RU2098407C1 - Method of synthesis of peroxyacetal lactone compound (variants) and lactone - Google Patents

Abstract

FIELD: organic chemistry. SUBSTANCE: product: peroxyacetal lactone compound of the formula (I):

where n = 1, 2, 3; m = 0, 1, 2; p = 0, 1; X - group

or

where R¹ and R² mean hydrogen atom or lower alkyl; or at n above 1 X can be branched and together with one of Y forms 6-membered saturated ring, and other Y can be a lower alkyl and can be bound with the same carbon atom that peroxy-group; R³ and R⁴ together form oxygen atom or each of R³ and R⁴ means hydrogen atom, or one of R³,R⁴ - hydrogen atom and another OR¹ - the group where R¹ - lower alkyl. Compounds were synthesized by oxidation in the presence of one or more metallic catalysts for oxidation of peroxy-compound of the formula (II):

where M, n, X, Y and p - as indicated above; R₅ - group -COOH, -C(O)R, -CRR(OH),

where R - lower alkyl, hydrogen; R¹ - lower alkyl, or both R¹ together with group -O-C-O to which they bound form cyclic acetal. Invention proposes a method of synthesis of peroxyacetal lactone compound of the formula (I) from compound of the formula (II). The latter is subjected for esterification with the following oxidation of esterification product in the presence of one or some metal-containing oxidation catalysts and its cyclization in solvent with acid catalyst - protonic acid or Lewis acid. Invention proposes also lactone of the formula:

Description

 The invention relates to new methods for producing cyclic persiacetal-lactone, β-lactol or ether compounds.

Кингхаосу является потенциальным противомалярийным агентом, который с успехом был использован для лечения больных малярией. Повторные вспышки штаммов малярии, устойчивых к обычной /хлорохиновой/ терапии, представляют всемирную проблему, и действительно, в настоящее время не существует универсального приемлемого способа лечения. Кингхаосу встречается в количестве около 0,1 /в расчете на сухой вес/ в однолетнем кустарнике кингхао /или Artemisiannua/, которые произрастают в большинстве провинций Китая. К сожалению, мировая потребность в кингхаосу значительно превосходит поставки, и поэтому весьма необходимы разработки биоактивных аналогов, или разработка альтернативных источников этого соединения. Соединение это получали полностью синтетическим способом в лабораториях, но из-за сложности строения полностью синтетический способ экономически невыгоден.The invention is especially important when used to produce biological active compounds containing peroxyacetal-lactone or - lactol functional groups. One of these biologically active compounds is Kinghaosu / Artemisinin /, formula

Kinghaosu is a potential antimalarial agent that has been successfully used to treat patients with malaria. Repeated outbreaks of malaria-resistant strains resistant to conventional / chloroquine / therapy represent a worldwide problem, and indeed, there is currently no universally acceptable treatment option. Kinghaosu is found in an amount of about 0.1 / calculated on dry weight / in the annual shrub of Kinghao / or Artemisiannua /, which grow in most provinces of China. Unfortunately, the worldwide need for Kinghaos far exceeds supply, and therefore it is very necessary to develop bioactive analogues, or develop alternative sources of this compound. This compound was obtained in a completely synthetic way in laboratories, but due to the complexity of the structure, a fully synthetic method is economically disadvantageous.

In one aspect, the invention provides a method for producing a compound comprising:
a / peroxyacetal lactone;
b / peroxyacetal lactol or
c / peroxyacetal ester functional group, including the oxidation of a compound containing:
i / hydroperoxyalkene carboxylic acid;
ii / hydroperoxyalkenaldehyde;
iii / hydroperoxyalkeneto or
iv / hydroperoxyalkane-alcohol functional group;
v / dialkyl acetals of the compounds in ii / and iii / as previously indicated, in the presence of one or more of their metal oxidation catalysts.

 The method of the invention can be carried out in one reactor, and it is called a direct method, or in several stages, then the method is called indirect.

в присутствии одного или более из металлических катализаторов окисления, до получения соединения формулы

где n 1,2,3, m 0,1,2, p 0,1, X

или

группы,
где R¹ и R² означают атом водорода или низший алкил, либо при n > 1, X может быть разветвлен и вместе с одним из Y образовывать шестичленное насыщенное кольцо, а другой Y может быть низшим алкилом, атомом водорода и может быть связан с тем же атомом углерода, что и пероксигруппа, R³ и R⁴ вместе означают атом кислорода или каждый из R³ и R⁴ атом водорода, или один из R³, R⁴ атом водорода, а другой OR¹ группа, где R¹ низший алкил.More specifically, a direct method involves oxidizing a compound of the formula

in the presence of one or more of the metal oxidation catalysts, to obtain a compound of the formula

where n 1,2,3, m 0,1,2, p 0,1, X

or

groups
where R ¹ and R ² mean a hydrogen atom or lower alkyl, or for n> 1, X can be branched and together with one of Y form a six-membered saturated ring, and the other Y can be lower alkyl, a hydrogen atom and can be associated with the same carbon atom as the peroxy group, R ³ and R ⁴ together mean an oxygen atom or each of R ³ and R ^{4 is} a hydrogen atom, or one of R ³ , R ^{4 is} a hydrogen atom, and the other is OR ¹ group, where R ^{1 is} lower alkyl .

 A direct process involves the oxidation of a hydroperoxy compound in the presence of one or more of the catalysts for the oxidation of cleavage of cyclization to give cyclic peroxyacetal lactone, lactol or ether.

 In accordance with the IUPAC nomenclature, acetals obtained from acids, ketones, aldehydes are all called acetals. However, usually acetals derived from ketones are called “ketals”. Thus, it should be borne in mind that the term “acetal” also includes acetals derived from ketones, that is, ketals.

 Those skilled in the art will appreciate that the method of the present invention can lead to one or more stereogenic / chiral / centers, the presence of which leads to the existence of stereoisomers. Thus, it should be borne in mind that the invention includes in its scope the production of stereoisomers. The invention also includes any isomer, or mixtures thereof, if obtained by the method of the invention.

 Scheme A illustrates a direct method when starting from cyclic hydroperoxyalkenoicarboxylic acid, α-aldehyde, β-ketone, β-alcohol, β-aldehyde acetal and keto acetal, respectively.

NB: на этой схеме представлен только один энантиомер для каждого хирального соединения. В каждом случае получают равное количество энантиомера.

NB: this diagram shows only one enantiomer for each chiral compound. In each case, an equal amount of enantiomer is obtained.

 An indirect method involves the esterification of a hydroperoxide to obtain a new intermediate hydroperoxide, followed by treatment with one or more of their catalysts in the presence of oxygen to carry out a new oxidation-cleavage-cyclization reaction to obtain cyclic peroxyacetal lactone.

включающий
i/ этерификацию соединения формулы:

до получения соединения формулы:

ii/ окисление в присутствии одного или более из металлических катализаторов окисления, до получения соединений формулы:

с последующей
iii/ обработкой протонной кислотой и кислотой Льюиса до получения целевого циклического пероксиацетальлактона;
где m, n, p, X, Y, R³ и R⁴ имеют указанные ранее значения.Thus, in another aspect of the present invention, a method for producing peroxyacetal lactone of the formula

including
i / esterification of a compound of the formula:

to obtain a compound of the formula:

ii) oxidation in the presence of one or more of the metal oxidation catalysts, to obtain compounds of the formula:

with subsequent
iii) treatment with protic acid and Lewis acid to obtain the desired cyclic peroxyacetal lactone;
where m, n, p, X, Y, R ³ and R ⁴ are as previously defined.

 The following Scheme B illustrates an indirect method in which cyclic hydroperoxyalkenecarboxylic acid is started.

