1,3-二(2-乙基己基)六氢-5-甲基-5-硝基嘧啶 | 56672-87-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 中文名称: 1,3-二(2-乙基己基)六氢-5-甲基-5-硝基嘧啶
• 英文名称: 1,3-bis-(2-ethyl-hexyl)-5-methyl-5-nitro-hexahydro-pyrimidine
• 英文别名: 1,3-bis-(β-ethylhexyl)-5-nitro-5-methyl-hexahydropyrimidine；1,3-Bis(2-ethylhexyl)hexahydro-5-methyl-5-nitropyrimidine；1,3-bis(2-ethylhexyl)-5-methyl-5-nitro-1,3-diazinane
• CAS: 56672-87-8
• 化学式: C₂₁H₄₃N₃O₂
• 分子量: 369.591
• InChiKey: LGMAAKQUWQWLTL-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.5
• 重原子数：
  26
• 可旋转键数：
  12
• 环数：
  1.0
• sp3杂化的碳原子比例：
  1.0
• 拓扑面积：
  52.3
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  1,3-二(2-乙基己基)六氢-5-甲基-5-硝基嘧啶 在 甲醇 、 镍 作用下， 100.0 ℃ 、6.86 MPa 条件下， 生成 海克替啶
  参考文献：
  名称：

  The Preparation of Some Hexahydropyrimidines from Nitroparaffins¹

  摘要：

  DOI：

  10.1021/ja01212a073

文献信息

• Process for the manufacture of
  申请人：Meditest Institut fur Medizinisch Pharmazeutische Untersuchungen GmbH

