CH679486A5 - - Google Patents

Abstract

A process for synthesizing oxygen-containing analogs of the antimalarial agent known as quinghaosu or artemisinin, and in particular compounds of formulae (I) and (II). The process employs as a reactant a vinylsilane that is subjected to an ozonolysis/acidification step which closes the oxygen-containing ring structure. The various products are claimed as aspects of this invention as is their use as antimalarials.

Description

The invention relates to new artemisinin analog compounds and processes for the preparation of these new as well as known compounds, e.g. the anti-malarial agent Qinghaosu (artemisinin). It also relates to new starting materials for carrying out these processes as well as anti-malarials which contain these new compounds. The invention is defined in independent claims 1, 6, 13-17 and 22-27. Special embodiments are claimed in the dependent claims.

A key step in the present process is the ozonolysis of a vinyl silane to incorporate oxygen functionality. One publication concerning the ozonolysis of a vinylsilane that can result in an alpha-hydroxyperoxyaldehyde is by George Buchi et al., Journal of the American Chemical Society, Vol. 100, 294 (1978). The publication shows this reaction in a different context. Another publication is from R. Ireland et al., Journal of the American Chemical Society, Vol. 106, 3668 (1984) and relates to silylation.

In another aspect, the invention uses unsaturated bicyclic ketones as reactants. Such materials and methods of making some thereof are given by W. Clark Still, Synthesis, No. 7, 453-4 (1976); Kazuo Taguchi et al., Journal of the American Chemical Society, Vol. 95, 7313-8 (1973); and E.W. Warnhoff et al., Journal of Organic Syntnesis, Vol. 32, 2664-69 (1967).

Another prior art of interest relates to the natural antimalarial product Qinghaosu. The antimalarial drug Qinghaosu has been used in China in the form of raw plant products since at least 168 BC. used. There has been an increased interest in this substance over the past 20 years. This has to be considered a clarification of its structure

guided. The modern chemical name is artemisinin.

The carbon atoms in artemisinin are numbered as above. In the following, whenever reference is made to a particular place in a compound of this general nature, it is based on this numbering whenever possible. For example, the carbon atoms bridged by the peroxide bridge are always identified as "4" and "6" carbon atoms, regardless of the fact that the invention can also apply to substances with structures of other bridge lengths in which these carbon atoms are actually different would be numbered.

Some of the products affected here are seco analog compounds, i.e. the 1, 2, 3, 4-ring structure evident in artemisinin is not closed in these compounds. However, the artemisinin numbering is also retained for these seco-analog compounds.

Publications relating to artemisinin and its derivatives are an article by Daniel L. Klayman dated May 31, 1985 in Science, Vol. 228, 1049 (1985); and the article in Chinese Medical Journal, Vol. 92, No. 12, 811 (1979). Two synthetic methods for artemisinin are described in the literature, namely by Wei-Shan Zhou, Pure and Applied Chemistry, Vol. 58 (5), 817 (1986); and by G. Schmid et al., Journal of the American Chemical Society, Vol. 105 624 (1983). None of these synthesis processes work with ozonolysis.

The interest in artemisinin has led to the desire for an effective and efficient process for the synthetic production of the substance and its analogues (including radiolabeled analogues) which is fulfilled by the invention.

A new process for the synthesis of multi-ring compounds with a plurality of ring oxygen has now been discovered. This process works with the ozonolysis of a vinyl silane to form the desired multi-ring material.

In one embodiment, the method is directed to the preparation of tetracyclic polyoxa compounds such as artemisinin of the following general formula IA.

In the general formula IA, X is -O-, -S- or

; R1 is an alkylene chain with a length of one to three carbon atoms with or without substituents; R2 is a covalent single bond or an alkylene chain with a length of one to five carbon atoms with or without substituents; R3 is an alkylene chain with a chain length of one to three carbon atoms with or without substituents; R4 is hydrogen or an alkylene group, with or without substituents; R5 and R6 are together a carbonyl oxygen or R5 is hydrogen, an alkyl or a substituted alkyl, while R6 is hydrogen, hydroxyl, an alkoxy, an OH group esterified with a carboxylic acid with a carbonic acid ester or a carbamic acid, an amido group or a urea group, and R10 is hydrogen or an alkyl or aryl with or without substituents.

The synthesis according to the invention, when used for the preparation of the tetracyclines of the general formula IA, comprises the ozonolysis and acidification of a vinylsilane compound according to the general formula II:

In the general formula II, R1 to R6 and X correspond to the definition for the tetracyclic polyoxa compounds of the general formula IA, and R7, R8 and R9 are each independently selected from C1-C10 hydrocarbon radicals.

According to a particular aspect, the invention provides a process for the synthesis of artemisinin by ozonolysis and acidification of the vinylsilane

The process of the invention can also be used to prepare seco-analog compounds of artemisinin which substantially retain the potency of the more complex parent compound. These analog compounds have the structure shown in general formula III.

In general formula III, R11 and R12 are each independently hydrogen, methyl or alpha-unsubstituted organic radicals having up to 12 carbon atoms, the total size of R11 plus R12 not being greater than 20 carbon atoms; R16 is hydrogen, alkyl or a substituted alkyl, while R17 is hydrogen, hydroxyl, alkoxy, an OH group esterified with a carboxylic acid, a carbonic acid ester or a carbamic acid, an amido group or urea group, or R16 and R17 together form a carbonyl oxygen; R18 and R19 are each hydrogen, alkyl or substituted alkyl, or R18 and R19 together form an organic ring; and R20 and R21 are each hydrogen, a C1-C10-alkyl or a substituted C1-C10-alkyl.

These Seco substances can be produced by the process given above, which works with ozonolysis of a vinylsilane and acid-catalyzed condensation of the hydroperoxide compound which results with a carbonyl (aldehyde or ketone). This procedure includes:

a) subjecting a vinylsilane of the general formula IV to ozonolysis to obtain a hydroperoxide of the general formula V, and

b) Reacting the hydroperoxide from formula V and a carbonyl of the general formula VI in the presence of an acid catalyst to form the desired Seco analog compound.

Artemisinin analogue tetracyclic polyoxa compounds are also obtained according to the general formula IXA:

in which m is 0 or 1; n is 0, 1, 2, 3, or 4; p is 0, 1 or 2, with the proviso that the sum of m plus p has a value from 0 to 2 inclusive; R22 and R23 together are a carbonyl oxygen; R24 is hydrogen, a C1-C10-alkyl or a substituted C1-C10-alkyl; R25 to R33 are each a hydrogen, an alkyl or a substituted alkyl by using a vinylsilane of the formula XI:

in which R <S> is a hydrocarbon radical with 1 to 10 carbon atoms and R <E> is an esterifying protective group which subjects to ozonolysis and acidifies the product obtained.

In further aspects, the invention provides antimalarial pharmaceutical compositions containing the above-indicated oxygen-substituted products.

The invention is explained in more detail using the drawing, for example. Show it:

Fig. 1 is a flow diagram showing the overall synthesis of an artemisinin analog compound; Fig. 2 is a flow chart showing an overall synthesis of artemisinin; Figures 3, 4 and 5 are flow charts showing routes to artemisinin analog compounds; 6 shows a flow chart for the establishment of Seco connections; 7 shows a flow chart for the incorporation of substituents into the seco compounds; and 8 and 9 flow charts for the preparation of artemisinin analog compounds using vinylsilanes of ketones with non-enolizable bridgeheads.

According to the invention, polyoxa-artemisinin analog compounds are produced by ozonolysis of vinylsilanes. These artemisinin analog compounds can be tetracyclic compounds according to the general formula I or IA, Seco analog compounds of the general formula III or bridgehead-substituted analog compounds of the general formula IX or IXA, depending on the specific materials with which the ozonolysis is carried out. In the definition of the groups indicated by the various X and R in these general formulas and in general formulas II and IV-VI, the possibility of "substituting" these groups is mentioned. The limits of this possible substitution can be expressed functionally as follows: A a possible substituent is a chemical group, a chemical structure or component which, when present in the compounds according to the invention, either does not significantly interfere with the production of the compound or does not significantly interfere with subsequent reactions of the compounds. Thus, suitable substituents are groups which are essentially inert under the various reaction conditions after their introduction, such as ozonolysis and acidification. Suitable substituents can also be groups which are predictably reactive under the conditions to which they are exposed, so that desired proportions are obtained in a reproducible manner.

Usual substituents are e.g. Saturated aliphatic groups including linear and branched alkyl groups with 1-20 carbon atoms such as methyl, ethyl, isopropyl, n-butyl, t-butyl, the hexyl groups including cyclohexyl, decyl, hexadecyl, eicosyl and the like. Also aromatic groups, which are generally 1- 20 aromatic carbon atoms, e.g. Aryl groups such as quinolines, pyridines, phenyls, naphthyls and aralkyls with up to approx. 20 total carbon atoms such as benzyls, phenylethyls and the like, and alkaryls with up to approx. 20 total carbon atoms such as the cylyls, ethylphenyls and the like CC double bonds contain amides, sulfonates, carbonyls, carboxyls, alcohols, esters, sulfonamides, carbamates, phosphates, carbonates, sulfides, sulfhydryls, with the proviso that ozonolysis can attack this unsaturation and cleave it oxidatively if it is present during the reaction , Sulfoxides, sulfones, nitro, nitroso, amino, imino, oximino, alpha, beta-unsaturated modifications thereof and the like, with the proviso that many of these functional groups can be attacked during the overall reaction sequence and may be suitably protected have to. If desired, they can then be freed from the protective group again in a later phase.

