KR100580940B1 - Process for preparing 2-amino-4-chloro-5-nitro-61H-pyrimidinone - Google Patents

Process for preparing 2-amino-4-chloro-5-nitro-61H-pyrimidinone Download PDF

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KR100580940B1
KR100580940B1 KR1020020039277A KR20020039277A KR100580940B1 KR 100580940 B1 KR100580940 B1 KR 100580940B1 KR 1020020039277 A KR1020020039277 A KR 1020020039277A KR 20020039277 A KR20020039277 A KR 20020039277A KR 100580940 B1 KR100580940 B1 KR 100580940B1
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윤석균
김철민
황상열
윤만영
남근혜
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주식회사 엘지생명과학
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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
    • B65G—TRANSPORT OR STORAGE DEVICES, e.g. CONVEYORS FOR LOADING OR TIPPING, SHOP CONVEYOR SYSTEMS OR PNEUMATIC TUBE CONVEYORS
    • B65G17/00—Conveyors having an endless traction element, e.g. a chain, transmitting movement to a continuous or substantially-continuous load-carrying surface or to a series of individual load-carriers; Endless-chain conveyors in which the chains form the load-carrying surface
    • B65G17/16—Conveyors having an endless traction element, e.g. a chain, transmitting movement to a continuous or substantially-continuous load-carrying surface or to a series of individual load-carriers; Endless-chain conveyors in which the chains form the load-carrying surface comprising individual load-carriers which are pivotally mounted, e.g. for free-swinging movement
    • B65G17/18—Conveyors having an endless traction element, e.g. a chain, transmitting movement to a continuous or substantially-continuous load-carrying surface or to a series of individual load-carriers; Endless-chain conveyors in which the chains form the load-carrying surface comprising individual load-carriers which are pivotally mounted, e.g. for free-swinging movement and move in contact with a guiding surface
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
    • B65G—TRANSPORT OR STORAGE DEVICES, e.g. CONVEYORS FOR LOADING OR TIPPING, SHOP CONVEYOR SYSTEMS OR PNEUMATIC TUBE CONVEYORS
    • B65G17/00—Conveyors having an endless traction element, e.g. a chain, transmitting movement to a continuous or substantially-continuous load-carrying surface or to a series of individual load-carriers; Endless-chain conveyors in which the chains form the load-carrying surface
    • B65G17/30—Details; Auxiliary devices
    • B65G17/32—Individual load-carriers
    • B65G17/34—Individual load-carriers having flat surfaces, e.g. platforms, grids, forks
    • B—PERFORMING OPERATIONS; TRANSPORTING
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    • B63B—SHIPS OR OTHER WATERBORNE VESSELS; EQUIPMENT FOR SHIPPING 
    • B63B27/00—Arrangement of ship-based loading or unloading equipment for cargo or passengers
    • B63B27/22—Arrangement of ship-based loading or unloading equipment for cargo or passengers of conveyers, e.g. of endless-belt or screw-type
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
    • B65G—TRANSPORT OR STORAGE DEVICES, e.g. CONVEYORS FOR LOADING OR TIPPING, SHOP CONVEYOR SYSTEMS OR PNEUMATIC TUBE CONVEYORS
    • B65G2201/00—Indexing codes relating to handling devices, e.g. conveyors, characterised by the type of product or load being conveyed or handled
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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
    • B65G—TRANSPORT OR STORAGE DEVICES, e.g. CONVEYORS FOR LOADING OR TIPPING, SHOP CONVEYOR SYSTEMS OR PNEUMATIC TUBE CONVEYORS
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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
    • B65G—TRANSPORT OR STORAGE DEVICES, e.g. CONVEYORS FOR LOADING OR TIPPING, SHOP CONVEYOR SYSTEMS OR PNEUMATIC TUBE CONVEYORS
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    • B65G2812/02673—Conveyors having endless traction elements with load-carrying surfaces supported by traction means the load-carrying surfaces being separated from each other, e.g. individual load carriers the load-carriers being arranged above, between or beside the traction means
    • B65G2812/02792—Conveyors having endless traction elements with load-carrying surfaces supported by traction means the load-carrying surfaces being separated from each other, e.g. individual load carriers the load-carriers being arranged above, between or beside the traction means the load-carriers being connected pivotally to the traction means
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Abstract

본 발명은 기존의 방법에 비해 간편하게 하기 화학식 1의 2-아미노-4,6-디클로로피리미딘으로부터 하기 화학식 3의 2-아미노-4-클로로-5-니트로-6(1H)-피리미디논 화합물을 제조하는 방법에 관한 것이다. The present invention provides a 2-amino-4-chloro-5-nitro-6 (1H) -pyrimidinone compound of the following general formula (3) from 2-amino-4,6-dichloropyrimidine of the following general formula (1). It relates to a method of manufacturing.