NB: на этой схеме изображен только один энантиомер для каждого хирального соединения. В каждом случае получают равное количество другого энантиомера.

NB: this diagram depicts only one enantiomer for each chiral compound. In each case, an equal amount of another enantiomer is obtained.

NB: на этой схеме изображен только один энантиомер для каждого хирального соединения. В каждом случае получают также равное количество другого энантиомера.Preferably, the starting hydroperoxides are prepared by oxidation of the corresponding alkenes as follows:

NB: this diagram depicts only one enantiomer for each chiral compound. In each case, an equal amount of another enantiomer is also obtained.

 Preferably, the alkene carboxylic acid has an alkyl or other substituent at the double bond, and an optionally substituted alkyl chain between the alkene and carboxyl groups. The alkyl chain preferably contains two, four or more carbon atoms, and may also contain one or more heteroatoms such as oxygen. Alkenylcarboxylic acid may be cyclic or acyclic. The process is preferably carried out in a single reactor.

 The invention is most suitable for producing kinghaos.

Кингхао кислота встречается в количестве 1-3% /на сухую массу/ в Artemisia annua, что гораздо больше, чем природное содержание кингхаосу, и ее легко экстрагировать из растения. Было предпринято несколько попыток превратить это соединение в кингхаосу, но ни одна из них не подходит для получения.According to the method of the invention, the starting material for the production of kinghaos, including the functional groups of alkenacarboxylic acid, is preferably kinghao acid / artemisic acid or artemanic acid / of the following formula:

Kinghao acid is found in an amount of 1-3% / dry weight / in Artemisia annua, which is much more than the natural content of kinghaosu, and it is easy to extract from the plant. Several attempts have been made to turn this compound into a kinghaos, but not one of them is suitable for production.

ii/ окисление дигидрокингхао кислоты до получения соответствующих гидропероксидов, и без выделения;
iii/ окисление в присутствии одного или более из металлических катализаторов окисления до получения кингхаосу.Thus, in another aspect of the invention, there is provided a method for converting kinghao acid to kinghaosa, comprising
i / recovery of kinghao acid to obtain a dihydrokinghao acid of the formula

ii) oxidation of dihydrokinghao acid to the corresponding hydroperoxides, and without isolation;
iii) oxidation in the presence of one or more of the metal oxidation catalysts to obtain kinghaos.

iii/ окисление в присутствии одного или более из металлических катализаторов окисления до получения промежуточных продуктов формулы

и без выделения;
iv/ обработку протонной или кислотой Льюиса в качестве катализатора до получения кингхаосу.In a further aspect of the present invention, there is provided a method for converting kinghao acid to kinghaosa, comprising
i / recovery of kinghao acid to obtain dihydrokinghao acid;
ii) oxidation of the dihydrokingha acid followed by methylation to obtain the methyl ester of a hydroperoxide of the formula:

iii / oxidation in the presence of one or more of the metal oxidation catalysts to obtain intermediates of the formula

and without isolation;
iv) treatment with protic or Lewis acid as a catalyst to obtain kinghaos.

 Next, the method of the invention will be described in more detail with respect to obtaining kinghaos.

 However, it should be understood that the invention is not limited to this preparation.

 In detail, the method of the present invention can be applied to the conversion of kinghao acid to kinghaosa in accordance with the direct method, as illustrated in Scheme C.

 A direct way of converting Kinghao acid to Kinghaosa / artemisinin /.

Вначале кингхао кислоту восстанавливают известными способами до получения дигидрокингхао кислоты. Затем эту кислоту превращают окислением в новые гидропероксиды. Без промежуточного выделения полученную смесь обрабатывают одним или более из металлических комплексных катализаторов в атмосфере кислорода, и проводят новую реакцию окисления-отщепления-циклизации до получения кингхаосу.

First, kinghao acid is reduced by known methods to obtain dihydrokinghao acid. This acid is then converted by oxidation to new hydroperoxides. Without intermediate isolation, the resulting mixture is treated with one or more of the metal complex catalysts in an oxygen atmosphere, and a new oxidation-cleavage-cyclization reaction is carried out to obtain kinghaos.

 Kinghaos can also be obtained indirectly, as illustrated in Scheme D.

 An indirect way to convert kinghao acid to kinghaosa.

Вначале кингхао кислоту восстанавливают известными способами до получения дигидрокингхао кислоты. Затем эту кислоту превращают, окисляя в соответствующие гидропероксиды карбоновой кислоты, которые затем метилируют до получения соответствующих третичного гидропероксида и его региоизомеров. Затем основной третичный гидропероксид обрабатывают одним или более из металлических комплексных катализаторов в атмосфере кислорода, и подвергают новой реакции отщепления кислорода до получения соответствующего пероксигемиацеталя и гидропероксида. Затем эти соединения циклизуют, используя кислотный катализатор до получения кингхаосу.

First, kinghao acid is reduced by known methods to obtain dihydrokinghao acid. This acid is then converted by oxidizing to the corresponding carboxylic acid hydroperoxides, which are then methylated to obtain the corresponding tertiary hydroperoxide and its regioisomers. The basic tertiary hydroperoxide is then treated with one or more of the metal complex catalysts in an oxygen atmosphere, and subjected to a new oxygen cleavage reaction to obtain the corresponding peroxy hemiacetal and hydroperoxide. Then these compounds are cyclized using an acid catalyst to obtain Kinghaos.

 In another embodiment, the above method can be carried out without initial reduction of kinghao acid to dihydrokinghao acid, and in this method, a compound known as dehydrokinghaosu / artemisitene / is obtained.

 Without a reduction step, the direct process leads to a reaction in a single reactor, as illustrated in Scheme E.

 A direct method of converting kinghao acid to dehydrokinghaosa / artemisitene /.

Кингхао кислоту превращают окислением в гидропероксиды, и, без выделения, полученную смесь обрабатывают, как описано ранее в прямом способе, до получения дегидрокингхаосу.

Kinghao acid is converted by oxidation to hydroperoxides, and, without isolation, the resulting mixture is treated as described previously in the direct process to obtain dehydrokinghaosu.

Непрямой способ получения дегидрокингхаосу проиллюстрирован на схеме F.By-products of this reaction, which are not formed in the indirect reaction, are new keto-aldehydes of the formula:

An indirect method for preparing dehydrokinghaos is illustrated in Scheme F.

 First, kinghao acid is converted by oxidation to the corresponding carboxylic acid hydroperoxides, which are then methylated to give the corresponding new tertiary methyl esters of the hydroperoxide and a mixture of regioisomeric hydroperoxides.

 The basic tertiary methyl ester of the hydroperoxide is then treated with one or more of the metal complex catalysts in an oxygen atmosphere, and subjected to a new oxidation-cleavage reaction to obtain a mixture of peroxyhemiacetal and dicarbonyl hydroperoxide. Then, peroxyhemiacetal and dicarbonyl hydroperoxide are cyclized by acid catalysis to give dehydrokinghaosu.

 An indirect way of converting kinghaos acid to dehydrokinghaos.

Новый метилпероксиацеталь, формула которого приводится далее, образуется также как результат реакции пероксиацеталя и гидропероксида с метанолом, который высвобождается во время реакции замыкания кольца, приводящей к получению дегидрокингхаосу.

The new methyl peroxy acetal, whose formula is given below, is also formed as a result of the reaction of peroxy acetal and hydroperoxide with methanol, which is released during the ring closure reaction, resulting in dehydrokinghaos.

Дегидрокингхаосу можно затем превратить известными способами в кингхаосу или другие активные противомалярийные соединения.