  公开号：US04010160A1

  公开（公告）日：1977-03-01

  The process provided for the production of high-purity 1,3-bis-(.beta.-ethexyl)-5-amino-5-methyl-hexahydropyrimidine, also known as hexetidin, by reacting 1,3-bis-(.beta.-ethylhexyl)-5-nitro-5-methyl-hexahydropyrimidine with naphthalene-1,5-disulphonic acid in a solvent to selectively preciptitate the novel intermediate compound 1,3-bis-(.beta.-ethylhexyl)-5-nitro-5-methyl-hexahydropyrimidine-naphthale ne-1,5-disulphonate, which is separated off, treated with aqueous alkali to produce 1,3-bis-(.beta.-ethylhexyl)-5-nitro-5-methyl-hexahydropyrimidine, and subsequently hydrogenated to produce high-purity hexetidin. The invention relates to an industrially practicable process for the manufacture of high-purity 1,3-bis(.beta.-ethylhexyl)-5-amino-5-methyl-hexahydropyrimidine of the formula ##STR1## which is also known by the name of hexetidin and in view of its antimicrobial activity is used as an antiseptic and insecticide. From M. Senkus, Journal of American Chemical Society, 68, 1611-1613 (1946), it is known to manufacture 5-nitrohexahydropyrimidine by reaction of an aliphatic amine with formaldehyde followed by reaction with an aliphatic nitro compound. These 5-nitro-hexahydropyrimidines are then hydrogenated in methanolic solution using raney nickel as catalyst, whereby the 5-amino-hexahydropyrimidines are formed. Similarly to this process described by Senkus, the 1,3-bis-(.beta.-ethylhexyl)-5-nitro-5-methyl-hexahydropyrimidine can be obtained by reaction of 2-ethylhexylamine with formaldehyde followed by reaction with nitroethane. The oily reaction product, which is yellowish in colour, contains 1,3-bis-(.beta.-ethylhexyl)-5-nitro-5-methyl-hexahydropyrimidine, which can always only be obtained as a crude product of 70 to 80% in mixture with impurities which are present at 20 to 30% in addition to the main product. As by-products there have chiefly been observed N.sub.1,N.sub.3 -bis(ethylhexyl)-2-nitro-2-methyl-1,3-propanediamine of the formula ##STR2## and small quantities of other substances. This process has the disadvantage that the mixture of main product and byproduct cannot be separated by distillation, because the substances have very high boiling points lying very close to one another. The highly impure mixture, which contains the desired nitro compound only up to 70 to 80% is then hydrogenated in an autoclave at 100 to 120 atmospheres overpressure in methanolic solution using raney nickel as catalyst. After blowing off the hydrogen, the contents of the autoclave after being freed from the catalyst by filtration are freed of water and organic solvents in a vacuum at a maximum temperature of 50.degree. C. The product thus obtained is a crude hexetidin containing at the most 70% and usually only 60% hexetidin and consequently unsuitable for use in pharmaceutical preparations. There has therefore already been proposed a purification process, in order to obtain the synthesized crude product in pharmaceutical quality. There is also known another process for the manufacture of hexetidin using the Schmidt reaction (Kawahara, Chem. Abstr. 58, 1963, column 13968 g), though this has no significance for industrial purposes since it includes dangerous process steps and likewise leads to a highly impure hexetidin. From German Offenlegungsschrift No. 2011078 there is known a process which is based on the fact that from solutions of the crude hexetidin obtained in known manner the not-readily-soluble hexetidin-naphthalene-1,5-disulphonate is selectively separated out by means of naphthalene-1,5-disulphonic acid. Under the conditions of this process the secondary constituents present in the form of impurities form substantially more readily soluble salts, which remain in solution during the precipitation of the disulphonate. For the solvents in this case there are used low aliphatic alcohols or mixtures thereof with water. Preferably, 60 to 70% isopropyl alcohol is suggested for this purpose. By introduction into aqueous alkali, preferably into dilute soda lye, the hexetidin base is released from the salt; it may be taken up in a water-immiscible organic solvent. By careful distillation-off of the solvent in a vacuum, the pure hexetidin is then obtained. Although this process leads to a hexetidin which is largely free of byproducts, it has the disadvantage that for manufacture of the 5-amino compound the whole crude hexetidin has to be hydrogenated. Also there is a danger that further impurities, hitherto absent, might be formed as a result of the action, proposed in German Offenlegungsschrift No. 2011078, of a strong acid and of a lye on the already hydrogenated, sensitive product. The object of the invention is to avoid the above-mentioned disadvantages. It has unexpectedly been found that 1,3-bis-(.beta.