Figure 112002021659559-pat00001
Figure 112002021659559-pat00001

Figure 112002021659559-pat00002
Figure 112002021659559-pat00002

Description

2-아미노-4-클로로-5-니트로-6(1Ｈ)-피리미디논의 제조방법 {Process for preparing 2-amino-4-chloro-5-nitro-6(1H)-pyrimidinone}Process for preparing 2-amino-4-chloro-5-nitro-6 (1H) -pyrimidinone}

본 발명은 하기 화학식 3의 2-아미노-4-클로로-5-니트로-6(1H)-피리미디논 화합물의 새로운 제조방법에 관한 것이다:The present invention relates to a novel process for the preparation of 2-amino-4-chloro-5-nitro-6 (1H) -pyrimidinone compound of the formula:

[화학식 3][Formula 3]

Figure 112002021659559-pat00003
Figure 112002021659559-pat00003

상기 화학식 3의 화합물은 항바이러스 핵산 유도체의 합성에 사용되는 피리미딘 유도체의 제조에 중간체로서 이용된다(참조: Alan Schwartz et al., US Patent, No. 4,939,252).The compound of formula 3 is used as an intermediate in the preparation of pyrimidine derivatives used for the synthesis of antiviral nucleic acid derivatives (Alan Schwartz et al., US Patent, No. 4,939,252).

기존에 화학식 3의 화합물은 문헌(참조: J. Heterocyclic Chem. 22:1035 (1985))에 알려진 방법으로 제조되어 왔다. 이 제조방법에 따르면, 하기 화학식 1 의 2-아미노-4,6-디클로로피리미딘을 수산화나트륨 및 아세트산과 반응시켜 하기 화학식 2의 2-아미노-6-클로로-4(3H)-피리미디논을 제조하여 정제한 후, 이를 진한 황산 및 질산과 반응시켜 화학식 3의 2-아미노-4-클로로-5-니트로-6(1H)-피리미디논 화합물을 제조할 수 있으며, 이를 반응도식으로 나타내면 하기 반응식 1과 같다. The compounds of formula 3 have been prepared previously by methods known from J. Heterocyclic Chem. 22: 1035 (1985). According to this preparation method, 2-amino-4,6-dichloropyrimidine of formula 1 is reacted with sodium hydroxide and acetic acid to react 2-amino-6-chloro-4 (3H) -pyrimidinone of formula 2 After the preparation and purification, it can be reacted with concentrated sulfuric acid and nitric acid to prepare 2-amino-4-chloro-5-nitro-6 (1H) -pyrimidinone compound of Chemical Formula 3, which is represented by the following scheme. Same as Scheme 1.

[화학식 1][Formula 1]

Figure 112002021659559-pat00004
Figure 112002021659559-pat00004

Figure 112002021659559-pat00005
Figure 112002021659559-pat00005

[화학식 3][Formula 3]

Figure 112002021659559-pat00006
Figure 112002021659559-pat00006

Figure 112002021659559-pat00007
Figure 112002021659559-pat00007

그러나 상기 방법에 따르면 화학식 2의 중간체 화합물을 반드시 분리, 정제 한 후, 이로부터 화학식 3의 화합물을 제조하여야 한다. 즉, 반드시 2단계의 공정을 거쳐야만 목적하는 화학식 3의 화합물을 얻을 수 있었던 것이다.However, according to the above method, the intermediate compound of Formula 2 must be separated and purified, and then the compound of Formula 3 must be prepared therefrom. In other words, the desired compound of formula 3 was obtained only through two steps.