The dehydrokinghaosa can then be converted by known methods into kinghaosa or other active anti-malarial compounds.

 Using this direct method has many advantages.

 Firstly, the direct method involves a reaction in a single reactor, which eliminates the various stages of separation and / or purification.

 Secondly, the initial methylation step is eliminated. The free acid then acts as an internal acid catalyst in the new oxidation-cleavage-cyclization process. Thus, the need for an external acid catalyst for the final cyclization disappears, but its presence accelerates the cyclization stage and increases the overall yield.

 The direct method can also be used to produce compounds such as kinghaoso, but without the carbonyl group, which is known as deoxykinghaosu or deoxyartemisinin. This production method is illustrated in Scheme G.

 A direct method of converting dehydrokinghao alcohol to deoxykinghaos / deoxyartemisinin /.

Вначале кингхао кислоту восстанавливают до дигидрокингхао кислоты, а затем это соединение превращают восстановлением в известный алкеновый спирт, который мы называем "дигидрокингхао спирт", через сложный эфир дигидрокингхао кислоты. Затем дигидрокингхао спирт превращают окислением в смесь гидропероксидов, которую обрабатывают одним или более из комплексных катализаторов в атмосфере кислорода до получения деоксикингхаосу.

First, kinghao acid is reduced to dihydrokinghao acid, and then this compound is converted by reduction to a known alkene alcohol, which we call "dihydrokinghao alcohol", through the dihydrokinghao acid ester. Then, the dihydrokinghao alcohol is converted by oxidation to a mixture of hydroperoxides, which is treated with one or more complex catalysts in an oxygen atmosphere to produce deoxykinghaos.

 As an antimalarial agent, deoxikinghaos is twice as active as kinghaos.

 The oxidation step of the invention is preferably a photosensitization oxidation which is carried out by treating an oxygen singlet in the presence of a Bengal Pink. It is preferable to conduct the reaction in a solvent such as acetonitrile.

Methylation is preferably carried out by treatment with diazomethane. It can be obtained from N-nitroso N-methylurea. Diazomethane is preferably added dropwise in a solution of diethyl ether. New oxidation-cleavage-cyclization and oxidation-cleavage is usually carried out by treating with one or more oxidizing transition metal complex catalysts such as Cu / OSO ₂ CF _3/2, Cu / II / propionate, 2-etilengeksanoat copper / II / other carboxylates of copper / II /, and various salts of iron / III /, such as Fe / phenanthroline / ₃ / PF _6/3. As other catalysts, salts of cobalt / II / and cobalt / III / can be used. It is preferable to conduct this reaction in a solvent such as acetonitrile, treating one or more of the above catalysts, or a combination of copper and iron catalysts. Other suitable solvents include dichloromethane, hexane, ethyl acetate and the like. If the iron catalyst is lowered, then the complete conversion may be somewhat slow. In this case, the formation of by-products of cleavage can significantly increase. This leads to an increase in the yield of the final product. The new reaction is carried out, preferably, at a temperature in the range of -30 ^° C. to -10 ^° C., and is preferably allowed to go to completion at room temperature.

 Closing the loop with the complex catalyst is usually carried out in the presence of para-toluenesulfonic acid.

 All of these reactions are the only way to obtain dehydrokinghaos, and provide the usual means of obtaining this potentially commercially valuable compound in large quantities. The only source of kinghaos is the annual shrub Artemisia annua. Since in comparison with 0.1% kinghaos there is a large amount (up to 3%) of kinghaos acid, the above method significantly increases the availability of kinghaos. Moreover, these methods make it possible to access anti-malarial agents structurally related to Kinghaos, but with increased activity.

 Specific embodiments of the present invention are further illustrated by the following examples. However, it should be borne in mind that the invention is not limited to the specific examples presented below.

Example 1. Obtaining kinghaos / artimisinin / from kinghao acid
Method 1. Direct conversion.

Оптически чистую кингхао кислоту /артеанновую или артемизиновую кислоту/, полученную из Artemisia annua восстанавливают боргидридом натрия в метаноле известным из литературы способом /X_u, X X, Zhu, J; Huang, D.-Z. Zhou, W. S. Tetrahedron 1986, 42, 819/ до дигидрокингхао кислоты. Ее превращают в гидропероксид следующим способом. Суспензию кислоты /289 мг, 1,22•10^-3 моля/ в 5 мл ацетонитрила, содержащего Бенгальский Розовый /6 мг/, интенсивно перемешивают в атмосфере азота при -30^oC, облучая вольфрамовой лампой /500 Вт/. Спустя 4 ч получают прозрачный раствор, и окисление завершается. Кроме третичного гидропероксида в результате фотоокисления получают небольшое количество /около 18%/ аллильного региоизомера, который не вступает в последующие реакции. Без выделения полученную смесь разбавляют 20 мл дихлорметана, а полученный раствор охлаждают до -20^oC. При перемешивании прикапывают раствор, содержащий C/OSO₂CF₃/₂ /44 мг, 0,1 экв./ в 0,5 мл ацетонитрила. Температуру поддерживают при -20^oC в течение 1 ч, после чего дают возможность повыситься до комнатной, после чего перемешивание продолжают еще 2 ч. Реакционную смесь выливают в 20 мл воды и экстрагируют эфиром /2•25 мл/. Объединенные экстракты промывают водой /10 мл/ и рассолом /10 мл/, а затем сушат над сульфатом магния. После выпаривания растворителя получают вязкое масло, которое после обработки на колонке с силикагелем с мгновенным испарением смесью эфир: петролейный эфир /1: 1/ получают кристаллический кингхаосу /артемизинин/ 165 мг, 48%/.

Optically pure kinghao acid (arteanic or artemisic acid) obtained from Artemisia annua is reduced with sodium borohydride in methanol in a manner known from the literature / X _u , XX, Zhu, J; Huang, D.-Z. Zhou, WS Tetrahedron 1986, 42, 819 / to dihydrokinghao acid. It is converted to hydroperoxide in the following manner. A suspension of acid / 289 mg, 1.22 • 10 ^-3 mol / in 5 ml of acetonitrile containing Bengal Pink / 6 mg /, is intensively stirred in a nitrogen atmosphere at -30 ^o C, irradiating with a tungsten lamp / 500 W /. After 4 hours, a clear solution is obtained, and the oxidation is complete. In addition to tertiary hydroperoxide, a small amount (about 18%) of the allylic regioisomer, which does not enter into subsequent reactions, is obtained as a result of photooxidation. Without isolation, the mixture was diluted with 20 mL dichloromethane and the resulting solution was cooled to -20 ^o C. While stirring, a solution containing the C / OSO ₂ CF _3/2/44 mg, 0.1 eq. / In 0.5 ml of acetonitrile. The temperature was maintained at -20 ^° C for 1 hour, after which it was allowed to rise to room temperature, after which stirring was continued for another 2 hours. The reaction mixture was poured into 20 ml of water and extracted with ether / 2 • 25 ml /. The combined extracts were washed with water / 10 ml / and brine / 10 ml /, and then dried over magnesium sulfate. After evaporation of the solvent, a viscous oil is obtained, which, after treatment on a silica gel column with instant evaporation with a mixture of ether: petroleum ether / 1: 1 /, gives crystalline Kinghaos / artemisinin / 165 mg, 48% /.