In the general formula I or IA, R1 is a C1-C3 alkylene chain which connects the “7” and “12” carbon atoms. The R1 bridge can be a methylene (-CH2-) unit or a two or three carbon atom long alkylene chain (-CH2-CH2- or -CH2-CH2-CH2-) with or without substituents. When R1 is substituted, the substituents replace hydrogen. R1 is preferably an alkylene with one or two carbon atoms and with up to two lower alkyl substituents. The term "lower" as a designation of the organic group size means one to ten carbon atoms. Particularly preferably R1 is a C 1 -C alkylene, especially with a lower alkyl substituent, e.g. Methyl.

R2 is a single covalent bond between the "1" and "7" carbon atoms or an alkylene chain 1-5 carbon atoms long, i. - (CH2) n = 1-5-, be between these two carbon atoms with or without substituents. More preferred R2 groups are alkylene bridges three to five carbon atoms long with 0 to 2 alkyl substituents.

R3 is an alkylene chain 1 to 3 carbon atoms long between the "1" and "4" carbon atoms. The carbon atom of the R3 chain adjacent to the "4" carbon atom may be substituted with one or two groups when R3 is 2 or 3 carbon atoms in length. Preferred groups for the substitution of R3 are lower alkyls. Preferred R3 groups are the 1 or 2 carbon atoms long alkylenes, the 2 carbon atoms long alkylenes being most preferred.

R4 is hydrogen or an alkyl group with or without substituents. Methyl and lower alkyl substituted methyl are preferred, with methyl being most preferred.

R5 and R6 together can be a carbonyl oxygen bonded to the "12" carbon position. Alternatively, R5 can be hydrogen, an alkyl or a substituted alkyl, while R6 is then hydrogen, hydroxyl, an alkoxy - preferably a lower alkoxy - one with a carboxylic acid, e.g. Acetic acid or substituted acetic acid, with a carbonic acid ester or a carbamic acid esterified OH group, an amido group or a urea group. Carbonyl is preferred. When R6 is hydroxyl, hydrogen, methyl and lower alkyl substituted methyl are preferred R5 groups.

R10 is hydrogen, alkyl or aryl with or without substituents. The preferred X groups are -O-, -S-,

where R10 is lower alkyl.

Most preferred X is -O-.

The vinylsilanes from which the tetracylic polyoxa compounds of the formula IA are formed are denoted by the general formula II. In this, R1 to R6 and X have the meanings given above with reference to the general formula I and R7, R8 and R9 are C1-C10 hydrocarbon radicals. Typical hydrocarbon radicals for this purpose are lower alkyls, aryls, alkaryls and aralkyls. When selecting these three R's, two or three of them are generally methyl groups. Typical silyl groups are trimethylsilyl, t-butyldimethylsilyl and phenyldimethylsilyl.

When the vinylsilanes of formula II are subjected to ozonolysis, two transition primary azonide and dioxetane intermediates are formed:

In the Seco analog compounds of the general formula III, R11 and R12 are each selected individually from hydrogen groups, methyl groups and alpha-unsubstituted organic components with up to 12 carbon atoms with the proviso that the total size of R11 and R12 is not more than 20 -C atoms, as mentioned. These components are unsubstituted in the alpha position, but they can be substituted in other positions. Typical R11 and R12 groups are the alkyls; unsaturated groups such as alkenyls, hexyls and the like; hydroxy substituted alkyls; Aryls such as benzyls; fluorinated, sulfonated or phosphorous alkyls, and the like. Simple lower alkyls are preferred.

R16 and R17 are selected according to the definition for R5 and R6 in formula I. R18 and R19 are hydrogen, alkyls or substituted alkyls and can additionally be linked to form an organic ring which links the "1" and "7" C atoms in a cycloalkylene ring, for example with 3-8 C atoms. A preferred configuration for R18 and R19 is that they are linked in a 6-part cycloalkylene ring with or without substituents.

R20 and R21 are each hydrogen, C1-C10 alkyl and substituted C1-C10 alkyl. It is often advantageous to be able to change the hydrophobic / hydrophilic character of the Seco analog compounds. Alkyls in these positions reduce the hydrophilic and increase the hydrophobic character. Alkyl substituents which are themselves substituted with an ionic group such as a carboxylic acid or sulfonic acid group increase the hydrophilic character. In preferred embodiments, R20 is C1-C10 alkyl, especially methyl, and R21 is hydrogen.

A vinylsilane of the general formula IV is subjected to ozonolysis in the preparation of the Seco analogs. In this silane, R13, R14 and R15 are hydrocarbon radicals. Ozonolysis forms the silyloxy hydroperoxides represented by the general formula V. In this R13 to R15 and R18 to R21 have the meanings given above.

Carbonyl compounds of the general formula VI are reacted with the hydroperoxide in the preparation of the seco compounds. R11 and R12 correspond to the definition with regard to the general formula III. Thus the carbonyl includes ketones and aldehydes.

In a further production process, the ozonolysis process with bridgehead ketones of the formula VIII can be used to obtain the tetracyclic artemisinin analogue compounds of the formula IXA:

In the bridgehead ketones defined by the general formula VIII, m is an integer, either 0 or 1; n is an integer, namely 0, 1, 2, 3 or 4; and the different R's are each hydrogen, alkyl and substituted alkyl.

Preference is given to n = 1 or 2 or 3. Substances in which the different R's are hydrogen, lower alkyls or substituted lower alkyls are also preferred. Substances in which at most one R or two R of the m methylenes and at most one R of the m methylenes are different from hydrogen are particularly preferred.

Some of the substances included in the general formula VIII are known compounds. (See Still for an indication of substances in which n = 1, m = 1 and all R = hydrogen; in which n = 2, m = 1 and all R = hydrogen; in which n = 3, m = 1 and all R = hydrogen; and in which n = 2, m = 1 and all R = hydrogen with the exception of R28, which is a methyl.)

The bridgehead ketones of the general formula VIII can be prepared as follows: If both R27 and R30 are hydrogen, the substances can be prepared by the cyclodialkylation of suitable enamines. The pyrolidine enamines are a well known family of materials that have been documented to be made from commercially available cyclic ketones and are therefore preferred. In a typical representative reaction, cyclohexane is converted to cyclohexenamine, which is then reacted with a 1,4-dichlorobut-2-ene to give a bicyclic ketone, as reaction 1 shows.

The reaction of the dialkylation reagent and the enamine occurs under effective alkylation conditions. These include anhydrous conditions; an aprotic reaction medium such as dimethylformamide, tetrahydrofuran or the like; and the general exclusion of oxygen from the reactor, such as with an inert gas cap. The reaction is usually carried out by adding a base such as an amine or the like, e.g. a trialkylamine, as well as the presence of a halide alkylation activator, e.g. of an alkali metal iodide. Approximately equimolar amounts of the dialkylation reagent and the enamine are used for the reaction. A representative preparation according to Still is given in Example 15.

In cases in which the bridgehead ketones have other R27 and R30 substituents than hydrogen, they can, using the methods of Taguchi et al. and Warnhoff et al. According to Taguchi et al. Saturated bridgehead ketones, which contain a carboxylic acid functionality at one of the bridgeheads, are produced. The carboxyl group can serve as a connection point for further substituents as required. The work by Warnhoff et al shows a method for introducing carboxyl and halogen substituents on both bridgehead carbon atoms of saturated bicyclic ketones. These groups, too, can in turn serve as active sites for any coupling of further R27 and R30 groups that may be desired. With suitable modification, the desired olefinic bond can be incorporated into the bicyclic structure.

The bicyclic bridgehead ketones of the formula VIII are converted into the vinylsilanes of the formula VII.

The three R <S> substituents are each selected individually from already defined C1-C10 hydrocarbon radicals.

If this vinylsilane is treated with ozone, the mixed carbonyl / ester vinylsilanes of the formula X * are formed

R <E> is an esterifying protecting group.

The vinylsilanes of the formula X * are versatile intermediate products. The carbonyl-containing arm can be manufactured using conventional chain extension techniques, e.g. the Wittig reaction. This creates a

Introduced unit in which R is a hydrogen, an alkyl or a substituted alkyl and p is an integer of 2. The product of this chain extension has the structure shown in the general formula XI.

These chain extension products can be deprotected and subjected to ozonolysis and acidification to give the desired tetracyclic structure. Alternatively, after protecting the carbonyl group such as an acetal or ketal, these substances can be derivatized in order to modify their structure and to form numerous other substitution patterns. In a further modification, the acid functionality and the carbonyl functionality can be protected (eg by esterification and by conversion into an acetal or ketal), after which the product is alkylated with addition of an R <F> group and the protective group is removed so that a product corresponding to the general formula XII * is obtained.

In this formula, the R <F> group is lower alkyl or substituted lower alkyl.

Removal of the protecting group, ozonolysis and acidification of each of these vinylsilanes results in the desired tetracyclic compounds. These are structurally defined by the general formula IX (or the general formula IX * below).