이에 본 발명자들은 기존의 2단계 공정보다 간편하고 우수한 제조방법을 개발하기 위해 노력하던 중, 화학식 1의 화합물로부터 수산화나트륨이나 아세트산을 사용할 필요없이 1단계 공정으로 화학식 3의 2-아미노-4-클로로-5-니트로-6(1H)-피리미디논 화합물을 제조할 수 있음을 확인하고 본 발명을 완성하게 되었다.Accordingly, the present inventors are trying to develop a simple and superior manufacturing method than the existing two-step process, 2-amino-4-chloro of the formula (3) in one step without the need to use sodium hydroxide or acetic acid from the compound of the formula (1) The present invention was completed by confirming that a -5-nitro-6 (1H) -pyrimidinone compound can be prepared.

따라서 본 발명의 목적은 화학식 3의 2-아미노-4-클로로-5-니트로-6(1H)-피리미디논의 새로운 제조방법을 제공하는 것이다.
It is therefore an object of the present invention to provide a novel process for the preparation of 2-amino-4-chloro-5-nitro-6 (1H) -pyrimidinone of formula (3).

본 발명은 하기 화학식 1의 2-아미노-4,6-디클로로피리미딘을 진한 황산 및 진한 질산과 함께 반응시켜 1단계 공정으로 하기 화학식 3의 2-아미노-4-클로로-5-니트로-6(1H)-피리미디논을 제조하는 방법에 관한 것이다. 따라서, 수산화나트륨과 같은 강염기나 아세트산과 같은 강산을 부가적으로 사용할 필요가 전혀 없을 뿐아니라, 중간체 화합물(화학식 2의 화합물)을 분리, 정제해야만 했던 기존의 2단계 공정에 비해 간편하고 우수한 제조방법을 제공한다. 이를 반응도식으로 나타내면 하기 반응식 2와 같다.The present invention reacts 2-amino-4,6-dichloropyrimidine of formula 1 with concentrated sulfuric acid and concentrated nitric acid in a one step process to 2-amino-4-chloro-5-nitro-6 of formula 3 1H) -pyrimidinone. Therefore, there is no need to additionally use a strong base such as sodium hydroxide or a strong acid such as acetic acid, as well as a simple and superior manufacturing method compared to the conventional two-step process in which the intermediate compound (compound of Formula 2) had to be separated and purified. To provide. This is represented by the scheme shown in Scheme 2 below.

[화학식 1][Formula 1]

Figure 112002021659559-pat00008
Figure 112002021659559-pat00008

[화학식 3][Formula 3]

Figure 112002021659559-pat00009
Figure 112002021659559-pat00009

Figure 112002021659559-pat00010
Figure 112002021659559-pat00010

상기 본 발명의 제조방법에 따라 화학식 3의 화합물을 얻은 후 통상적인 전환 방법에 따라 그의 염, 수화물 및 용매화물을 제조할 수 있다. After the compound of Formula 3 is obtained according to the preparation method of the present invention, salts, hydrates, and solvates thereof may be prepared according to conventional conversion methods.

이하, 본 발명을 상세히 설명한다.Hereinafter, the present invention will be described in detail.

화학식 1의 화합물을 진한 황산에 용해시킨 후, 진한 질산을 천천히 적가하여 화학식 3의 화합물을 수득한다. 본 반응에서 사용되는 진한 황산은 90중량% 이상의 진한 황산 수용액이며 일반적으로 화학식 1의 화합물 1g을 기준으로 2 내지 10g을 사용한다. 또한, 사용되는 진한 질산은 90중량% 이상의 진한 질산 수용액이며 통상 화학식 1의 화합물을 기준으로 1 내지 10당량을 사용하나, 바람직하게는 1.2 내지 6.0당량을 사용한다. 이때, 진한 황산과 진한 질산의 부피비가 중요하며, 진한 질산:진한 황산을 1:3 이상의 부피비로 사용하는 것이 바람직하나, 특히 1:4 내지 1:6의 부피비로 사용하는 것이 좋다.After dissolving the compound of Formula 1 in concentrated sulfuric acid, concentrated nitric acid is slowly added dropwise to obtain the compound of Formula 3. The concentrated sulfuric acid used in the reaction is 90% by weight or more aqueous concentrated sulfuric acid, and generally 2 to 10 g based on 1 g of the compound of formula (1). In addition, the concentrated nitric acid used is 90% by weight or more aqueous concentrated nitric acid solution is usually used 1 to 10 equivalents based on the compound of the formula (1), preferably 1.2 to 6.0 equivalents. At this time, the volume ratio of concentrated sulfuric acid and concentrated nitric acid is important, and it is preferable to use concentrated nitric acid: concent sulfuric acid in a volume ratio of 1: 3 or more, but particularly preferably in a volume ratio of 1: 4 to 1: 6.