¹ H NMR spectrum / 400 MHz, CDCI ₃ /, δ 1.002 / 3H, d, J / Me.6 / = 6 Hz, 6-CH ₃ /, 1.03-1.12 / 2H, m /, 1.209 / 3H, d, J / Me.9 / = 7.2 Hz, 9-CH ₃ /, 1.33-1.53 / 3H, m /, 1.466 / 3H, s, 3-CH ₃ /, 1.73 -1.81 / 2H, m /, 1.86-1.93 / 1H, m /, 2.39-2.48 / 1H, m /, 3.398 / 1Nb, dddd, J / 8a, 8 a 7, 3, J / 8a, 8 b / = 7.3, J / 8a, 9 / 7.3, J / 8a, 7 a / 5.4 Hz, 5.862 / 1H, s, H-12 /.

 By adding 0.1 equivalent of para-toluenesulfonic acid to the reaction mixture, 0.5 hours after the addition of the metal catalyst, acceleration of the reaction and the formation of kinghaos are achieved in higher yield.

 Example 2. Method 2. Indirect conversion.

Дигидрокингхао кислоту /103,1 мг, 4,36•10^-4 моля/ фотоокисляют способом, описанным ранее. Растворитель удаляют в вакууме из реакционной смеси до получения сырой смеси гидропероксида карбоновой кислоты и ее региоизомера в отношении 4,5: 1 по данным ¹H ЯРМ. Полученную смесь растворяют в диэтиловом эфире /17,5 мл/ и прикапывают раствор диазометана, полученный из N-ниторо-N- метилмочевины /350 мг/ в диэтиловом эфире /17,5 мл/ при 0^oC. Добавление диазометанового раствора продолжают до тех пор, пока по данным тонкослойной хроматографии не происходит полного превращения свободного гидропероксида карбоновой кислоты в сложные метиловые эфиры. Полученную смесь обрабатывают 5% водной уксусной кислотой для разложения избытка диазометана. Полученную смесь промывают водой, водным бикарбонатом натрия и рассолом. Эфирный раствор сушат /сульфат магния/, а затем выпаривают досуха до получения вязкого масла. Основной /третичный/ гидропероксид, известное соединение /Jung, M. El Sohly, H.N. Groom E.M. J. Org. Chem. 1986, 51,819/ выделяют на хроматографической колонке с силикагелем с мгновенным испарением смесью диэтиловый эфир-петролейный эфир /3:7/, как вторую фракцию /72,2 мг, 70%/. Гидропероксид /72,2 мг, 2,55•10^-4 моля/ в 4 мл ацетонитрила обрабатывают Fe/фенантролин/₃/PF₆/₃0,03 экв./ в ацетронитриле /0,9 мл/, а затем Cu/OSO₂CF₃/₂/ 0,1 экв./ в 0,5 мл ацетонитрила при 0^oC. Спустя 30 мин реакционную смесь обрабатывают, как описано ранее, до получения неочищенного продукта, который растворяют в дихлорметане /20 мл/. Добавляют моногидрат пара-толуолсульфокислоты /15 мг, 7,65•10^-5 моля/, и полученную смесь перемешивают при комнатной температуре в течение 4 ч. Затем ее выливают в смесь эфир-вода. Эфирный слой выделяют, а водный слой экстрагируют эфиром. Объединенные эфирные слои обрабатывают обычным способом до получения неочищенного продукта, который обрабатывают на хроматографической колонке с силикагелем с мгновенным испарением смесью эфир-петролейный эфир /6:4/ до получения кингхаосу в виде тонких иголок /20,1 мг, 28% из гидропероксида/.

Dihydrokinghao acid / 103.1 mg, 4.36 x 10 ^-4 moles / photooxidize by the method described previously. The solvent was removed in vacuo from the reaction mixture until a crude mixture of the carboxylic acid hydroperoxide and its regioisomer was obtained in a ratio of 4.5: 1 according to ¹ H NMR. The resulting mixture was dissolved in diethyl ether / 17.5 ml / and a diazomethane solution obtained from N-nitoro-N-methylurea / 350 mg / in diethyl ether / 17.5 ml / was added dropwise at 0 ^° C. The addition of the diazomethane solution was continued until until, according to thin-layer chromatography, complete conversion of free carboxylic acid hydroperoxide to methyl esters takes place. The resulting mixture was treated with 5% aqueous acetic acid to decompose an excess of diazomethane. The resulting mixture was washed with water, aqueous sodium bicarbonate and brine. The ethereal solution was dried (magnesium sulfate) and then evaporated to dryness to give a viscous oil. Basic / tertiary / hydroperoxide, known compound / Jung, M. El Sohly, HN Groom EMJ Org. Chem. 1986, 51.819 / isolated on a chromatographic column with silica gel with instant evaporation with a mixture of diethyl ether-petroleum ether / 3: 7 / as the second fraction / 72.2 mg, 70% /. Hydroperoxide / 72,2 mg, 2,55 • 10 ^-4 mol / in 4 mL of acetonitrile was treated with Fe / phenanthroline / ₃ / PF _6/3 0.03 eq. / In atsetronitrile / 0.9 ml / and then Cu / OSO ₂ CF _3/2 / 0.1 eq. / in 0.5 ml of acetonitrile at 0 ^o C. After 30 minutes, the reaction mixture was worked up as previously described to give crude product, which was dissolved in dichloromethane / 20 ml /. Para-toluenesulfonic acid monohydrate (15 mg, 7.65 x 10 ^-5 mol) was added, and the resulting mixture was stirred at room temperature for 4 hours. Then it was poured into ether-water. The ether layer was isolated, and the aqueous layer was extracted with ether. The combined ether layers are processed in the usual way to obtain a crude product, which is processed on a chromatographic column with silica gel with instant evaporation with a mixture of ether-petroleum ether / 6: 4 / to obtain kinghaos in the form of thin needles / 20.1 mg, 28% from hydroperoxide /.

 Example 3. Obtaining dehydrokinghaosu / artemisinin / from kinghao acid.

 Method 1. Direct conversion.

Кингхао кислоту /32 мг, 1,37•10^-4 моля/ в 1,5 мл ацетонитрила, содержащего Бенгальский Розовый /примерно 0,5 мг/ при -30^oC в атмосфере кислорода превращает в свободные гидропероксиды карбоновой кислоты, соответствующие метиловым сложным эфиром гидропероксидов, описанных далее. Без выделения полученную смесь разбавляют дихлорметаном /5,4 мл/, и полученный раствор охлаждают до -20^oC. При перемешивании прикапывают раствор, содержащий Fe /фенантролин/₃/PF₆/₃/0,002 экв. / и Cu/OSO₂CF₃/₂/0,1 экв./ в 0,6 мл ацетонитрила. Температуру поддерживают -20^oC в течение 1 ч, а затем дают нагреться до комнатной температуры, причем эту смесь перемешивают еще 2 ч. Побочные продукты реакции /которые не образуются в способе 2, приводимом далее/ по данным тонкослойной хроматографии для реакционной смеси являются кето-альдегидами.

Kinghao acid / 32 mg, 1.37 • 10 ^-4 mol / in 1.5 ml of Bengal Pink containing acetonitrile / about 0.5 mg / at -30 ^o C in an oxygen atmosphere turns into free carboxylic acid hydroperoxides corresponding to methyl complex hydroperoxide ester described below. Without isolation, the mixture was diluted with dichloromethane / 5.4 ml / and the resulting solution was cooled to -20 ^o C. While stirring, a solution containing the Fe / phenanthroline / ₃ / PF _6/3 / 0.002 equiv. And / Cu / OSO ₂ CF _3/2 / 0.1 eq. / In 0.6 ml of acetonitrile. The temperature was maintained at -20 ^° C for 1 h, and then allowed to warm to room temperature, and this mixture was stirred for another 2 h. By-products of the reaction (which were not formed in method 2 below), according to thin-layer chromatography for the reaction mixture, were keto aldehydes.

