H) 7.4-7.5 (3H) 8.4 (1H) ppm

(C) 3-(2-클로로-5-플루오로-6-(피리딘-2-일-티오)피리미딘-4-일)-2-(2,4-디플루오로페닐)-1-(3,5-디브로모-1H-1,2,4-트리아졸-1-일)부탄-2-올 (화학식 3c)의 합성(C) Synthesis of 3- (2-chloro-5-fluoro-6- (pyridin-2-yl-thio) pyrimidin- Synthesis of 3,5-dibromo-1H-1,2,4-triazol-1-yl) butan-2-ol (Formula 3c)

질소 대기하에서 아연 분말 14.0g, 납 분말 0.7g을 무수 테트라하이드로퓨란 70ml를 투입 교반하고 요오드 분말 29.8g을 무수 테트라하이드로퓨란 100ml에 용해하여 50℃이하에서 적가하였다. 적가 완료 후 1시간 교반하고 -15℃이하로 냉각하였다. 상기 수득된 4-(1-브로모에틸)-2-클로로-5-플루오로-6-(피리딘-2-일-티오)피리미딘(화학식 5c) 18.3g(52.5m㏖), 1-(2,4-디플루오로페닐)-2-(3,5-디브로모-1H-1,2,4-트리아졸-1-일)에탄온(화학식 4b) 16.8g(44.1m㏖), 요오드 분말 3.7g을 무수 테트라하이드로퓨란 100ml에 용해하여 -5℃이하에서 1시간 동안 적가하고 적가 완료 후 1시간 추가 교반하였다. 반응이 종결된 후 정제수 400ml을 투입하고 실온에서 1시간 교반하였다. 고체 잔류물은 여과하여 제거 후 메틸렌클로라이드 350ml 투입하여 추출하였다. 유기층은 10% HCl 수용액 200ml로 세척하고 다시 4% NaHSO3 수용액 200ml로 세척하고 7% NaHCO3 수용액 300ml로 세척하고 다시 2% 에틸렌다이아민테트라아세트산 수용액으로 세척하였다. 유기층에 남아 았는 물은 MgSO4 처리 제거 후 여과 하고 진공 농축하고 이소프로필에테르 100ml을 투입하고 실온에서 1시간 교반 후 0℃로 냉각하여 2시간 교반후 여과하고 진공 건조하여 3-(2-클로로-5-플루오로-6-(피리딘-2-일-티오)피리미딘-4-일)-2-(2,4-디플루오로페닐)-1-(3,5-디브로모-1H-1,2,4-트리아졸-1-일)부탄-2-올(화학식 3c) 17.9g(27.5m㏖)을 얻었다.(수율: 62%)Under a nitrogen atmosphere, 14.0 g of zinc powder and 0.7 g of lead powder were mixed with 70 ml of anhydrous tetrahydrofuran, and 29.8 g of iodine powder was dissolved in 100 ml of anhydrous tetrahydrofuran. After completion of dropwise addition, the mixture was stirred for 1 hour and cooled to -15 캜 or lower. The resultant 4- (1-bromoethyl) -2-chloro-5-fluoro-6- (pyridin-2-yl-thio) pyrimidine (Formula 5c) 18.3g (52.5m㏖), 1 ( 2,4-difluorophenyl) -2- (3, 5-dibromo--1H-1,2,4- triazol-1-yl) ethanone (formula 4b) 16.8g (44.1m㏖), 3.7 g of iodine powder was dissolved in 100 ml of anhydrous tetrahydrofuran, and the mixture was added dropwise at -5 ° C or lower for 1 hour. After completion of dropwise addition, the mixture was further stirred for 1 hour. After completion of the reaction, 400 ml of purified water was added thereto, followed by stirring at room temperature for 1 hour. The solid residue was filtered off and extracted with 350 ml of methylene chloride. The organic layer was washed with 10% HCl aqueous solution and 200ml again washed with 4% NaHSO 3 solution 200ml, and washed with 7% NaHCO 3 solution and washed 300ml of 2% aqueous solution of ethylene diamine tetra acetic acid back to. The water remaining in the organic layer was filtered off with MgSO 4, concentrated in vacuo, and 100 ml of isopropyl ether was added. After stirring at room temperature for 1 hour, the mixture was cooled to 0 ° C and stirred for 2 hours. The mixture was filtered and dried under vacuum to obtain 3- (2,4-difluorophenyl) -1- (3,5-dibromo-lH-pyrrolo [2,3-d] pyrimidin- 17.9 g (27.5 mmol) of the 1,2,4-triazol-1-yl) butan-2-ol ( chemical formula 3c ) was obtained (yield: 62%