The ozonolysis reaction

The process of the invention uses an ozonolysis reaction in forming the desired artemisinin analogue compounds. This is carried out at low temperatures in a liquid reaction medium. Ozone is extremely reactive and it is advantageous to use low temperatures in order to avoid side reactions between the ozone and other areas of the vinylsilane molecule. The low temperature can be between a high value of about 15 ° C. and a low value equal to the freezing point of the reaction solvent, which can be -100 ° C. or lower. Very good results are achieved at dry ice / acetone bath temperatures (-78 ° C.), and a preferred temperature range is between -100 ° C. and about -25 ° C., the most preferred temperatures being in the range between -70 ° C. and -80 ° C.

The reaction solvent used in this reaction is chosen so that compatibility with the highly reactive ozone is guaranteed. In general, ethers, both linear and cyclic, should be avoided as they are easily converted to peroxides, creating a risk of explosion. The solvents used are polar organic solvents, preferably lower alcohols such as methanol, ethanol, the propanols and ethylene and propylene glycols; lower ketones such as acetone and methyl ethyl ketone; and the liquid esters such as ethyl acetate. Of these solvents, the lower alcohols, particularly methanol, are preferred.

The reaction is carried out by mixing the vinylsilane with the reaction medium and then adding the ozone. The amount of ozone is preferably regulated in such a way that no excesses occur. Good results are obtained when the amount of ozone is limited to a maximum of 1.25 equivalents, based on the amount of vinylsilane present, with ozone levels of about 0.75 to about 1.25 equivalents, based on the amount of vinylsilane present, being preferred are. Although lower ozone levels can be used, they are not preferred because they result in lower yields.

The reaction is very quick and ends within a few minutes at most. Very good results are achieved within periods in the range from 15 s to approx. 15 min. It is advantageous to limit this reaction time.

The reaction product is then treated with acid. If the final product is a non-bridgehead substituted tetracyclic product, it will contain a dioxetane which is isolated and then recycled. This can be done by vacuum stripping the solvent or other similar processes that minimize the possibility of a degradation reaction. In the case of the secomaterials or the bridgehead-substituted tetracyclic products, the acidification can be carried out without separating off the intermediate product.

The ozonolysis reaction product or the isolated dioxetane is treated with acid in order to rearrange these transition intermediates and to obtain the desired tetracyclic products or Seco analogs. This reaction can be carried out in a non-aqueous liquid reaction phase, with halogenated hydrocarbons such as chloroform and the like being preferred. The acid used should have at least a moderate concentration corresponding to a pK value of approx. 5 to approx. 0.1 and can be an organic or an inorganic acid. Mixtures of acids can be used if desired. Typical acids are acetic acid; the substituted acetic acids such as trichloroacetic acid, trifluoroacetic acid and the like. And other strong organic acids such as alkylsulfonic acid and the like. The mineral acids such as the hydrohalic acids, e.g. HCl, HBr, etc., the oxo acids such as HClO3 and the like; Sulfuric acid and phosphoric acid and the like can also be used, but should be checked before use to determine whether they cause undesirable side reactions.

The rearrangement reaction is only catalyzed by the acid, so that basically only trace amounts of acid are required. However, the use of more than just a trace amount of acid may be preferred. The best practice is to monitor the progress of the reaction and, if necessary, add acid to achieve and maintain an acceptable reaction rate. In particular, the amount of acid added is normally at least about an equivalent based on the amount of product present. Although large excesses are not necessary, they can be used, and the preferred amount of acid is between about 1 to about 10, in particular about 1 to about 2 equivalents, based on the amount of product present. This reaction does not require high temperatures. It runs to completion overnight at room temperature. The reaction can also be completed either more quickly or more slowly, depending on the acid and solvent used. Higher temperatures can, if desired, be used if it is ensured that they do not lead to unacceptable losses in yield. Temperatures between about -100 ° C. and about +50 ° C. can be used, with temperatures between about -20 ° C. and about +30 ° C. being preferred and those between about 0 ° C. and about +20 ° C are particularly preferred. As expected, the reaction times are inversely related to the temperature, times in the range from 1 hour to about 24 hours being useful.

The product of the acid catalyzed rearrangement can be worked up and purified using chromatographic techniques and the like.

The procedures shown in Figure 5 can be used to obtain products in which the 12-substituent is not carbonyl oxygen. As this figure shows, the carbonyl can be reduced without the reduction-sensitive peroxy group being impaired, namely through the use of sodium borohydride (according to the report by M.-m. Liu et al. In Acta Chim Sinica, Vol. 37, 129 [1979]). This reduction converts the carbonyl into a lactol. The lactol hydroxyl can be converted into an ester by reaction with a suitable acid anhydride or acid halide or active ester.

Typical examples of these reactants are acetic anhydride, propionic anhydride, maleic anhydride and their substituted analogs, alkanoyl chlorides and the like. This reaction is carried out in an aprotic solvent, such as an ether or halogenated hydrocarbon (e.g. dichloromethane), at a moderate temperature between about 0 ° C and room temperature for approx Performed 0.5-5 h. An ether can also be formed, for example by contacting the alcohol with methanol or an R * -CH2-OH alcohol corresponding to the ether residue in the presence of a Lewis acid such as BF3. BF3 is shown as an etherate and forms a complex with the alcohol and causes ether formation at -10 ° C. to room temperature in 0.5-5 hours. The added alcohol is a good solvent. A carbonate can be formed from the alcohol, such as by reacting it with an organic chloroformate such as alkyl chloroformate. This in turn takes place at -10 ° C. to room temperature in 0.5-5 h in an aprotic solvent, as was used for the formation of the ester. All of these products can be recovered using conventional work-up.

The overall procedure

The ozonolysis reaction is part of an overall synthetic plan for obtaining the desired artemisinin analogues.

The scheme shown in FIG. 1 is a stereoselective total synthesis of artemisinin 18 (Qinghaosu) and 13-desmethylartemisinin 13, starting from the known sulfoxide 1 (obtainable from R (+) - Pulegon, William R. Roush and Alan E. Walts, J Amer. Chem. Soc. 106, 721 (1984). Treatment of the dianion derived from 1 with the known bromide 2 gave a mixture of diastereomeric sulfoxides 3, which was reduced directly in wet THF with aluminum-mercury amalgam to give the ketone 4 The ketone 4 was reacted with p-toluenesulfonyl hydrazide to give hydrazone 5. The conversion of the hydrazone 5 to N, N, N min, N min -tetramethylethylenediamine with n-butyllithium and quenching of the resulting vinyl anion with dimethylformamide gave the unsaturated aldehyde 6.

The direct reduction of aldehyde 6 with diisobutylaluminum hydride gave allylic alcohol 7, which was silylated with trimethylsilyl chloride and imidazole to give silyl ether 8. Deprotonation of allylic ether 8 with tert-butyl lithium in THF gave product 9 from the Brook's rearrangement product. The acetylation of 9 then led to the acetate 10. Deprotonation of the ester 10 with lithium-N-cyclohexyl-N-isopropylamide (LICA), followed by the in situ ester-enolate rearrangement according to Claisen, gave the carboxylic acid 11.

The carboxylic acid 11 could be converted to the 13-desmethylartemisinin 13 as follows. Treatment of 11 with silica gel impregnated with oxalic acid gave keto acid 12. Low temperature ozonolysis of 12 in methanol gave an unstable dioxetane intermediate, which was immediately treated with CF3CO2H in CDCl3 to give (Scheme I) the Nor -Analogs of Artemisinin, 13th

Alternatively (scheme II, FIG. 2), 11 could be esterified to give the ester 14, which could be methylated to give a mixture of monomethylated products 15 and 16 in a ratio of 3: 1. This ester mixture was treated sequentially with KOH in methanol, followed by oxalic acid on wet silica gel, so that the stereoisomerically pure keto acid 17 was obtained after chromatography.

Finally, ozonolysis of 17 in methanol at -78 ° C. gave an unstable dioxetane intermediate which, after evaporation of the methanol, was treated with dilute, moist CF3CO2H in CDCl3, after which optically pure artemisinin 18 was obtained. As shown in the examples, the synthetic material 18 was identical to naturally obtained Qinghaosu. This synthetic material is useful as an antimalarial agent.

In an important field of application, this synthesis sequence can be modified slightly in order to obtain radiolabelled artemisinin. This can be done efficiently and simply by using C-14 based CH3I in the alkylation of compound 14. This will incorporate the radioactive label into the 13-position where it is stable and non-labile. The product of this synthesis is particularly useful in the biological testing of artemisinin, its metabolic fate, absorption and the like being easily followed because of the built-in radioactive label.

As the general formula I shows, the invention allows the stereospecific synthesis of many tetracyclic polyoxa compounds besides artemisinin. In these cases one could apply the synthesis schemes according to the figures with appropriate modifications. E.g. To change R1 from the 1-C-alkylene bridge of FIGS. 1 and 2 to a 2 or 3-C bridge, the -CH2-COOH group in compound 11 or compound 15 can be homologated to the corresponding higher analog compounds. The R1 bridge can be substituted with alkyl groups by alkylation with X-alkyl, where X is a residual group such as a halide (e.g. I or Br), a tosylate, a mesylate or the like. This alkylation can take place before or after the homologation, depending on the specific position on the R1 group that is to be substituted.