반응은 20~80℃의 온도에서 수행할 수 있으나, 30~50℃에서 반응을 수행하는 것이 바람직하다. 또한, 반응시간은 일반적으로 10분 내지 5시간이 소요되나, 바람직하게는 30분 내지 2시간 동안 반응을 수행한다.The reaction may be carried out at a temperature of 20 ~ 80 ℃, it is preferable to carry out the reaction at 30 ~ 50 ℃. In addition, the reaction time generally takes 10 minutes to 5 hours, but preferably performs the reaction for 30 minutes to 2 hours.

이때, 반응온도가 낮거나, 반응시간이 너무 짧거나, 또는 진한 질산의 양이 부족하면, 미반응의 화학식 1 화합물이 많이 얻어진다. 반대로, 반응온도가 너무 높거나, 반응시간이 너무 길거나, 또는 진한 질산의 양이 많으면, 두개의 니트로기가 도입되어 화학식 3의 화합물이 분해됨으로써 하기 화학식 4의 화합물과 같은 불순물이 생성될 수 있으므로 좋지 않다.At this time, when the reaction temperature is low, the reaction time is too short, or the amount of concentrated nitric acid is insufficient, a large amount of unreacted formula (1) compound is obtained. On the contrary, if the reaction temperature is too high, the reaction time is too long, or the amount of concentrated nitric acid is high, two nitro groups may be introduced to decompose the compound of Formula 3, thereby producing impurities such as the compound of Formula 4 below. not.

Figure 112002021659559-pat00011
Figure 112002021659559-pat00011

반응이 완결되면 반응용액을 차가운 물에 가하고 물의 온도를 15℃이하로 유지한다. 생성된 노란색 고체를 여과하고 물로 세척하여 목적하는 화학식 3의 2-아미노-4-클로로-5-니트로-6(1H)-피리미디논 화합물을 얻는다. 화학식 3의 화합물은 또한 염의 형태로 수득될 수도 있다.When the reaction is completed, the reaction solution is added to cold water and the water temperature is kept below 15 ℃. The resulting yellow solid is filtered and washed with water to afford the desired 2-amino-4-chloro-5-nitro-6 (1H) -pyrimidinone compound of formula (3). The compound of formula 3 may also be obtained in the form of a salt.

본 발명을 하기 실시예에 의하여 더욱 구체적으로 설명한다. 그러나, 하기 실시예는 본 발명에 대한 이해를 돕기위한 것일 뿐, 어떤 의미로든 본 발명의 범위가 실시예로 한정되는 것은 아니다.The present invention is explained in more detail by the following examples. However, the following examples are only intended to help the understanding of the present invention, and the scope of the present invention is not limited to the examples in any sense.

실시예 1Example 1

2-아미노-4-클로로-5-니트로-6(1H)-피리미디논의 제조Preparation of 2-Amino-4-chloro-5-nitro-6 (1H) -pyrimidinone

상온에서 2-아미노-4,6-디클로로피리미딘 14.2g(86.6mmol)을 진한 황산 수용액(95중량%) 100ml에 용해시킨 후, 진한 질산 20ml(90중량%, 약 449.6mmol)을 30℃ 이하에서 적가하였다. 반응용액을 30~45℃에서 약 30분 동안 교반한 후, 얼음 500g에 가하고 교반하여 반응을 완료시켰다. 생성된 노란색 고체를 여과하고, 물로 세척한 후, 질소 건조시켜 표제화합물 11.6g(수율 70.3%)을 수득하였다. After dissolving 14.2 g (86.6 mmol) of 2-amino-4,6-dichloropyrimidine in 100 ml of concentrated aqueous sulfuric acid solution (95% by weight) at room temperature, 20 ml (90% by weight, about 449.6 mmol) of concentrated nitric acid were dissolved at 30 ° C or lower. Dropped at The reaction solution was stirred at 30 to 45 ° C. for about 30 minutes, and then added to 500 g of ice to complete the reaction. The resulting yellow solid was filtered, washed with water and dried under nitrogen to give 11.6 g (70.3% yield) of the title compound.