1H NMR(400MHz, CDCl3) δ 1.0~1.1(3H) 3.9~4.0(1H) 4.3~4.7(2H) 6.7~6.8(2H) 7.4~7.6(4H) 8.2(1H) ppm 1 H NMR (400 MHz, CDCl 3 )? 1.0-1.1 (3H) 3.9-4.0 (1H) 4.3-4.7 (2H) 6.7-6.8 (2H) 7.4-7.6 (4H) 8.2

(D) 2-(2,4-디플루오로페닐)-3-(5-플루오로피리미딘-4-일)-1-(3,5-디브로모-1H-1,2,4-트리아졸-1-일)부탄-2-올 (화학식 2)의 합성(D) 2- (2,4-Difluorophenyl) -3- (5-fluoropyrimidin-4-yl) Triazol-1-yl) butan-2-ol (Formula 2)

상기 수득된 3-(2-클로로-5-플루오로-6-(피리딘-2-일-티오)피리미딘-4-일)-2-(2,4-디플루오로페닐)-1-(3,5-디브로모-1H-1,2,4-트리아졸-1-일)부탄-2-올(화학식 3b) 12.9g(19.8m㏖)을 테트라하이드로퓨란 100ml 투입 교반 용해하고 아연 분말 8.8g을 투입하고 50℃로 승온한 후 포름산암모늄(NH4HCO2) 11.6g을 정제수 55ml에 용해하여 1시간 동안 적가하였다. 적가 완료 후 승온하여 8시간 환류 교반하였다. 실온으로 냉각하고 여과하여 고체 잔류물을 제거하 후 에틸아민 60ml로 추출하였다. 7% NaHCO3 수용액 100ml로 세척하고 유기층은 진공 농축하였다. 농축액에 에탄올 126ml 투입 용해하고 소듐 아세테이트 3.8g, 10% Pd/C 3.1g을 투입하고 수소가스를 5kgf/cm2을 채우고 45℃로 승온하여 12시간 교반하였다. 실온으로 냉각하고 여과하여 고체 잔류물을 제거하고 진공 농축하였다. 정제수 100ml, 메틸렌클로라이드 100ml을 투입 교반하여 추출하고 유기층은 정제수 80ml로 다시 세척하였다. 유기층에 남아 았는 물은 MgSO4 처리 제거 후 여과하고 진공 농축하고 이소프로필알코올 35ml을 투입한 후 승온하여 용해시키고 정제수 160ml를 서서히 적가하여 결정화시켰다. 적가 완료 후 실온에서 1시간 교반한 후 0℃로 냉각하여 2시간 더 교반하여 여과하고 진공 건조하여 2-(2,4-디플루오로페닐)-3-(5-플루오로피리미딘-4-일)-1-(1H-1,2,4-트리아졸-1-일)부탄-2-올(화학식 2) 5.6g(16.0m㏖)을 얻었다.(수율: 82%)The obtained 3- (2-chloro-5-fluoro-6- (pyridin-2-yl-thio) pyrimidin- 12.9 g (19.8 mmol) of 3,5-dibromo-1H-1,2,4-triazol-1-yl) butan-2-ol ( formula 3b ) were dissolved in 100 ml of tetrahydrofuran, And the temperature was raised to 50 ° C. 11.6 g of ammonium formate (NH 4 HCO 2 ) was dissolved in 55 ml of purified water, and the solution was added dropwise for 1 hour. After the dropwise addition, the mixture was heated to reflux and stirred for 8 hours. Cooled to room temperature and filtered to remove the solid residue and then extracted with 60 ml of ethylamine. Washed with 7% NaHCO 3 aqueous solution and 100ml organic layer was concentrated in vacuo. To the concentrate, 126 ml of ethanol was added and dissolved, and 3.8 g of sodium acetate and 3.1 g of 10% Pd / C were charged. The hydrogen gas was charged to 5 kgf / cm 2 and the temperature was raised to 45 캜 and stirred for 12 hours. Cooled to room temperature and filtered to remove the solid residue and concentrate in vacuo. 100 ml of purified water and 100 ml of methylene chloride were added and extracted by stirring, and the organic layer was washed again with 80 ml of purified water. The water remaining in the organic layer was removed by treatment with MgSO 4 , filtered and concentrated in vacuo. 35 ml of isopropyl alcohol was added, and the mixture was heated to dissolve and 160 ml of purified water was gradually added dropwise to crystallize. After completion of dropwise addition, the mixture was stirred at room temperature for 1 hour, cooled to 0 ° C, stirred for 2 hours, filtered and vacuum dried to obtain 2- (2,4-difluorophenyl) -3- yl) -1- (1H-1,2,4- triazol-1-yl) butane-2-ol (formula II) was obtained 5.6g (16.0m㏖) (yield: 82%)