The R2 bridge is given by the ring structure in connection 1. In Fig. 1, compound 1 is shown as a cyclohexanone-based material. One could just as well start from cyclopropanone (with retention of a C-C single bond R2), cyclobutanone (with retention of R2 as -CH2), cyclopentanone, etc. In either case, the carbons of the starting aldehyde can be substituted with desired alkyl groups on R2.

R3 is determined by the type of side chain containing the residual group in alkylating agent 2 in FIG. So if this side chain is changed in terms of length or substitution, the same applies to R3.

R4 can also be changed by changing the other substituent on the carbon atom between the two ether oxides in compound 2. In compound 2 this group is a methyl and R4 is a methyl. When this group is changed to a hydrogen or a substituted methyl, R4 follows accordingly.

The manufacturing processes of Figures 1 and 2 result in products of general structures 1-4, in which X = -O-. Fig. 3 shows a modification of the scheme of FIG. 1, wherein connections are generated in which X = -S- or

The scheme of Figure 3 begins with acid 11. This material is converted to the acid chloride 19 by conventional treatment with oxalyl chloride ClCOCOCl, thionyl chloride, or the like. Acid chloride 19 can then enter into a nucleophilic substitution with H2S or the amine NH2R10 with the addition of a -S- or

as X in compounds 20a and 20b, respectively. These compounds of the general formula II can be treated further by ozonolysis according to the invention, so that corresponding X = -S- and

desmethyl materials of general formula I can be obtained.

Fig. 4 shows a method for inserting -S- and

Groups in the artemisinine structure. The mixture of esters 15 and 16 with primary amine produced according to FIG. 2 is shown in a scheme

contacted to give the mixture of amides 21 and 22. Alternatively, esters 15/16 can be hydrolyzed to the mixture of acids 25 and 26 with methanolic KOH. This mixture can be converted to the corresponding mixed acid chlorides by the procedure described in FIG. 3, and the acid chlorides can be mixed with

are reacted so that the mixture of amides 21 and 22 is obtained.

The mixture of amides 21 and 22 is then treated with methanolic base, followed by treatment with silica gel impregnated with oxalic acid, so that the ketoamide 23 of the general formula II is obtained. This material is subjected to ozonolysis to give the NR10 analog compound 24 of artemisinin.

To incorporate a sulfur X into the structure, the mixed acid chlorides 25 and 26 are reacted with H2S to give 27 and 28. When this material is treated with the oxalic acid on silica gel, the sulfur compound 29 of the general formula II is formed. After ozonolysis, the compound 30 of the general formula I results.

R5 and R6 together are a carbonyl oxygen in the compounds 13 and 18 in FIGS. 1 and 2. This carbonyl can be reduced without affecting the reduction-sensitive peroxy group using sodium borohydride as described by M.-m. Liu et al. in Acta Chim. Sinica, Vol. 37, 129 (1979). This reduction converts the carbonyl into a lactol (hemiacetal, where R5 = H and R6 = OH). The R5 hydrogen can be replaced by an alkyl group by alkylation with X-alkyl. An R6-OH can be converted to an ether or ester by known methods.

The further possible configuration for R5 and R6 according to the general formula I can be generated according to FIG. In each of the five sequences shown in FIG. 5, for the sake of brevity, the reaction with oxalic acid to split off the side chain protection and to form the ketone has been omitted as shown in FIGS. 1, 2 and 4 and replaced by "...".

In one of these sequences, mixed esters 15 and 16 are reduced to alcohols 31 and 32 with lithium aluminum hydride. After removal of the side chain protection, ozonolysis gives compound 33, in which R5 and R6 are hydrogen

In the next variant, 31 and 32 are oxidized to aldehyde 34, which after removal of the protective group and ozonolysis results in compound 35 in which R5 and R6 are OH and H.

Aldehyde 34 can be alkylated with Grignard reagent to give alcohol 36. This can be carried on to give compound 37 of formula I, where R5 and R6 are alkyl and H.

Alcohol 36 can be oxidized to aldehyde 38. This material can be removed from the protecting group and ozonolytic to give 39, where R5 and R6 are alkyl and OH.

According to another variant, aldehyde 38 can again be treated with Grignard reagent to add another alkyl group (the same or different from 38) and this product can be deprotected and ozonated to give 11. It should be noted with this last sequence that if both alkyl groups are identical, they can be added to esters 15 and 16 at once using excess Grignard reagent.

It should also be noted that the reactions of FIG. 5 could be carried out with the acid chloride of the acid compound 11 of FIG. 1, so that the corresponding desmethyl materials are obtained.

6 shows a production scheme in which two representative secoderivatives are produced. In this process, an unsaturated (allylic) alcohol (which is shown in FIG. 6 as cyclohexenylmethanol, for example) is converted into the corresponding silyl ether 5. Allylic silyl ether 5 is then deprotonated in TMEDA with s-butyllithium to give a Brooks rearrangement product 6. The hydroxyl of 6 is then esterified (e.g. acetylated) to give ester 7. This is then e.g. deprotonated with lithium-N-cyclohexyl-N-isopropylamide (LICA) in THF, followed by an ester / enolate rearrangement carried out in situ according to Claisen, to give carboxylic acid-substituted vinylsilane 8.

This vinylsilane 8 is then subjected to ozonolysis. The ozonolysis reaction product contains a transition dioxetane that can be observed spectroscopically. The dioxane material rearranges to give hydroperoxide 1. The hydroperoxide is converted to the desired Seco analog by reaction with a ketone of general formula IV in the presence of acid, as already described.

As the general formula III shows, the invention provides a range of Seco analogs of artemisinin, wherein R16 and R17 together are a carbonyl oxygen. To obtain the full range of these substances one could use the synthesis scheme of the figure with appropriate modifications. To e.g. R11 and R12 can be changed in relation to the 1- or 2-C-alkylene according to FIG

Use carbonyl in the reaction with hydroperoxide 1.

In the same way, R18 and R19 are determined by the structure of the allyl alcohol 4. One could just as well start from other ring structures such as cyclopentene or from separate R18 and R19 groups that are on both sides of the olefinic bond of compound 4. In the case of the propionic anhydride of FIG. 6, a methyl and a hydrogen are obtained in these positions. Acetic anhydride produces two hydrogens. When these esterifying agents are replaced by agents having other substituted and unsubstituted groups, the R20 and R21 groups are changed accordingly. It is also possible to change the R20 and R21 groups by alkylation and the like.

To obtain analog compounds in which R16 and R17 are not carbonyl oxygen, the methods shown in Fig. 7 can be used. The carbonyl can be reduced as previously described. An ether such as ether 11 can also be formed, such as by contacting alcohol 9 with methanol or an alkyl-CH2-OH alcohol corresponding to the remainder of the ether in the presence of a Lewis acid such as BF3. BF3 reads out as an etherate and forms a complex with the alcohol and causes the ether to be formed at -10 ° C. to room temperature in 0.5-5 hours. The added alcohol is a good solvent. A carbonate such as carbonate 12 can be formed from 9 or the like by reacting 9 with an organic chloroformate such as an alkyl chloroformate. This again takes place at -10 ° C. to room temperature within 0.5-5 hours in an aprotic solvent how it was used for the formation of the ester 10. All of these products can be recovered using conventional organic processing.

When the method is used with bridgehead substituted materials, the reactions of Figures 8 and 9 can be used. In the reactions shown there, the conversion of the ketone to the vinylsilane can be carried out using all known methods for silylating a carbonyl functionality. In this case, a process works which proceeds with good efficiency and good yield, with the direct use of bis (trialkylsilyl) methyllithium. This reactant can by the method according to Grobel and Seebach, Chem. Ber. 110, 852 (1977). The silylation is carried out by contacting the ketone and the silylation reagent in approximately equimolar amounts (0.75 to about 1.33 equivalents of silylation complex, based on the ketone present) at temperatures as low as -100 ° C. to about 0 ° C., again in an aprotic anhydrous reaction phase. The product of this silylation can be extracted into a non-polar organic phase and worked up by washing with water, brine and the like. The product can e.g. be purified by chromatographic methods.

The ozonolytic cleavage reaction used in Figures 8 and 9 is an adaptation of the R.E. Claus and S.L. Schreiber, Org. Syn. 64, 150 (1985). This reaction is carried out essentially under the conditions that apply to ozonolysis. The reaction solvent used is the same as the materials used in ozonolysis and is chosen so that it is compatible with the highly reactive ozone. Of these solvents, the lower alcohols, especially methanol mixed with halogenated hydrocarbons and especially dichloroethylene, are preferred. In the case of Fig. 8, an optimal solvent was a 5: 1 volume ratio of methylene chloride and methanol. The solvent plus the presence of an acid acceptor such as an alkali metal carbonate or bicarbonate gave the best results. This acid acceptor is useful to prevent the alcohol in the reaction medium from combining with an aldehyde in the reaction product. The acid acceptor can advantageously be used if, as in the case of FIG. 8, this reaction is undesirable.