Реакционную смесь выливают в воду /10 мл/ и экстрагируют эфиром /2•25 мл/. Объединенные экстракты промывают водой /10 мл/ и рассолом /10 мл/, а затем сушат над сульфатом магния. После выпаривания растворителя остается вязкое масло, которое обрабатывают на хроматографической колонке с силикагелем с мгновенным испарением смесью эфир-петрлейный эфир /1:1/ до получения кристаллического дегидрокингхаосу /артемизитена/ 5 /14,4 мг 38/.

The reaction mixture was poured into water / 10 ml / and extracted with ether / 2 • 25 ml /. The combined extracts were washed with water / 10 ml / and brine / 10 ml /, and then dried over magnesium sulfate. After evaporation of the solvent, a viscous oil remains, which is treated on a chromatographic column with silica gel with instant evaporation with a mixture of ether-petroleum ether / 1: 1 / to obtain crystalline dehydrokinghaos / artemisitene / 5 / 14.4 mg 38 /.

 Example 4. Method 2. Indirect conversion.

 a / Oxidation of Kinghao acid.

A suspension of kinghao acid / arteanic or artemisic acid / / 338.2 mg, 1.44 • 10 ^-3 mol / in 35 ml of Bengal Pink containing acetonitrile / 6 mg /, is intensively mixed in an oxygen atmosphere at -30 ^o C, when irradiated tungsten lamp / 500 W /. After 4 hours, a clear solution is obtained, and the oxidation is complete. The solvent was removed under reduced pressure to obtain a crude mixture of carboxylic acid hydroperoxides in a ratio of 4.5: 1 according to ¹ H NMR. The resulting mixture was dissolved in diethyl ether / 17.5 ml / and treated dropwise with a diazomethane solution obtained from N-nitroso-N-methylurea / 350 mg / in diethyl ether / 17.5 ml / at 0 ^° C. The addition of the diazomethane solution was continued until, according to thin-layer chromatography, the conversion of carboxylic acid hydroperoxides to its methyl esters is complete. The resulting mixture was treated with 5% aqueous acetic acid to decompose the excess diazomethane. The resulting mixture was washed with water, aqueous sodium bicarbonate, and then brine. The ethereal solution was dried over magnesium sulfate and then evaporated to dryness to obtain a viscous oil. The main / tertiary / hydroperoxide, a new compound, is isolated by chromatography on silica gel with flash evaporation with diethyl ether-petroleum ether / 3: 7 / as a second fraction / 287.4 mg, 71% /.

¹ H NMR spectrum / 400 MHz, CDCl ₃ / δ 0.981 / 3Н, d, J / Me, 6 / 6.4 Hz, 6-CH ₃ /, 1.18-1.27 / 1Н, m, Н6 /, 1.209 / 3H, s, 3-CH ₃ / 1.27-1.38 / 2H, m /, 1.514 / 1H, gggg, J _hem = 12.5, J / 8 b 8a / 12.5, J / 8β , 7β / = 3.5 Hz, Н8 b /, 1.527 / 1Н, dggd, J 13.0, J 7.3, J 3.0, J 0.8 Hz, Н5a /, 1.72 1.79 / 1H, m /, 1.804 / 1H, dggd, J _heme 12.3, J / 8 a 8a / = 3.5, J / 8 8α7α / 3.5 Hz, J / 8α7β / 3.5 Hz, H 8a / , 1.834 / 1H, dggd, J = 12.6 J = 3.3 J 3.3 Hz / 1.971 / 1H, ggg, J = 13.1 J = 10.8 J = 3.5 Hz / 2.048 / 1H, dggd, J = 13.1 J = 7.5 J = 5.8 Hz / 3.141 / 1H, wide d, J / 8a 8 b / 12.6 Hz, H8A /, 3.741 / 3H, s, OCH ₃ / , 4.978 / 1H, ddd, J 12.8a / = 1.6 J = 1.6 J = 1.6 J = 0.8 Hz H12 /, 5.581 / 1H, dd J _heme = 1.1 Jmethylidene, 8a = 1.1 Hz, N methylidene /, 6.362 / 1H, d, J _hem = 1.1 Hz, H methylidene /, 7.575 / 1H, br s, W _{h / 2} 2.0 Hz, OOH /.

Третичный гидропероксид /106,3 мг, 3,78•10^-4 моля/ в 5 мл ацетонитрила обрабатывают Fe/фенантролин/₃/ P F₆/₃/ 0,03 экв. в 0,6 мл ацетонитрила/, а затем Cu/OSO₂CF₃/ ₂/0,1 эквивалент в 0,5 мл ацетонитрила/ при 0^oC в атмосфере кислорода. Реакционную смесь перемешивают в течение 30 мин при медленном нагревании до комнатной температуры, а затем выливают в смесь эфира и воды. Водную фазу экстрагируют эфиром, и объединенные экстракты промывают водой до исчезновения окраски, а затем рассолом. Органическую фазу сушат над сульфатом магния, а затем растворитель удаляют при пониженном давлении до получения вязкого масла, анализ которого по данным ¹H ЯМР спекроскопии, указывает на то, что оно состоит, главным образом, из продуктов окисления. Его выделяют на хроматографической колонке с силикагелем с мгновенным испарением, обрабатывая смесью эфир-петролейный эфир /6:4/, в виде нестабильного вязкого масла /62,5 мгБ 53%/. Пролонгированное экспонирование смеси окисленных продуктов на силикагеле приводит к разложению более полярного продукта. Продукты окисления находятся в равновесной смеси пероксигемиацеталя и свободного дикабонилгидропероксида. Оба являются новыми соединениями.b / Cleavage-oxidation to obtain peroxyhemiacetal and dicarbonyl hydroperoxide

The tertiary hydroperoxide / 106,3 mg, 3,78 • 10 ^-4 mol / 5 ml of acetonitrile was treated with Fe / phenanthroline / ₃ / PF _6/3 / 0.03 eq. in 0.6 ml of acetonitrile /, and then Cu / OSO ₂ CF _3/2 / 0.1 equivalent in 0.5 mL of acetonitrile / at 0 ^o C in an oxygen atmosphere. The reaction mixture was stirred for 30 minutes while slowly warming to room temperature, and then poured into a mixture of ether and water. The aqueous phase is extracted with ether, and the combined extracts are washed with water until the color disappears, and then with brine. The organic phase is dried over magnesium sulfate, and then the solvent is removed under reduced pressure to obtain a viscous oil, the analysis of which according to ¹ H NMR spectroscopy indicates that it consists mainly of oxidation products. It is isolated on a chromatographic column with silica gel with instant evaporation, treated with a mixture of ether-petroleum ether / 6: 4 /, in the form of an unstable viscous oil / 62.5 mgB 53% /. Prolonged exposure of a mixture of oxidized products on silica gel leads to the decomposition of a more polar product. The oxidation products are in an equilibrium mixture of peroxyhemiacetal and free dicabonyl hydroperoxide. Both are new compounds.

BRν _max / CHCl ₃ / 3580-3450 / s.//, 3450-3130 / s.//, 3001 / sr. 2956 / s /, 2940 / s /, 2872 / sr /, 2854 / sr /, 1732 / s /, / C = 0 /, 1714 / r / s / / C = 0 /, 1627 / s /, 1443 / s /, 1285 / sr /, 1167 / s /, 1100 / sr /, 961 / sr /, 909 / sr / cm ^-1 .