1H NMR(400MHz, CDCl3) δ 1.0~1.1(3H) 4.1(1H) 4.2~4.7(2H) 6.4(1H) 6.7~6.8(2H) 7.5(1H) 7.5~7.6(1H) 7.9(1H) 8.6(1H) 8.9(1H) ppm 1 H NMR (400 MHz, CDCl 3 )? 1.0-1.1 (3H) 4.1 (1H) 4.2-4.7 (2H) 6.4 (1H) 6.7-6.8 (2H) 8.6 (1H) 8.9 (1H) ppm

(E) (2R,3S)-2-(2,4-디플루오로페닐)-3-(5-플루오로피리미딘-4-일)-1-(1H-1,2,4-트리아졸-1-일)부탄-2-올 (화학식 1: 보리코나졸)의 합성(E) (2R, 3S) -2- (2,4-difluorophenyl) -3- (5-fluoropyrimidin- -1-yl) butan-2-ol (formula 1: boriconeazole)

상기 수득한 2-(2,4-디플루오로페닐)-3-(5-플루오로피리미딘-4-일)-1-(1H-1,2,4-트리아졸-1-일)부탄-2-올(화학식 2) 5.6g(16.0m㏖)을 아세톤 80ml에 투입 교반 용해시키고 (1R)-(-)-10-캠포설폰산 3.8g을 메탄올 30ml에 용해하여 1시간 동안 적가하였다. 적가 완료 후 승온하여 1시간 환류 교반하고 서서히 0℃냉각한 후 2시간 교반하여 여과하였다. 여과 고체를 메틸렌클로라이드 30ml, 정제수 30ml, NaHCO3 1.9g 투입하고 1시간 교반 후 정치하여 층분리하였다. 유기층은 7% NaHCO3 수용액 30ml로 세척하고 다시 정제수 30ml로 세척하였다. 유기층에 남아 았는 물은 MgSO4 처리 제거 후 여과하고 진공 농축하고 이소프로필알코올 8ml 투입한 후 승온하여 용해시키고 정제수 50ml를 서서히 적가하여 결정화시켰다. 적가 완료 후 실온에서 1시간 교반한 후 0℃로 냉각하여 2시간 더 교반하여 여과하고 진공 건조하여 보리코나졸(화학식 1) 2.4g(6.9m㏖)을 얻었다.(수율: 43%, 광학순도 99.95% 이상)The resulting 2- (2,4-difluorophenyl) -3- (5-fluoropyrimidin-4-yl) -1- (1H- 5.6 g (16.0 mmol) of the compound represented by the formula (2 ) was added to 80 ml of acetone and dissolved by stirring, and 3.8 g of (1R) - (-) - 10-camphorsulfonic acid was dissolved in 30 ml of methanol and added dropwise for 1 hour. After completion of dropwise addition, the temperature was raised, and the mixture was refluxed for 1 hour, cooled slowly at 0 ° C, and then stirred for 2 hours for filtration. 30 ml of methylene chloride, 30 ml of purified water and 1.9 g of NaHCO 3 were added to the filtrate, followed by stirring for 1 hour, followed by layer separation. The organic layer was washed with water and washed with 30ml of purified water back to 7% NaHCO 3 aqueous solution 30ml. The water remaining in the organic layer was filtered off with MgSO 4 , filtered and concentrated in vacuo. 8 ml of isopropyl alcohol was added, and the mixture was heated to dissolve and 50 ml of purified water was gradually added dropwise to crystallize. After completion of dropwise addition, the mixture was stirred at room temperature for 1 hour, cooled to 0 캜, stirred for further 2 hours, filtered and vacuum dried to obtain 2.4 g (6.9 mmol) of boricone sol ( formula 1 ) 99.95% or more)