The product of the ozonolytic cleavage can be processed and recovered. In the case of sensitive products, processing takes place under reducing conditions, e.g. in the presence of an alkylamine and an anhydride such as acetic anhydride. In cases where the product is less sensitive, the conditions need not be reducing.

The recovered product can be treated with a strong acid, e.g. a mineral acid, preferably hydrochloric acid, are treated to obtain the tetracylic compounds of the formula IX. This product can be recovered by extraction into an organic layer which is then washed, dried and, if desired, column chromatographed and the like. The optional chain extension and alkylation steps can be carried out as described.

Use of the products

The compounds according to the invention all contain the peroxy bond which can lead to radical intermediates in vivo and which have antiprotozoal activities against a wide range of parasites such as Toxoplasma, Leishmania, Trypanosoma etc. in addition to Plasmodia. Tests have shown that they are highly effective in this application. They offer effectiveness against drug-resistant forms of malaria and can even affect cerebral malaria, where they can interrupt coma and lower fever. These substances should also have worm-abortion activity against diseases such as Schistosoma and Trichinella, etc. (Docampo, R. et al., Free Radicals in Biology, Vol. VI, Chapter 8, p. 243, 1984, Academic Press, Inc.) For this use, the compounds will normally be combined with known vehicles or carriers which will be administered to patients in need of such treatment. It can be administered orally or by injection. Characteristic vehicles are described in Remington's Pharmaceutical Sciences, Alfonso R. Gennaro, ed. Mack Publishing Company, Easton, PA. (1985).

For oral administration, the compounds can be formulated as elixirs and suspensions in sterile aqueous vehicles, and they can also be prepared in admixture with binders, carriers, diluents, solubilizers and the like as powders, pills or capsules. Characteristic liquid carriers are sterile water and sterile sugar syrup. Characteristic solids are starch, dextrose, mannitol, microcrystalline cellulose and the like.

For administration as an injection, the substances can be formulated as solutions / suspensions in aqueous media such as injectable saline solution, injectable water and the like. They can also be in the form of suspensions or solutions in non-aqueous media, e.g. as injectables such as corn oil, peanut oil, cottonseed oil, mineral oil, ethyl oleate, benzyl benzoate and the like. The non-aqueous media can in some cases allow the administration of substantial amounts of the drug as a depot drug into the fat layer of the patient, so that a long-term administration of the drug to the patient he follows.

The materials of the invention are used in relatively large doses. Usually doses of about 100 mg / d up to 10,000 mg / d are used. The actual dose used will depend on the individual patient's response to the drug and the degree of disease. In a particularly preferred application, the compounds are used against Plasmodia, and doses are required which are between 0.1-10 times the dose of natural artemisinin.

The peroxide bond inherent in all compounds, and the free radicals it can generate, are also suitable for a wide range of industrial chemical applications.

The following examples serve to illustrate the invention.

example 1

2,5,5-trimethyl-2- (2 min - (1 min min -R-methyl-3 min min -oxocyclohex-2 min min -yl) -ethyl-1,3-dioxane (4)

5R-methyl-2-phenylsulfinylcyclohexanone (1, Fig. 1) (7.14 g, 30.0 mmol) in dry THF (75 ml) at -30 ° C. under argon gas was treated with a lithium diisopropylamide solution (prepared from 9 ml or 64.5 mmol of diisopropylamine and 41.6 ml of a 1.55 M solution of n-BuLi in hexane) in dry THF (75 ml) followed by dry hexamethylphosphoramide (HMPA) (30 ml). The mixture was stirred at -30 ° C. for 3 h, and then 2- (2 min -bromoethyl) -2,5,5-trimethyl-1,3-dioxane (2, Fig. 2) ( 8.42 ml, 36.0 mmol) supplied. The mixture was stirred at -30 ° C. for 1 hour and then warmed to room temperature for more than 1 hour. The mixture was poured into ice-cold saturated ammonium chloride solution (100 ml) and extracted with diethyl ether (2 x 100 ml). The organic layers were washed with water (3 x 100 ml) and brine (100 ml), dried (MgSO4) and in vacuo evaporated to give 15.1 g of the crude alkylation product (3, Fig. 1). This was dissolved in THF (675 ml), to which water (75 ml) was added, followed by 7.5 g of amalgamated aluminum foil strips (prepared by dipping aluminum foil strips in 2% aqueous mercury dichloride for 15 seconds, followed by washing with absolute ethanol and diethyl ether ). The mixture was stirred at room temperature for 2 h and then filtered under reduced pressure while the solids were washed with diethyl ether (500 ml). The filtrate was washed with 5% sodium hydroxide solution (3 x 500 ml), water (500 ml) and brine (500 ml). The aqueous phases were extracted sequentially with diethyl ether (500 ml) and the combined organic phases dried (MgSO4) and im Vacuum evaporates to give 10.35 g of raw material. This was purified by thin layer chromatography on 207 g of Kieselgel 60 (230-240 mesh), eluting with EtOAc / hexane (10:90) -> (15:85) to give the product 4 (Fig. 1) (4.0 g, 50%) as colorless \ l. IR (thin film): 2960 (s), 2940 (m), 2880 (m), 1716 (s) cm <-> <1>. NMR (400 MHz, CDCl3): delta 3.501 (1 H, d, J 11 Hz), 3.496 (1 H, d, J 11 Hz), 3.454 (1 H, d, J 11 Hz), 3.450 (1 H, d, J 11 Hz), 2.30 (3 H, m), 2.01 (2 H, m), 1.83 (1 H, m), 1.65 (6 H, m), 1.34 (3H, s), 1.03 (3H, d, J 7 Hz), 0.93 (6H, s). C13-NMR (400 MHz, CDCl3): delta 213.2, 99.1, 70.5, 70.3, 57.1, 41.6, 41.4, 38.4, 33.5, 33.3 , 29.9, 25.6, 22.7, 21.7, 20.8, 20.5. MS (m / e): 268 (M <+>), 253 (M-Me). Analysis: Found: C, 71.73; H 10.33. C16H28O3 requires C, 71.64; H 10.45%.

Example 2

2,5,5-trimethyl-2- [2 min - (1 min min R-methyl-3 min min -oxocyclohex-2 min min -yl) - ethyl] 1,3-dioxane-p-tosylhydrazone (5)

A mixture of the ketone (4, Fig. 1) (3.60 g, 13.44 mmol), dry THF (100 ml), p-tosylhydrazine (2.49 g, 13.41 mmol) and pyridine was allowed to cool and then evaporated in vacuo to give 8.5 g of raw material. This was purified by thin layer chromatography on 170 g of silica gel 60 (230-400 mesh) and eluted with EtOAc / hexane (25:75) -> (40:60) to give the product 5 (FIG. 1) (5.5 g, 94%) as a gummy solid. IR (CHCl3): 3120 (m), 2955 (s), 2875 (s), 1735 (m), 1635 (2), 1605 (w), 1500 (w cm 1. NMR (CDCl3) : delta 8.53 (1 H, broad), 7.81 (2 H, d, J 8 Hz), 7.20 (2 H, d, J 8 Hz), 3.44 (4 H, s), 2.39 (3 H, s), 2.19 (3 H, m), 1.54 (8 H, m), 1.27 (3 H, s), 1.24 (3 H, d, J 5 Hz), 0.97 (3H, s), 0.93 (3H, s). MS (m / e): 437 (M + H <+>), 421 (M-Me).

Example 3

2,5,5-trimethyl-2- [2 min (1 min min -methyl-3 min min -3 min min -formylcyclohex-3 min min - en-2 min min -yl) ethyl] 1,3-dioxane ( 6)

A solution of the hydrazone (5, Fig. 1) (220 mg, 0.505 mmol) in dry TMEDA (10 ml) at -20 ° C. under argon gas was mixed with n-BuLi (1.30 ml of a 1.55 M solution in Hexane, 2.02 mmol) was added. The mixture was stirred at room temperature for 30 min and then cooled to 0 ° C. After the dropwise addition of dry DMF (0.5 ml), the mixture was stirred at 0 ° C. for 30 min and then poured into ice-cold saturated ammonium chloride solution (20 ml). It was then extracted with ethyl acetate (2 × 20 ml) and washed with saturated ammonium chloride solution (20 ml), water (20 ml) and brine (20 ml). The combined organic extracts were dried (Na2SO4) and evaporated in vacuo to give 175 mg of crude material which was purified by preparative TLC and eluted with EtOAc / hexane (15:85) to give the product 6 (Fig. 1) (77 mg , 55%) as light yellow \ l.IR (thin layer): 2960 (s), 2870 (m), 2710 (w), 1685 (s), 1635 (w) cm <-> <1>. NMR (400 MHz, CDCl3): delta 9.38 (1H, s), 6.73 (1H, t, Jr Hz), 3.472 (1H, d, J 11 Hz), 2.28 (2 H, m), 1.91 (1 H, m), 1.71 (5 H, m), 1.39 (2 H, m), 1.31 (3 H, s), 0.94 (3 H, s), 0.89 (3 H, s), 0.86 (3 H, d, J 7 Hz). C13-NMR (400 MHz, CDCl3): delta 194.7, 151.2, 99.0, 70.3, 41.6, 37.7, 35.0, 29.9, 28.5, 27.5 , 25.1, 23.9, 23.0, 22.7, 21.0, 18.6, 14.1. MS (m / e): (M-Me).