-ethylhexyl)-5-amino-5-methyl-hexahydropyrimidine of pharmaceutical purity can be obtained by adding naphthalene-1,5-disulphonic acid in aqueous alcoholic solution to a mixture occurring in the case of the synthesis according to Senkus and containing 1,3-bis-(.beta.-ethylhexyl)-5-nitro-5-methyl-hexahydropyrimidine up to about 60 to 80% and about 20 to 40% of other by-products, and by separating off the thus selectively precipitated 1,3-bis-(.beta.-ethylhexyl)-5-nitro-5-methyl-hexahydropyrimidine-1,5-disul phonate. From this hitherto unknown compound of the following formula, which also has superior fungicidal and bactericidal properties, ##STR3## there can be obtained as a free base high-purity 1,3-bis-(.beta.-ethylhexyl)-5-nitro-5-methyl-hexahydropyrimidine, from which 1,3-bis-(.beta.-ethylhexyl)-5-amino-5-methyl-hexahydropyrimidine of pharmaceutical purity can be obtained by hydrogenation. The new compound 1,3-bis-(.beta.-ethylhexyl)-5-nitro-5-methyl-hexahydropyrimidine-naphthale ne-1,5-disulphonate is obtained by reaction of crude 1,3-bis-(.beta.-ethylhexyl)-5-nitro-5-methyl-hexahydropyrimidine with naphthalene-1,5-disulphonic acid in a solvent. Particularly suitable as the solvent are low aliphatic alcohols such as methyl alcohol, ethyl alcohol and especially isopropyl alcohol in mixtures thereof with water. The mixture ratio of alcohol to water should advantageously be greater than 1:1, preferably 2:1 to 5:1. The N.sub.1,N.sub.3 -bis-(ethylhexyl)-2-nitro-2-methylpropanediamine-1,5-disulphonate, which is the main impurity, is dissolved. Also the other accompanying substances are soluble in the aqueous/alcoholic medium. The selectively precipitated 1,3-bis-(.beta.-ethylhexyl)-5-nitro-5-methyl-hexahydropyrimidine-naphthale ne-1,5-disulphonate is centrifuged off, washed with aqueous isopropyl alcohol, preferably 80% isopropyl alcohol, and dried at 50.degree. to 60.degree. C. The white crystals, which occur in very high yields, have a purity of more than 99%. The nitro base is separated from the salt by addition to aqueous alkali, preferably dilute soda lye or potash lye. Suitable for taking up the separated nitro base are water-immiscible solvents such as butyl alcohol, acetic acid ethyl ester, petroleum ether and chlorinated hydrocarbons, preferably methylene chloride. It has been found that methylene chloride is particularly suitable for taking up the nitro base because, in advantageous contrast to petroleum ether, it can easily be removed from the nitro base without great application of heat, whereby there is formed a particularly pure 1,3-bis-(.beta.-ethylhexyl)-5-nitro-5-methyl-hexahydropyrimidine of light colour. A further advantage of the use of methylene chloride lies in that less than half the quantity of this solvent is required for taking up the hexetidin compared to the necessary quantity of petroleum ether. The new intermediate product is then hydrogenated in known manner to form hexetidin of pharmaceutical purity. With the aid of this new compound, the rest of the synthesization, i.e. the hydrogenation, does not proceed on mixed products as in the case of the known processes, but rather it is only one homogeneous substance which is treated. In this way, the starting quantity and working time of the treatment are reduced. Also there is obtained a hexetidin which from the economic point of view is purer than in the case of all the other known processes, since the separation of the by-products which in the known methods are also hydrogenated is an extremely elaborate operation. The 1,3-bis-(.beta.-ethylhexyl)-5-nitro-5-methyl-hexahydropyrimidine exhibits completely different properties compared to hexetidin. Thus, for example, this nitro compound does not form a salt with oxalic acid, but merely an oily liquid. For selective purification, however, the formation of salt in the form of solids is necessary, so that these can be separated from the impurities. In contrast to this, the oxalate of hexetidin is crystalline, since in this case the salt formation takes place by way of the primary amino group. Instead of the primary amino group in the 5-position of the hexetidin, which alone forms a salt despite the considerable supply of acid in accordance with German Offenlegungsschrift No. 2011078, the nitro compound used in accordance with the invention for purification purposes contains no primary amino group. It is therefore unexpected that with naphthalene-2,5-disulphonic acid it should nevertheless form a salt in the form of a precipitate. It is current teaching that tertiary amines are screened off in their basic centres by long-chain and (as in the case of the nitro compound) in particular by branched-chain radicals and are sterically hindered in such a way that they are not capable of salt formation. Also, the nitro compound is greatly reduced in its basicity by the long-chain aliphatic radicals. It was thus necessary to overcome a series of generally held prejudices in order to arrive at the process in accordance with the invention.