1H NMR(400MHz, CDCl3) δ 1.0~1.1(3H) 4.1(1H) 4.2~4.7(2H) 6.4(1H) 6.7~6.8(2H) 7.5(1H) 7.5~7.6(1H) 7.9(1H) 8.6(1H) 8.9(1H) ppm 1 H NMR (400 MHz, CDCl 3 )? 1.0-1.1 (3H) 4.1 (1H) 4.2-4.7 (2H) 6.4 (1H) 6.7-6.8 (2H) 8.6 (1H) 8.9 (1H) ppm

Claims (7)

삭제delete 삭제delete 삭제delete 삭제delete 삭제delete 하기 화학식 10의 화합물 또는 화학식 11의 화합물을 옥시염화인(POCl3)과 반응시켜 하기 화학식 9의 화합물을 합성하는 단계;
상기 화학식 9의 화합물과 할로에탄 화합물과 반응시켜 하기 화학식 8의 화합물을 합성하는 단계;
상기 화학식 8의 화합물을 하기 화학식 7의 티올 화합물과 반응시켜 하기 화학식 6의 화합물을 합성하는 단계;
상기 화학식 6의 화합물을 할로겐 공여체(halogen donor)와 반응시켜 상기 화합물(화학식 6)의 에틸기의 1번 위치를 할로기로 치환시켜 하기 화학식 5의 화합물을 합성하는 단계;
상기 화학식 5의 화합물과 하기 화학식 4의 화합물을 리포마스키 유형 커플링 반응시켜 하기 화학식 3의 화합물을 합성하는 단계;
상기 화학식 3의 화합물에서 치환기인 티올기 및 클로로기를 제거하여 하기 화학식 2의 라세메이트 보리코나졸을 수득하는 단계; 및
상기 화학식 2의 라세메이트 화합물을 광학적 활성산을 이용하여 광학분리하는 단계를 포함하는, 하기 화학식 1의 보리코나졸의 제조 방법.
Figure 112016128728953-pat00026

(상기 화학식들에서
R은 페닐, 피리딘, 피리미딘, 티아졸, 벤조티아졸, 벤조옥사졸, 이미다졸, 1-메틸이미다졸, C1~C4 알킬 또는 이들 화합물의 치환체이고, 상기 치환체의 치환기는 각각 독립적으로 할로, 니트로 및 메톡시 중에서 선택된 1종 이상이다.)
Reacting a compound of formula (10) or a compound of formula (11) with phosphorus oxychloride (POCl 3 ) to synthesize a compound of formula (9);
Reacting the compound of Formula 9 with a haloethane compound to synthesize a compound of Formula 8;
Reacting the compound of Formula 8 with a thiol compound of Formula 7 to synthesize a compound of Formula 6;
Reacting the compound of formula (6) with a halogen donor to form a compound of formula (5) by replacing the 1-position of the ethyl group of the compound of formula (6) with a halo group;
Reacting a compound of formula (5) with a compound of formula (4) to give a compound of formula (3);
Removing the thiol group and the chloro group as substituents in the compound of Formula 3 to obtain racemicate boricconazole of Formula 2; And
A process for producing a boricone sol represented by the following formula (1), comprising optically separating a racemate compound of the formula (2) using an optically active acid.
Figure 112016128728953-pat00026

(In the above formulas
R is phenyl, pyridine, pyrimidine, thiazole, benzothiazole, benzoxazole, imidazole, 1-methylimidazole, C 1 -C 4 alkyl or substituents of these compounds, And is at least one selected from halo, nitro and methoxy.
제6항에 있어서,
상기 할로겐 공여체는 N-브로모숙신이미드(NBS), N-요도숙신이미드(NIS) 또는 N-클로로숙신이미드(NCS)인, 보리코나졸의 제조 방법.The method according to claim 6,
Wherein the halogen donor is N -bromosuccinimide (NBS), N -iodosuccinimide (NIS) or N -chlorosuccinimide (NCS).
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