Example 4

2,5,5-trimethyl-2- (2 min - (1 min min R-methyl-3 min min hydroxymethylcyclo-hex-3 min min -en-2 min min -yl) ethyl) 1,3-dioxane (7 )

The aldehyde (6, Fig. 1) (1.1 g, 4.04 mmol) in dry THF (10 ml) was added dropwise from a needle to diisobutylaluminum hydride (DIBAL) (4.21 ml of a 1.2 M solution in toluene, 5.05 mmol) in dry THF (30 ml) at -78 ° C. under argon gas. The mixture was stirred at -78 ° C. for 30 min and then warmed to room temperature over 30 min. The mixture was poured into ice-cold saturated potassium sodium tartrate solution (50 ml) and extracted with ethyl acetate (2 x 50 ml). The organic extracts were washed with saturated potassium sodium tartrate solution, dried (MgSO4) and evaporated in vacuo to give product 7 (Fig. 1) (1.14 g, 100%) as a colorless. IR (CHCl3): 3850 (m), 3430 (m, broad), 2990 (s), 2945 (s), 2915 (s), 2855 (s), 1660 (w) cm <-> <1> .NMR (CDCl3): delta 5.68 (1H, m), 3.99 (2H, s), 3.53 (2H, d, J 11 Hz), 3.35 (2H, d, J 11 Hz), 1.94 (3 H, m), 1.61 (8 H, m), 1.30 (3 H, s), 0.98 (3 H, s), 0.88 (3 H, d, J 6 Hz), 0.81 (3 H, s). MS (m / e): 267 (M-Me). Analysis: Found: C, 72.60; H 10.53. C17H30O3 requires C 72.34; H 10.64%.

Example 5

2,5,5-trimethyl-2- (2 min - (1 min min R-methyl-3 min min -trimethylsilyloxymethylcyclohex-3 min min -en-2 min min -yl) ethyl) 1, 3-dioxane (8)

Imidazole (242 mg, 3.55 mmol) and trimethylchlorosilane (116 mg, 1.065 mmol) were added to alcohol 7 (FIG. 1) (100 mg, 0.355 mmol) in dry DMF (4 ml) at 0 ° C. under argon gas. The mixture was stirred at 0 ° C. for 1 h, then poured into ice-cold water (20 ml) and extracted with diethyl ether (2 × 20 ml). The organic extracts were washed with water (20 ml) and brine (20 ml), dried (MgSO4) and evaporated in vacuo to give the product 8 (Fig. 1) (126 mg, 100%) as a colorless. IR (CHCl3): 3000 (s), 2950 (s), 2920 (s), 2860 (s) cm <-> <1>. NMR (CDCl3): delta 5.60 (1H, m), 3.98 (2H, s), 3.48 (2H, d, J 11 Hz), 3.32 (2 H, d, J 11 Hz), 1.92 (3 H, m), 1.54 (7 H, m), 1.25 (3 H, s), 0.92 (3 H, s), 0.85 (3 H, d, H 7 Hz), 0.80 (3 H, s), 0.05 (0 H, s). MS (m / e): 354 (M +), 339 (M-Me).

Example 6

2,5,5-trimethyl-2- (2 min - (1 min min R-methyl-3 min min -trimethylsilyl-hydroxymethylcyclohex- 3 min min -en-2 min min -yl) ethyl) 1,3-dioxane (9)

A solution of the silyl ether 8 (FIG. 1) (7.20 g, 20.3 mmol) in dry THF (100 ml) at -78 ° C. under argon gas was given t-BuLi (23.9 ml of a 1.7-M Solution in pentane, 40.6 mmol) was added. The mixture was stirred at -30 ° C. to -40 ° C. for 2.5 hours and then cooled down to -78 ° C. A mixture of acetic acid (15 ml) and THF (50 ml) was slowly added and the resulting mixture was poured into ice-cold saturated sodium hydrogen carbonate solution (200 ml). This was extracted with chloroform (3 × 200 ml) and washed with brine (200 ml). The combined organic extracts were dried (MgSO4) and evaporated in vacuo to give 8.20 g of crude material. This was purified by thin layer chromatography on 246 g of silica gel 60 (230-400 mesh), eluting with EtOAc / hexane (10:90 ) -> (30:70) to obtain the product 9 (Fig. 1) (2.60 g, 36%) and the alcohol 7 (2.50 g, 44%). IR (CHCl3): 3550 (w, broad), 3000 (s), 2955 (2), 2870 (s) cm <-> <1>. NRM (CDCl3): delta 5.53 (1H, m), 3.84 (1H, m), 3.57 (2H, d, J 11 Hz), 3.37 (2H, d, J 11 Hz), 2.01 (3H, m), 1.63 (8H, m), 1.34 (3H, s), 1.01 (3H, s), 0.92 (3H , d, J 7 Hz), 0.85 (3H, s), 0.04 (9H, s). MS (m / e): 354 (M +), 353 (M-H), 337 (MOH). Analysis: Found: C, 66.02; H 10.58; Si 6.87. C20H38SiO3.1 / 2 EtOAc requires C, 66.33; H 10.55; Si 7.04%.

Example 7

2,5,5-trimethyl-2- (2 min - (1 min min R-methyl-3 min min -trimethylsilylhydroxymethylcyclohex- 3 min min -en-2 min min -yl) ethyl) 1,3-dioxane acetate ester (10)

To a solution of alcohol 9 (Fig. 1) (354 mg, 1.00 mmol) in diethyl ether (10 ml) at room temperature under argon gas were added dry pyridine (0.17 ml, 2.00 mmol), acetic anhydride (0.15 ml , 1.50 m mol) and 4-dimethylaminopyridine (10 mg) were added. The mixture was stirred at room temperature for 16 h and then poured into ice-cold water (20 ml). This was extracted with diethyl ether (2 x 20 ml). The combined organic layers were dried (MgSO4) and evaporated in vacuo to give product 10 (Fig. 1) (376 mg, 95%) as colorless. IR (CHCl3): 3000 (m), 2960 (s), 2930 (s), 2875 (s), 1725 (s), 1645 (w) cm <-> <1>. NMR (CDCl3): delta 5.34 (1 H, m), 5.08 (1 H, m), 3.40 (4 H, m), 2.06 (3 H, s), 2.05- 1.20 (10H, m), 1.35 (3H, s), 1.01 (3H, s), 0.88 (6H, m), 0.01 (9H, s). MS (m / e): 396 (M +), 395 (M-H). Analysis: Found: C, 65.24; H 10.13. C22H40SiO4.1 / 2 H2O requires C 65.19; H 10.12%.

Example 8

2,5,5-trimethyl-2- (2 min - (4 min min -carboxymethyl-1 min min R-methyl-3 min min - trimethylsilylmethylene cyclohex- 2 min min -yl) ethyl-1,3-dioxane (11)

Freshly distilled dry cyclohexylisopropylamine (0.51 mg, 3.976 mmol) in dry, distilled THF (5 ml) at 0 ° C. under argon gas, n-BuLi (1.92 ml of a 1.6 M solution in hexane, 3.976 mmol) added. The mixture was stirred at 0 ° C. for 10 min and then cooled down to -78 ° C. The ester 10 (Fig. 1) (609 mg, 1.538 mmol) in dry distilled THF (5 ml) was added dropwise over 30 min and the mixture was stirred at -78 ° C. for 3 h followed by room temperature for 4 d . Then the mixture was poured into ice-cold saturated ammonium chloride solution (20 ml) with 38 drops of 5N hydrochloric acid and extracted with chloroform (3 x 20 ml). The organic extracts were washed with brine (20 ml), dried (MgSO4) and evaporated in vacuo to give 754 mg of crude material. This was purified by thin layer chromatography on 76 g of silica gel 60 (230-400 mesh), eluting with (1 % HOAc / EtOAc) / hexane (7:93) → (50:50) to give product 11 (Fig. 1) (361 mg, 59%). IR (CHCl3): 3575 (w), 3030 (w, broad), 3000 (m), 2955 (s), 2870 (m), 1710 (s), 1610 (w) cm <-> <1>. NMR (CDCl3): delta 8.17 (1H, broad), 5.21 (1H, s), 3.28 (4H, m), 2.38 (2H, m), 2.00- 1.00 (11H, m), 1.12 (3H, s), 0.75 (9H, m), -0.12 (9H, s). MS / m / e): 396 (M <+>), 381 (M-Me). High resolution MS: found 396.270. C2H40SiO4 requires 396.269.