  该过程提供了一种高纯度1,3-双-(β-乙基己基)-5-氨基-5-甲基-六氢嘧啶（也称为六乙啶）的生产方法，通过将1,3-双-(β-乙基己基)-5-硝基-5-甲基-六氢嘧啶与萘-1,5-二磺酸在溶剂中反应，选择性地沉淀新的中间化合物1,3-双-(β-乙基己基)-5-硝基-5-甲基-六氢嘧啶-萘-1,5-二磺酸，将其分离，用水溶性碱处理后生成1,3-双-(β-乙基己基)-5-硝基-5-甲基-六氢嘧啶，随后进行加氢以产生高纯度的六乙啶。该发明涉及一种工业可行的制造高纯度1,3-双（β-乙基己基）-5-氨基-5-甲基-六氢嘧啶的过程，其化学式为##STR1##，也称为六乙啶，并且由于其抗菌活性而被用作防腐剂和杀虫剂。从M. Senkus，Journal of American Chemical Society，68，1611-1613（1946）中已知通过将脂肪胺与甲醛反应，然后与脂肪硝基化合物反应来制造5-硝基六氢嘧啶。这些5-硝基六氢嘧啶然后在甲醇溶液中使用Raney镍作为催化剂进行加氢，从而形成5-氨基六氢嘧啶。类似于Senkus所描述的这个过程，可以通过将2-乙基己胺与甲醛反应，然后与硝基乙烷反应来获得1,3-双-(β-乙基己基)-5-硝基-5-甲基-六氢嘧啶。油状反应产物呈黄色，包含1,3-双-(β-乙基己基)-5-硝基-5-甲基-六氢嘧啶，该产物总是只能作为70至80％的原始产物与杂质混合物一起获得，其中杂质占总量的20到30％。主要观察到的副产物是N.sub.1，N.sub.3-双（乙基己基）-2-硝基-2-甲基-1,3-丙二胺，其化学式为##STR2##和少量其他物质。该过程的缺点是，主产品和副产品的混合物无法通过蒸馏分离，因为这些物质的沸点非常接近。高度不纯的混合物仅包含最多70％的所需硝基化合物，通常仅包含60％的六乙啶，因此不适用于制药制剂。因此，已经提出了一种纯化过程，以获得制成的原始产品的制药质量。也已知另一种使用Schmidt反应（Kawahara，Chem. Abstr. 58，1963，栏13968 g）制造六乙啶的过程，但是由于包括危险的过程步骤并且同样导致高度不纯的六乙啶，因此对于工业目的没有意义。从德国Offenlegungsschrift No. 2011078中已知一种基于从已知方式获得的粗六乙啶的溶液中使用萘-1,5-二磺酸选择性地沉淀出不易溶解的六乙啶-萘-1,5-二磺酸的过程。在这个过程的条件下，以杂质形式存在的次要成分形成相当易溶的盐，这些盐在沉淀二磺酸盐的过程中保持在溶液中。在这种情况下，用低级脂肪醇或其与水的混合物作为溶剂。为此，最好建议使用60至70％的异丙醇。通过引入水溶性碱，优选是稀释的苏打液，将六乙啶碱从盐中释放出来；它可以在不与水相混的有机溶剂中吸收。通过在最高50℃的真空下仔细蒸馏去除溶剂，然后获得纯六乙啶。虽然这个过程导致的六乙啶基本上不含副产物，但它的缺点是为了制造5-氨基化合物，必须将整个粗六乙啶加氢。此外，根据德国Offenlegungsschrift No. 2011078提出的作用，强酸和碱对已经加氢的敏感产品产生的其他杂质可能会形成。该发明的目的是避免上述缺点。出乎意料地发现，可以通过将萘-1,5-二磺酸以水醇溶液的形式加入到根据Senkus合成的混合物中，该混合物含有1,3-双-(β-乙基己基)-5-硝基-5-甲基-六氢嘧啶约60至80％和约20至40％的其他副产物，并通过分离因此选择性沉淀的1,3-双-(β-乙基己基)-5-硝基-5-甲基-六氢嘧啶-1,5-二磺酸来获得制药纯度的1,3-双-(β-乙基己基)-5-氨基-5-甲基-六氢嘧啶。从这种迄今未知的化合物的以下化学式中，该化合物也具有优越的杀菌和杀菌作用，可以获得高纯度的1,3-双-(β-乙基己基)-5-硝基-5-甲基-六氢嘧啶，从而可以通过加氢获得制药纯度的1,3-双-(β-乙基己基)-5-氨基-5-甲基-六氢嘧啶。通过将粗1,3-双-(β-乙基己基)-5-硝基-5-甲基-六氢嘧啶与萘-1,5-二磺酸在溶剂中反应可以获得新的中间产物1,3-双-(β-乙基己基)-5-硝基-5-甲基-六氢嘧啶-萘-1,5-二磺酸。适合作为溶剂的是低级脂肪醇，例如甲醇，乙醇，特别是其与水的混合物的异丙醇。醇与水的混合比例应优于1：1，最好为2：1至5：1。主要杂质N.sub.1，N.sub.3-双（乙基己基）-2-硝基-2-甲基-1,3-丙二胺-1,5-二磺酸是可溶的。其他伴随物质在水/醇介质中也是可溶的。选择性沉淀的1,3-双-(β-乙基己基)-5-硝基-5-甲基-六氢嘧啶-萘-1,5-二磺酸被离心，用水异丙醇，优选为80％异丙醇洗涤，并在50℃至60℃下干燥。白色晶体非常高产，纯度超过99％。通过加入水溶性碱，优选是稀释的苏打液或钾液，将硝基基团从盐中分离出来。适合吸收分离的是水不相溶的溶剂，例如丁醇，醋酸乙酯，石油醚和氯化烃，优选为二氯甲烷。发现二氯甲烷特别适合吸收硝基基团，因为与石油醚相比，它可以轻松地从硝基基团中去除而无需大量加热，从而形成颜色较浅的特别纯净的1,3-双-(β-乙基己基)-5-硝基-5-甲基-六氢嘧啶。使用二氯甲烷的另一个优点在于，与石油醚所需的必要量相比，吸收六乙啶所需的这种溶剂的数量不到一半。然后，可以以已知方式加氢新的中间产物以形成制药纯度的六乙啶。借助这种新化合物，合成的其余部分，即加氢，不像已知过程中的混合物那样进行，而是只处理了一个均匀的物质。通过这种方式，处理的起始量和工作时间减少了。此外，从经济角度来看，所获得的六乙啶比所有其他已知过程中的纯度更高，因为在已知方法中也加氢的副产品的分离是一项极其繁琐的操作。1,3-双-(β-乙基己基)-5-硝基-5-甲基-六氢嘧啶与六乙啶完全不同。例如，这种硝基化合物不会形成草酸盐，而只会形成油状液体。然而，为了进行选择性纯化，需要形成固体形式的盐，以便将其与杂质分离。相反，六乙啶的草酸盐是结晶的，因为在这种情况下，盐的形成通过主要氨基团进行。根据德国Offenlegungsschrift No. 2011078的规定，尽管供应了相当多的酸，但与六乙啶中仅含一种主要氨基团的情况不同，在用于纯化目的的硝基化合物中不含有主要氨基团。因此，出乎意料地是，该化合物在使用萘-2,5-二磺酸时仍然会形成沉淀的盐。通常认为，长链和（如在硝基化合物的情况下）特别是支链基团通过其碱性中心屏蔽了三级胺并使其受到立体位阻，因此无法形成盐。此外，长链脂肪基团显着降低了硝基化合物的碱性。因此，必须克服一系列普遍存在的偏见才能到达本发明的过程。
• US4010160A
  申请人：——

  公开号：US4010160A

  公开（公告）日：1977-03-01
• US4048169A
  申请人：——

  公开号：US4048169A

  公开（公告）日：1977-09-13
• The Preparation of Some Hexahydropyrimidines from Nitroparaffins¹
  作者：Murray Senkus

  DOI：10.1021/ja01212a073

  日期：1946.8