¹ H NMR / 400 MHz, CDCl ₃ / peroxy hemiacetal δ 0.933 / 3H, d, J / Me, 6 / = 6.4 Hz, 6-CH ₃ / 0.96-1.20 / 2H, m /, 1.217 / 3H, s, 3-CH ₃ /, 1.26-1.39 / 3H, m /, 1.56-2.24 / 4H, m /, 2.32-2.45 / 1H, m, H6 / , 2.94-3.01 / 1H, dd, J / 8a8 b / = 9.6, J = 8a8 a / = 7.1 Hz, H8a /, 3.804 / 3H, s, OCH ₃ /, 5.468 / 1H , s, methylidene /, 6.260 / 1H, s, methylidene /, 9.617 / 1H, d, J / 12.5a / = 2.5 Hz, H12 /, dicarbonyl hydroperoxide d 0.991 / 3H, d, J / Me, 6 / = 6.4 Hz, 6-CH ₃ /, 0.96-1.20 / 2H, m / 1.26-1.39 / 3H, m /, 1.56-2.24 / 4H, m /, 2.141 / 3H, s, 3-CH ₃ /, 2.585 / 1H, ddd, J _hem = 17.6, J _4.5 = 9.3 J _4.5 = 6.1 Hz H4 /, 2.713 / 1H ddd, J _heme 17.6, J _4.5 = 9.3 J _4.5 = 6.1 Hz, H4 /, 3.197 / 1H, dd, J / 8a8b / = 13.3 J8a8a / = 3.5 Hz, H8a /, 3.840 / 3Н, s, OCH ₃ /, 5.597 / 1Н, s, methylidene /, 6.383 / 1Н, s, methylidene / 9.340 / 1Н, dd, J = 1.5 J = 1.5 Hz, Н12 /, 10399 / 1H, s, OOH /.

Preliminary irradiation with d 9.6 / H12 peroxyhemiacetal leads to an increase of d 5.47 / methylidene, peroxymethalal / by 1% and by d 3.80 / OCH ₃ / by 1% Spectrum ¹³ C NMR / 100 MHz, CDCl ₃ / d: 20.049, 20.369, 20.568, 22.070, 22.515, 23.513, 26.986, 27.256, 27.790, 29.644, 29.886, 32.078, 33.777, 34.672, 35.144, 40.701, 41.657, 43.407, 43.862, 46.348, 52.278 / OCH ₃ peroxyhemiacetal /, 52 / OCH ₃ , dicarbonyl hydroperoxide /, 58.546, 92.29 / C12a, dicarbonyl hydroperoxide /, 92.31 / C12a, peroxyhemiacetal /, 105.90 / C3, dicarbonyl hydroperoxide /, 125.02 / methylidene, C, peroxyhemiacetal /, 129.01 / methylidene, C, dicarbonyl hydroperoxide /, 138.55 / C9 dicarbonyl hydroperoxide /, 139.70 / C9, peroxygene iatsetal /, 166,20 / C10, peroxyhemiacetal /, 170,41 / C10, dikarboniogidroperoksid /, 201,39 / C12, peroxyhemiacetal /, 203,14 / C12, dicarbonyl /, 209,14 / C3, dicarbonyl /.

 c / Joint cyclization of peroxyhemiacetal and dicarbonyl hydroperoxide to dehydrokinghaos / artemisitene /.

A mixture of peroxyhemiacetal and dicarbonyl hydroperoxide is obtained, as described previously, from tertiary hydroperoxide (110.3 mg, 3.92 x 10 ^-4 mol). The resulting mixture of products is immediately dissolved in dichloromethane / 5 ml / and treated with paratoluene sulfonic acid monohydrate / 0.3 equiv. /. The resulting mixture was stirred for 4 hours at room temperature, then ether-water was poured into the mixture. The ether layers are treated as described previously to obtain a viscous oil, which, after flash evaporation on a silica gel column chromatography with ether-petroleum ether / 6: 4 /, gives the dihydrokinghaos / artemisitin / in the form of fine needles / 47.9 mg, 43% from tertiary hydroperoxide, or 30% from kinghao acid /, mp 164-166 ^° C., known compound.

¹ H NMR spectrum / 400 MHz, CDCl ₃ /, d 1.017 / 3H, d, J / Me, 6 / = 5.9 Hz, 6-CH ₃ /, 1.15-1.27 / 1H, m /, 1.42-1.63 / 3H, m including Н8 /, 1.43-1.48 / 1Н, m, Н6 /, 1.459 / 3Н, s, 3-CH ₃ /, 1.72-1.80 / 2Н, m, including Н8 /, 1.94-2.01 / 1Н, m /, 2.04-2.10 / 1Н, m /, 2.37-2.45 / 1Н, m /, 2.550 / 1Н , dd, J / 8a, 8 b / = 13.6, J / 8a, 8 a / = 4.5 Hz, H8a /, 5.672 / 1H, dd, J _heme = 1.1, J methylidene, J8a = 1 , 1 Hz, methylidene /, 5.995 / 1H, s, H12 /, 6.570 / 1H, dd, J _hem = 1.2, J methylidene, 8-0.5 Hz, H methylidene /.

Methyl peroxyacetal (17.8 mg, 14%) in a ring closure reaction is also obtained in the reaction of peroxy hemiacetal and dicarbonyl hydroperoxide with methanol, resulting in dehydrokinghaos
Example 5. The conversion of dihydrokinghao alcohol to deoxokinghaos.

Дигидрокингхаосу спирт /артеаннуинол/ получают, восстанавливая сложный метиловый эфир дигидрокингхао кислоты литий-алюминийгидридом в эфире в соответствии с литературными данными /Je, B, Wu, J L.Tetrahedron 1989, 45, 7287).

The dihydrokinghaosol alcohol (arteannuinol) is prepared by reducing the dihydrokinghao methyl ester with lithium aluminum hydride in ether according to published data (Je, B, Wu, J L. Tetrahedron 1989, 45, 7287).

Dihydrokinghao alcohol / 43.9 mg, 1.97 • 10 ^-4 mol / in 2.5 ml of Bengal Pink containing acetonitrile / approximately 0.5 mg / is irradiated in an atmosphere of oxygen at -30 ^o C for 2 hours to obtain a mixture hydroperoxides containing predominantly tertiary hydroperoxide. The mixture was diluted with dichloromethane, cooled to -15 ^o C, and then treated with Cu / OSO ₂ CF _3/2 / 0.2 eq. / Acetonitrile / 0.4 ml / over 1 h 45 min with gradual warming to room temperature . The reaction mixture was quenched with water and then treated as described previously to obtain a viscous oil. It is processed on a chromatographic column with silica gel with flash evaporation with a mixture of ether-petroleum ether / 2: 3 / to obtain deoxokinghaos as a white solid / 19 mg, 36% of dihydrokinghao alcohol /. Spectroscopic data are in accordance with the literature / cm. Jung, M; Li. X. Bustos, DA Elsohly, HN Mc.Chesney, JD Tetrahedron Lett.

 Example 6. The conversion of model compounds to peroxyacetal lactone.

 Method 1. Direct conversion.

Соединение а, новое соединение, получают из известной смеси соответствующего сложного метилового эфира и региоизомера двойной связи сложного эфира /Claus, P.K.Vierhapper, F.W.Willer, R.L.J.Org. Chem. 1977, 42, 4016/ за счет гидролиза смеси гидрооксидом лития в водном диметоксиэтане, разделяя полученную смесь карбоновых кислот в процедуре иодолактонизации /Corey E.J. Wright, S.W.J. Org. Chem. 1988, 53, 5980/. Кислоту а/134 мг, 7,97•10^-4 моля/ в 4 мл ацетонитрила, содержащую Бенгальский Розовый /3 мг/, в атмосфере кислорода облучают, как описано далее, для кингхао кислоты до получения рацемического гидропероксида b, и региоизомеров двойной связи в отношении 1: 1. Полученную смесь разбавляют дихлорметаном /16 мл/, а затем обрабатывают Cu/OSO₂CF₃/₂/0,1 экв. / в ацетонитриле /0,2 мл/ в атмосфере кислорода при 0^oC. Это приводит к мгновенной конверсии соединения b в полярное промежуточное соединение. Другие региоизомеры соединения b, по-видимому, не реагируют в этих условиях. Реакционной смеси дают нагреться до комнатной температуры, и ее перемешивают в течение 4 ч. Затем эту смесь выливают в воду и экстрагируют эфиром, как описано далее для получения кингхаосу, до получения вязкого масла. Его обрабатывают на хроматографической колонке с мгновенным испарением смесью эфир-петролейных эфир 7:3 до получения рацемического соединения в виде бесцветной смолы /51 мг, 30%/.