Example 9

4R-methyl-3- (3 min -oxobutyl) 2-trimethylsilylmethylene-cyclohexylacetic acid (12)

To silica gel 60 (70-230 mesh, 400 mg) in dichloromethane (4 ml) was added 10% aqueous oxalic acid (4 drops) with stirring. The mixture was stirred at room temperature for 5 minutes. Then the ketal 11 (Fig. 1) (150 mg, 0.38 mmol) in dichloromethane (4 ml) was added and the mixture was stirred for an additional 6 h. The mixture was filtered under vacuum and the solid was washed with dichloromethane (8 ml). The filtrate was evaporated in vacuo to obtain 131 mg of raw material. This was purified by thin layer chromatography on 13 g of silica gel 60 (230-400 mesh), eluting with (1% HOAc / EtOAc) / hexane (50:50) -> (90:10) to give the product 12 (Fig. 1) (77 mg, 65%) as a solid. IR (CHCl3): 3580 (w), 3040 (m, broad), 2970 (s), 1710 (s), 1610 (m) cm <-> <1>. NMR (CDCl3): delta 8.53 (1st H, broad), 54.0 (1 H, s), 2.70 (1 H, m), 2.47 (5 H, m), 2.10 (3 H, s), 1.75 (7 H, m), 0.85 (3 H, d, J 7 Hz), 0.03 (9 H, s). MS (m / e): 310 (M +), 295 (M-Me), 277 (M-Me-H2O). High resolution MS: found 310.197. C17H30SiO3 requires 310.196.

Example 10

13-desmethylartemisinin (13)

Ozonated oxygen (0.48 bar [7 psi], 0.4 l / min, 70 v) was filtered through a sintered glass frit into a solution of ketone 12 (Fig. 1) (77 mg, 0.248 mmol) in dry methanol (20 ml ) at -70 ° C for 68 s. The mixture was evaporated in vacuo to give 84 mg of material which was dissolved in deuterochloroform (0.4 ml) in an NMR tube. 10 drops of a 10% solution of trifluoroacetic acid in deuterochloroform were added, and the mixture was kept at room temperature for 5 h and then kept at 4 ° C. for 16 h and then kept at room temperature for 6 h. The mixture was purified by thin layer filtration on 7.7 g of Kieselgel 60 (230-400 mesh) covered with a pad of sodium hydrogen carbonate, eluting with EtOAc / CHCl3 (10:90) to give 13-desmethylartemisinin (13, Fig. 1) (26 mg, 39%). IR (CHCl3): 2990 (w), 2950 (m), 2920 (m), 2855 (m), 1735 (s) cm <-> <1>. 400 MHz-NMR (CDCl3): delta 5.89 (1 H, s), 3.18 (1 H, dd, J 7, 18 Hz), 2.02 (1 H, m), 1.87 (1 H, m), 1.83 (1 H, m), 1.66 (2 H, m), 1.45 (3 H, s), 1.33 (5 H, m), 0.99 (3 H, d, J 5 Hz). MS (m / e): 268 (M +), 253 (M-Me).

Example 11

2,5,5-trimethyl-2- (2 min - (4 min min -carbomethoxymethyl-1 min min R-methyl- 3 min min -trimethylsilylmethylene cyclohex-2 min min -yl) ethyl) 1,3-dioxane (14)

To carboxylic acid 11 (Fig. 2) (59 mg, 0.149 mmol) in dry acetone (5 ml) was added powdered anhydrous potassium carbonate (21 mg, 0.15 mmol) followed by dimethyl sulfate (14 µL, 0.15 mmol) . The mixture was heated to reflux for 3 h, then poured into ice-cold 0.1 M sodium carbonate solution (20 ml) and extracted with diethyl ether (2 x 20 ml). The organic extracts were washed with brine (20 ml), dried (MgSO4) and evaporated in vacuo to give 57 mg of crude material. This was purified by preparative TLC, eluting with EtOAc / -hexane (10:90) to give the product 14 (Fig. 2) (39 mg, 64%), NMR (CDCl3): delta 5.30 (1 H, s), 3.58 (3 H, s).

Example 12

2,5,5-trimethyl-2- (2 min -4 min min - (1 min min min -carbomethyloxyethyl) -1 min min R-methyl- 3 min min -trimethylsilylmethylene cyclohex-2 min min yl) ethyl) 1,3-dioxane (15/16)

N-Butyllithium (1.6 M in hexane, 1.06 ml or 1.697 mmol) was added to a solution of dry THF (3 ml) and dry isopropylcyclohexylamine (280 μl or 1.697 mmol) under argon gas at 0-5 ° C. After 10 min at 0-5 ° C., 400 μl of the resulting lithium amide solution (0.24 mmol) of a 0 ° C. solution of the ester 14 (FIG. 2) (35 mg or 0.0854 mmol) in dry THF (1 ml) was added. After 1 h at 0 ° C., the ester enolate solution was treated with CH3I (30 μl or 0.482 mmol). After 1 h at 0 ° C., the reaction mixture was poured into saturated aqueous NH4Cl (30 ml) and extracted with 2 × 25 ml EtOAc. The combined organic layer was washed with 1 x 20 ml H2O, dried over anhydrous MgSO4, filtered and the solvent removed on a rotovap. The remaining glass was chromatographed on a TLC plate (250 μm, silica gel) with 10% Et2O-pentane to give a 3: 1 mixture of 15:16 (FIG. 2) as a clear glass, 25 mg or 60% yield . NMR (400 MHz, CDCl3): delta 5.30 (s, 1 H), 3.5 (s, 3 H), 3.5 (m, 1 H), 1.33 (s, 3 H), 1 .05 (d, J = 6.8 Hz, 3 H), 0.98 (s, 3 H), 0.91 (d J = 7.2 Hz, 3 H), 0.87 (s, 3 H ), 0.090 (s, 9H).

Example 13

3S- (3 min -oxobutyl) 2-trimethylsilylmethylene-1R, 4R, 7S-menthan-8-acid (17)

10% aqueous KOH (20 μl) was added to a solution of the ester 15/16 (FIG. 2) (21 mg or 0.0495 mmol), dissolved in reagent grade methanol (3 ml), under argon gas at room temperature. The mixture was refluxed until hydrolysis was complete (approx. 6 hours, determined by TLC). The reaction mixture was cooled to room temperature and poured into 1% aqueous HOAc (25 ml) and extracted with 3 x 20 ml EtOAc. The combined organic layer was washed with 2 x 15 ml H2O, dried over anhydrous MgSO4, filtered and the solvent removed on a rotovap. The resulting crude acid was dissolved in CH2Cl2 (approx. 0.5 ml) and a well-stirred slurry of silica gel (50 mg, 70-230 mesh silica gel 60) in CH2Cl2 (0.5 ml), which was treated with 10% aqueous oxalic acid (20 mu l). After 18 h at room temperature under argon gas, the slurry was filtered and washed with CH2Cl2 (10 ml). The solvent was evaporated to give crude acid 17 (Fig. 2) (21 mg). The crude acid was purified on a TLC plate (250 μm, silica gel), eluting with 40% EtOAc / hexane (containing 0.4% HOAc). This gave 17 (Fig. 2) (13 mg or 81% yield) with approximately 25% isomeric contamination (the 7R analog). The isomeric mixture of acids was chromatographed again as before and pure 17 (Figure 2) was isolated as a white solid (8.4 mg or 52% overall yield from 15/16). NMR (400 MHz, CDCl3): delta 5.35 (s, 1 H), 2.73 (dq, J = 6.8, 12 Hz, 1 H), 2.3-2.6 (m, 3 H ), 2.13 (s, 3 H), 1.10 (d, J = 7.2 Hz, 3 H), 0.92 (d, J = 6.8 Hz, 3 H), 0.087 (s, 9 H).

Example 14

Artemisinin (18)

The keto acid 17 (FIG. 2) (3.5 mg or 0.0108 mmol) was dissolved in dry methanol (1 ml) and placed under argon gas in a 1.77 g screw-cap vial. The solution was cooled to -78 ° C., the seal was removed and a stream of O3 / O2 (0.48 bar [7 psi], 0.4 l / min, 70 V) was blown in until a pale blue color was seen (approx . 10 s). The closure was reattached and the solution was left to stand at -78 ° C. for 5 min. The solution was then flushed with argon (5 min) and warmed to room temperature. The solvent was carefully removed under high vacuum (0.02 mmHg) and the resulting solid was kept under high vacuum for 30 minutes. This product was dissolved in CDCl3 (0.75 ml) and CF3CO2H (10 μl) added. The mixture was kept at room temperature for 4 h and then at -20 ° C. for 18 h. The reaction mixture was evaporated to dryness in a high vacuum and then chromatographed on TLC (250 μm, silica gel) with 20% EtOAc / hexane to give pure 18 (Fig. 2) (1 mg or 33% yield). The synthetic 18 (Fig. 2) was identical to authentic materials according to proton and carbon NMR (400 MHz). Furthermore, according to TLC, it was identical in different solvent systems.

Example 15

1. Overall synthesis of racemic 13,14-desmethylartemisinin 1 according to FIG. 8.

The bicyclic ketone 2, which is obtained in good yield from cyclohexanone by the method according to Still (W.C. Still, Synthesis, 453 [1976]), was treated with bis (trimethylsilyl) methyllithium to give the diene 3 in a yield of 56%. The disubstituted double bond of 3 was selectively converted by treatment with ozone in methanol: dichloromethane (volume ratio 1: 5) in the presence of sodium hydrogen carbonate. The crude ozonolysis product was then reacted with Et3N / Ac2O to give the ester-aldehyde 4 in 43% yield. This unstable aldehyde was used immediately in the reaction with lithium methoxyethyldiphenylphosphine oxide (S. Warren et al., JCS Perkin I, 3099 (1979) to obtain a complex diastereomeric mixture of the phosphine oxides 5. It was more practical and efficient, 5 without prior purification to the enol ether 6 by treating 5 with NaH / THF. Thus, the enol ether 6 was prepared from aldehyde 4 in 54% yield. Ester hydrolysis of 6 gave acid 7, acidification of which gave keto acid 8 in an overall yield of 54% from 6 Finally, low temperature ozonolysis of 8 in methanol followed by careful solvent evaporation gave an intermediate dioxetane which was immediately treated with CF3CO2H in moist CDCl3 to give Analog 1 in 33% isolated yield.