13C NMR(400MHz, DMSO-d6) δ: 152.1, 151.2, 150.2 13 C NMR (400 MHz, DMSO-d 6 ) δ: 152.1, 151.2, 150.2

Mass(ESI, M+1) 191Mass (ESI, M + 1) 191

본 발명에 따르면, 화학식 3의 2-아미노-4-클로로-5-니트로-6(1H)-피리미디논을 화학식 1의 2-아미노-4,6-디클로로피리미딘으로부터 1단계 공정에 의해 제조하게 되므로 기존의 2단계 공정, 즉 화학식 2의 화합물을 중간체로서 정제하여 수득한 후 다시 반응시키는 공정에 비해 매우 간편하고 우수하다. 또한, 수산화나트륨과 같은 강염기나 아세트산과 같은 강산을 부가적으로 사용할 필요가 전혀 없을 뿐아니라, 기존의 방법에서 중간체로 분리되어야 하는 화학식 2의 화합물을 분리, 정제할 필요도 없다. According to the present invention, 2-amino-4-chloro-5-nitro-6 (1H) -pyrimidinone of formula 3 is prepared from a 2-amino-4,6-dichloropyrimidine of formula 1 by a one step process Therefore, compared to the conventional two-step process, that is, the compound of formula 2 is purified and obtained as an intermediate and then reacted again, it is very simple and excellent. In addition, there is no need to additionally use a strong base such as sodium hydroxide or a strong acid such as acetic acid, and there is no need to separate and purify the compound of formula 2 to be separated into an intermediate by conventional methods.

Claims (7)

하기 화학식 1의 화합물을 진한 황산에 용해시킨 후, 여기에 진한 질산을 가하여 반응시킴을 특징으로 하여 하기 화학식 3의 화합물, 그의 염, 또는 수화물을 제조하는 방법:Dissolving a compound of formula 1 in concentrated sulfuric acid, and then reacting with concentrated nitric acid, to prepare a compound of formula 3, a salt thereof, or a hydrate thereof: [화학식 1][Formula 1]
Figure 112006004892339-pat00012
Figure 112006004892339-pat00012
 [화학식 3][Formula 3]
Figure 112006004892339-pat00013
Figure 112006004892339-pat00013
 제1항에 있어서, 진한 황산이 90중량% 이상의 진한 황산 수용액인 방법.The method of claim 1 wherein the concentrated sulfuric acid is at least 90% by weight aqueous concentrated sulfuric acid. 제2항에 있어서, 황산을 화학식 1의 화합물 1g에 대하여 2 내지 10g의 양으로 사용하는 방법.The process of claim 2 wherein sulfuric acid is used in an amount of 2 to 10 g per 1 g of compound of formula 1. 제1항에 있어서, 진한 질산이 90중량% 이상의 진한 질산 수용액인 방법.The method of claim 1 wherein the concentrated nitric acid is at least 90% by weight aqueous concentrated nitric acid solution. 제4항에 있어서, 질산을 화학식 1의 화합물에 대하여 1 내지 10당량의 양으로 사용하는 방법.5. The process of claim 4, wherein nitric acid is used in an amount of 1 to 10 equivalents based on the compound of formula 1. 제1항에 있어서, 진한 질산과 진한 황산을 1:3 이상의 부피비로 하여 황산을 과량 사용하는 방법.The method according to claim 1, wherein the sulfuric acid is used in an excess of concentrated nitric acid and concentrated sulfuric acid in a volume ratio of 1: 3 or more. 제1항에 있어서, 반응을 20~80℃의 온도에서 수행하는 방법.The process of claim 1 wherein the reaction is carried out at a temperature of 20-80 ° C.
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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4939252A (en) * 1989-04-20 1990-07-03 Hoffmann-La Roche Inc. Novel intermediates for the preparation of Carbovir

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Publication number Priority date Publication date Assignee Title
US4939252A (en) * 1989-04-20 1990-07-03 Hoffmann-La Roche Inc. Novel intermediates for the preparation of Carbovir

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Title
J.Heterocyclic Chem.;1985; 22; 1035 *
Tetrahedron Letters, 0040-4039, 42(9), pp.1793-1795, 2001] *

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