Compound a, a new compound, is prepared from a known mixture of the corresponding methyl ester and the regioisomer of the ester double bond / Claus, PKVierhapper, FWWiller, RLJOrg. Chem. 1977, 42, 4016 / by hydrolysis of the mixture with lithium hydroxide in aqueous dimethoxyethane, separating the resulting mixture of carboxylic acids in the iodolactonization procedure / Corey EJ Wright, SWJ Org. Chem. 1988, 53, 5980 /. Acid a / 134 mg, 7.97 • 10 ^-4 mol / in 4 ml of Bengal Pink containing acetonitrile / 3 mg /, is irradiated in an oxygen atmosphere, as described below, for kinghao acid to obtain racemic hydroperoxide b, and regioisomers of double bond 1: 1. The mixture was diluted with dichloromethane / 16 ml / and then treated with Cu / OSO ₂ CF _3/2 / 0.1 eq. (in acetonitrile / 0.2 ml) in an oxygen atmosphere at 0 ^° C. This leads to the instant conversion of compound b to a polar intermediate. Other regioisomers of compound b do not appear to react under these conditions. The reaction mixture was allowed to warm to room temperature, and it was stirred for 4 hours. Then this mixture was poured into water and extracted with ether, as described below to obtain kinghaos, to obtain a viscous oil. It is treated on a chromatographic column with flash evaporation with a mixture of ether-petroleum ether 7: 3 to obtain the racemic compound in the form of a colorless resin / 51 mg, 30% /.

 Example 7. Method 2. Indirect conversion.

Кислоту а /110 мг, 6,54•10^-4 моля/ превращают в рацемический гидропероксид b и смесь его региоизомеров, как описано ранее. Неочищенную смесь гидропероксидов растворяют в эфире и обрабатывают избытком диазометана при 0^oC. Рацемические сложные эфиры гидропероксида d/96 мг, 45%/ выделяют с помощью хроматографии с мгновенным испарением, обрабатывая смесью эфир-петролейный эфир 3:7 смесь сложноэфирных гидропероксидов, полученную после метилирования. Гидропероксид d /96 мг, 4,48•10^-4 моля/ в ацетонитриле /5 мл/ в атмосфере кислорода обрабатывают /Fe/фен/₃/PF₆/ ₃/0,03 экв./ в 1 мл ацетонитрила, а затем Cu/OSO₂CF₃/₂/ 0,1 экв./ в 0,5 мл ацетонитрила при 0^oC. Спустя 30 мин реакционную смесь обрабатывают до получения неочищенной смеси продуктов, состоящей из пероксигемиацеталя и гидропероксидных аналогов тем, которые описаны для непрямой конверсии кингхао кислоты и дегидрокингхаосу (артемизитен), описанный ниже. Раствор смеси в дихлорметане (20 мл), содержащей паратолуолсульфокислоту (26 мг, 1,34•10^-4 моля), перемешивают в течение 4 ч при комнатной температуре. После описанной ранее обработки получают вязкое масло, которое после очистки с помощью мгновенной хроматографии с использованием смеси эфир-петролейный эфир 7:3 дает рацемический пероксиацетальлактон (c) (48 мг, 50% от a).

Acid a / 110 mg, 6.54 x 10 ^-4 moles / is converted to racemic hydroperoxide b and a mixture of its regioisomers, as previously described. The crude mixture of hydroperoxides is dissolved in ether and treated with an excess of diazomethane at 0 ^° C. The racemic esters of hydroperoxide d / 96 mg, 45% / are isolated by flash chromatography by treatment with a 3: 7 ether-petroleum ether mixture obtained from the ester hydroperoxides obtained after methylation. Hydroperoxide d / 96 mg, 4,48 • 10 ^-4 mol / acetonitrile / 5 mL / treated in the atmosphere of oxygen / Fe / dryer / ₃ / PF _6/3 / 0.03 eq. / In 1 ml of acetonitrile, and then Cu / OSO ₂ CF _3/2 / 0.1 eq. / in 0.5 ml of acetonitrile at 0 ^o C. After 30 minutes, the reaction mixture was treated to give the crude product mixture consisting of the peroxyhemiacetal and hydroperoxide analogues to those described for the indirect Kinghao acid conversion and dehydrokinghaosu (artemisitene), described below. A solution of the mixture in dichloromethane (20 ml) containing paratoluene sulfonic acid (26 mg, 1.34 • 10 ^-4 mol) was stirred for 4 hours at room temperature. After the previously described treatment, a viscous oil is obtained which, after purification by flash chromatography using a 7: 3 ether-petroleum ether mixture, gives racemic peroxyacetal lactone (c) (48 mg, 50% of a).

 Data characterizing the compound (c) in examples 6 and 7.

ИКν_макс (CHCl₃) 2936 ср, 2869 сл, 1770 оч.сильн. 1451 сл. 1295 сл. 1329 ср. 1211 ср. 1193 ср. 1164 ср. 1099 сл. 962 сл. 941 сл. 914 сл. см^-1. ¹H ЯМР δ 1,5-1,7(м,Н5), 1,7(3Н,с,CH₃), 1,7-2,0(м,Н4 и Н6), 2,1 (2Н, т, J4', 3'= 8,2 Гц, Н4'), 2,6 (2Н, т, J3',4' 8,2 Гц, Н3'), 5,4 (1Н,с, Н6'), ¹³C ЯМР d 19,6, C5; 23,6, CH₃; 29,0, CH₂; 29,7, 2•CH₂; 34,4, C3'; 84,7, C7; 123,1 C6'; 141,3, C3; 176,5 C2'. Масс. спектр (C.I.) m/z 219 (14), 213(3), 185(8), 181(16), 167(100), 153(25), 149(16), 121(17), 83(11), 71(48), 61(41).

IR _max (CHCl ₃ ) 2936 sr, 2869 sl, 1770 pts. 1451 words 1295 words 1329 cf. 1211 cf. 1193 cf. 1164 cf. 1099 words 962 words 941 words 914 words cm ^-1 . ¹ H NMR δ 1.5-1.7 (m, H5), 1.7 (3H, s, CH ₃ ), 1.7-2.0 (m, H4 and H6), 2.1 (2H, t, J4 ', 3' = 8.2 Hz, H4 '), 2.6 (2H, t, J3', 4 '8.2 Hz, H3'), 5.4 (1H, s, H6 ') ¹³ C NMR d 19.6; C5; 23.6, CH ₃ ; 29.0, CH ₂ ; 29.7, 2 • CH ₂ ; 34.4, C3 '; 84.7, C7; 123.1 C6 '; 141.3, C3; 176.5 C2 '. Mass spectrum (CI) m / z 219 (14), 213 (3), 185 (8), 181 (16), 167 (100), 153 (25), 149 (16), 121 (17), 83 (11 ), 71 (48), 61 (41).

 Example 8. The conversion of dimethyl acetal to artemether.

Диметилацеталь дегидрокингхао альдегида получали с помощью окисления дигидрокингхао спирта в условия Swern и затем перемешивания получающегося альдегида в метаноле в присутствии кислотной смолы Даукс 50W. Диметилацеталь (49 мг, 0,18 ммоля) облучался в присутствии Rose Bengal в смеси ацетонитрила (1,5 мл) и дихлорметана (0,5 мл) в атмосфере кислорода при температуре ниже -30^oC. Спустя 2 ч, когда превращение в гидроперекиси завершилось, реакционная смесь разбавлялась дихлорметаном (7 мл) и затем добавлялся трифторметансульфонат меди (II) (0,018 ммоля, 0,18 мл, 0,1 М в ацетонитриле) при -20^oC. Перемешивание продолжалось при данной температуре в течение 1 ч перед тем, как реакционная смесь оставлялась подогреваться до комнатной температуры и гасилась выливанием в смесь эфира и воды. Обычная обработка давала вязкое масло, которое очищалось с помощью мгновенной хроматографии на силикагеле с использованием смеси эфир/петролейный эфир 15:85, давая β -артемэфир в качестве первой фракции в виде кристаллического твердого вещества (6,2 мг, 11%) и смесь, содержащую a аотемэфир и продукт его перегруппировки, пероксиацеталь, в соотношении 1:1 (7 мг, 12%).

Dimethylacetal dehydrokinghao aldehyde was prepared by oxidizing the dihydrokinghao alcohol under Swern conditions and then mixing the resulting aldehyde in methanol in the presence of Dowx 50W acid resin. Dimethyl acetal (49 mg, 0.18 mmol) was irradiated in the presence of Rose Bengal in a mixture of acetonitrile (1.5 ml) and dichloromethane (0.5 ml) in an atmosphere of oxygen at a temperature below -30 ^o C. After 2 hours, when the conversion to hydroperoxide was completed, the reaction mixture was diluted with dichloromethane (7 ml) and then copper (II) trifluoromethanesulfonate (0.018 mmol, 0.18 ml, 0.1 M in acetonitrile) was added at -20 ^° C. Stirring was continued at this temperature for 1 h before the reaction mixture was allowed to warm to room temperature and was quenched by pouring Ira and water. Conventional work-up gave a viscous oil, which was purified by flash chromatography on silica gel using an ether / petroleum ether mixture of 15:85 to give β-artemether as the first fraction as a crystalline solid (6.2 mg, 11%) and the mixture containing a aotamether and its rearrangement product, peroxyacetal, in a 1: 1 ratio (7 mg, 12%).

 The spectroscopic data obtained for both epimers of artemether corresponded to the literature data (Li.J. Ju. PL Li, LQ Chen J / Z /; Li, LQ Gai, JZ Wang, DS Zheng, JP Kexue Tongbao 1979, 24, 667).

 Example 9. The conversion of diethyl acetal to arteether.

Диэтилацеталь дигидрокингхао альдегида (23,6 мг, 0,083 ммоля) полученный по способу, аналогичному получению диметилацеталя, как описано для случая с диметилацеталем, давая β -артеэфир (2 мг, 8% ) в виде кристаллического твердого вещества и смесь, содержащую a -артеэфир и продукт его перегруппировки, пероксиацеталь, в соотношении 18:82 (5,6 мг, 22%). Данные спектроскопии, полученные для обоих эпимеров, согласовывались с данными, приведенными в литературе (Li, y; Ju, P.L. Chen, y.x. Li, L.Q. Gai, j.z. Wang, D.S. Zheng, J.P. Acta Pharm. Sinica 1981, 16, 429).

Diethyl acetal dihydrokinghaaldehyde (23.6 mg, 0.083 mmol) obtained by a method similar to the preparation of dimethyl acetal, as described for the case of dimethyl acetal, yielding β-artether (2 mg, 8%) as a crystalline solid and a mixture containing a-arteether and the product of its rearrangement, peroxyacetal, in a ratio of 18:82 (5.6 mg, 22%). The spectroscopic data obtained for both epimers were consistent with literature data (Li, y; Ju, PL Chen, yx Li, LQ Gai, jz Wang, DS Zheng, JP Acta Pharm. Sinica 1981, 16, 429).

Claims (10)

1. The method of producing peroxyacetal lactone compounds of General formula I

where n is 1,2,3;
m 0,1,2;
p 0.1;

where R ¹ and R ² mean a hydrogen atom or lower alkyl, or for n> 1 X can be branched and together with one of Y form a six-membered saturated ring, and the other Y can be lower alkyl, hydrogen and can be bonded to the same atom carbon as peroxy;
R ³ and R ⁴ together mean oxygen or each of R ³ and R ^{4 is} hydrogen, or one of R ³ , R ^{4 is} hydrogen, and the other is an OR ¹ group, where R ^{1 is} lower alkyl,
characterized in that the peroxy compound of the general formula II

where m, n, X, Y, p have the indicated meanings;
R ⁵ groups COOH, -C (O) R,

where R is lower alkyl, hydrogen
R 'lower alkyl or both R' together with the —O — C — O group to which they are attached form a cyclic acetal,
subjected to oxidation in the presence of one or more metal oxidation catalysts. 2. A method of producing a peroxyacetal lactone compound of the general formula I

where the meanings of the radicals are indicated above,
characterized in that the compound of general formula II is subjected to esterification

where R ^{5 is} a COOH group;
m, n, p, X, Y have the indicated meanings,
followed by oxidation of the compounds of General formula III

where the meanings of the radicals are defined above,
in the presence of one or more metal-containing oxidation catalysts to give a compound of general formula IV

and general formula V

which are treated with an acid catalyst in a solvent, using protic acid or Lewis acid. 3. The method according to claim 1 or 2, characterized in that in the case of obtaining Kinghaos formula A

use the corresponding hydroperoxide of formula II obtained by reduction of kingha acid of formula VI

followed by oxidation of the resulting dihydrokingha acid of formula III

4. The method according to p. 2, characterized in that in the case of obtaining a kinghaoso of the formula A, the corresponding hydroperoxide of the formula II obtained by reducing the kinghaic acid of the formula VI is used, followed by the oxidation of the dihydroxinghaic acid of the formula VII thus obtained to produce the hydroperoxide of the formula II, which is methylated. 5. The method according to claim 1 or 2, characterized in that to obtain a compound of dehydrokinghaosus of formula VIII

using the corresponding hydroperoxide of formula II obtained by oxidation of kingha acid of formula VI.  6. The method according to p. 2, characterized in that in the case of obtaining a dehydrokinghaosus of formula VIII, the corresponding hydroperoxide of formula II obtained by oxidation of kinghaic acid of formula VI is used, and the hydroperoxide of formula II is then methylated.  7. The method according to claim 1 or 2, characterized in that in the case of obtaining deoxokingoha use hydroperoxide of the formula II, obtained by the oxidation of dihydrokinghaalcohol.  8. The method according to any one of claims 1 to 7, characterized in that one or more oxidizing complex salts of the transition metal of copper (II), iron (III), cobalt (II) or cobalt (III) are used as a catalyst. 9. The method according to claim 8, characterized in that one or more complex transition metal salts selected from Cu (DSO ₂ CF ₃ ) ₂ , Cu (II) propionate, Cu (II) -2 ethylhexanoate are used as a catalyst , Fe (phenanthroline) ₃ (PF ₆ ) ₃ . 10. The method according to claim 1 or 2, characterized in that the starting material is a hydroperoxide of formula II obtained by oxidation of a compound of formula IIa

where m, n, p, X, Y and R ⁵ have the meanings of claim 1. 11. Lactone Formulas

about