Example 16

Preparation of 10-trimethylsilylmethylene bicyclo [4.3.1] -dec-2-en (3)

Bis (trimethylsilyl) methyllithium was produced according to a method according to Grobel and Seebach (B. Th. Grobel and D. Seebach, Chem. Ber. 110, 852 [1977]); a solution of bis (trimethylsilyl) methane (2.85 ml, 13.3 mmol) in THF (20 ml) and HMPT (5 ml) at -78 ° C., a solution of s-BuLi (7, 66 ml with 1.74 M in pentane) were added. The resulting light green solution was warmed to -40 ° C. After 8 h at -40 ° C., the resulting red solution was cooled to -78 ° C., and a solution of bicyclo [4.3.1] dec-2-en-10-one (2, FIG. 3) (2.00 g, 13.3 mmol) in THF (5 ml) was added. The reaction was warmed to 5 ° C. over 13 h, then stirred with H 2 O (50 ml) and extracted into hexane (2 × 50 ml). The combined hexane layers were washed with H 2 O (4 × 100 ml) and brine (100 ml) , dried over Na2SO4 and evaporated to give 3.00 g of a yellow oil, which was purified by column chromatography on silica gel. After eluting with EtOAc / hexane, some (0.35 g) starting ketone was recovered and the desired diene 3 (Fig. 8) was isolated as a colorless (1.64 g, 56.0% yield).

NMR (400 MHz): delta 5.67 (AB gradient, 2 H, CH = CH-), 5.18 (s, 1 H, = CH (TMS)), 2.85 (bs, 1 H, bridgehead H), 2.26 (m, 4H, = CH-CH2-), 2.05 (m, 1H), 1.79-1.55 (m, 3H), 1.41 (s, 1 H), 1.28 (m, 1H), 0.07 (s, 9H, SiCH3).

Example 17

Production of methyl-syn-2 (3- (2-acetaldehyde) -2 (E.Z.) - trimethylsilylmethylene cyclohexyl) acetate (4)

According to the method of Schreiber (RE Claus and SL Schreiber, Org. Syn. 64, 150 [1985]), a stream of O3 / O2 was passed through a stirred slurry of NaHCO3 (12 mg) in a solution of 10-trimethylsilylmethylene bicyclo [4.3.1 ] -dec-2-en (400 mg, 1.82 mmol), dry CH2Cl2 (15 ml) and absolute methanol (3 ml) at -78 ° C. The disappearance of the starting material was monitored by periodic TLC (SiO2 in EtOAc / hexane) before the mixture was purged with inert gas, warmed to room temperature, filtered, diluted with dry benzene (30 ml) and reduced to a colorless solution of approx. 10 ml under reduced pressure ml was concentrated. This concentrate was diluted with dry CH2Cl2 (15 ml) and treated sequentially with triethylamine (0.39 ml) and acetic anhydride (0.58 ml). After 4 h at room temperature, the reaction was stirred with 10% aqueous HCl (3 mL) and H2O (20 mL). The aqueous layer was separated and extracted with Et2O (2 x 25 mL). The combined organic layers were washed with H2O (25 ml), saturated aqueous NaHCO3 (2 x 30 ml) and brine (2 x 60 ml), dried over Na2SO4 and evaporated to give a yellow oil which was purified by column chromatography on silica gel . After elution with EtOAc / hexane, the unstable aldehyde 4 (Fig. 8) was obtained as a colorless (215 mg or 43.7% yield), which was obtained from a 1: 1 mixture of E: Z isomers according to NMR (90 MHz) and used immediately.

NMR (90 MHz); delta 9.70 (m, 1H, -CHO), 5.30 (s, 1H, = CH (TMS)), 3.65 (d, 3H, -CO2CH3), 3.50-2.05 (m, 6H), 1.90-1.10 (bm, 6H), 0.12 (d, 0H, SiCH3).

Example 18

Preparation of methyl-syn-2 (3-methoxy-2 (E, Z) butenyl- 2- (E, Z) trimethylsilylmethylene cyclohexyl) acetate (6)

A solution of n-BuLi (0.821 ml with 1.6 M in hexanes) was added dropwise to a solution of diisopropylamine (0.184 ml, 1.31 mmol) in THF (10 ml) at 0 ° C. After 10 min at 0 ° C., a solution of (1-methoxyethyl) diphenylphosphine oxide (S. Warren et al., JCS Perkin I, 3099 [1979]) (307 mg, 1.19 mmol) in THF (5 ml) added. After 10 min at 0 ° C., the resulting brick-red solution was cooled to -78 ° C. and a solution of aldehyde 4 (FIG. 3) (215 mg, 0.796 mmol) in THF (5 ml) was added through a cannula. After 1 h at -78 ° C, the resulting yellow solution was warmed to ambient temperature, stirred with saturated aqueous NH4Cl (20 ml) and extracted with Et2O (2 x 20 ml). The combined ethereal layers were washed with saturated aqueous NH4Cl (20 ml). , Brine (820 ml), saturated aqueous NaHCO3 (2 x 15 ml) and brine (2 x 25 ml), dried over Na2SO4 and evaporated to give 433 mg of yellow foam, from which a purified sample of the diastereomeric adduct mixture 5 (Fig 8) was obtained and examined spectrally.

NMR (90 MHz): delta 8.25-7.24 (bm, 10H, ArH), 5.75-4.90 (m, 3H, HO-CH), 3.67 (q, 3H, -CO2CH3), 3.30 (q, 3H, -OCH3), 3.30-0.69 (m, 15H), 0.70 (q, 9H, SiCH3).

The crude adduct mixture 5 (FIG. 8) was placed in THF (4 ml) and added via cannula to a stirred NaH suspension (24 mg of an 80% dispersion, 0.80 mmol) in THF (8 ml). After 3 h at ambient temperature, the resulting suspension was stirred with saturated aqueous NH4Cl (15 ml) and hexane (50 ml). The separated organic layer was washed with saturated aqueous NH4Cl (15 ml) and brine (25 ml), dried over Na2SO4 and evaporated to give 344 mg of orange, which was purified by column chromatography on silica gel. After elution with EtOAc / hexane, enol ether 6 (Fig. 8) was obtained as a colorless \ l (140 mg, 54.3% yield from 4), which is a mixture of four diastereomers according to NMR and TLC (SiO2 in EtOAc / hexane) was.

NMR (90 MHz): delta 5.10 (m, 1H, -CH), 4.18 (bm, 1H, -CH (OMe)), 4.48 (m, 3H, OCH3), 3, 17-0.90 (m, 15H), 0.07 (d, 9H, SiCH3).

Example 19

Preparation of syn-2 (3 (3-oxobutyl) -2 (E, Z) trimethylsilylmethylene cyclohexyl) acetic acid (8)

To a solution of the ester 6 (Fig. 8) (90.0 mg, 0.278 mmol) in MeOH (10 ml) was added 6N KOH (0.69 ml, 15 equiv.). The solution was heated to reflux for 12 h and stirred for an additional 12 h at ambient temperature. The resulting yellow solution was acidified with saturated aqueous NH4Cl (35 mL and extracted with Et OAc (2 x 20 mL). The combined organic layers were washed with brine (2 x 30 mL), dried over Na2SO4 and evaporated to give acid 7 (Fig. 8) as a yellow \ l, which was a relatively pure E: Z mixture according to NMR and was used without further purification.

NMR (90 MHz): delta 5.23 (m, 1H, = CH), 4.26 (bt, 1H, MeO-C = CH), 3.48 (m, OCH3), 3.40-0 .90 (m, 15H), 0.07 (d, 9H, SiCH3).

The yellow \ l was placed in CH2Cl2 (10 ml) and stirred with silica gel (70-230 mesh) with the addition of freshly prepared 10% aqueous oxalic acid (50 ml). After 2 h at ambient temperature the solid was filtered off and washed with CH2Cl2 (100 ml). The filtrate was concentrated in vacuo to give a yellow oil which was purified by column chromatography on silica gel. After elution with HOAc / EtOAc / hexane, keto acid 8 (FIG. 8) was obtained as a yellow \ 1 (77 mg, 93.9% yield from enol 7).

NMR (90 MHz): delta 5.23 (d, 1 H, = CH), 3.30-2.30 (m, 6 H), 2.13 (s, 3 H, COCH3), 2.00- 1.00 (bm, 8H), 0.07 (d, 9H, SiCH3).

Example 20

Production of (+/-) 13,14-desmethylartemisinin (1)

An O3 / O2 stream was passed through a solution of the keto acid 8 (FIG. 8) (17 mg, 0.057 mmol) in absolute MeOH (2 ml) at -78 ° C. until no more starting material was determined by TLC (HOAc / EtOAc / Hexane) could be detected. The resulting pink solution was warmed to ambient temperature and concentrated in vacuo to a yellow foam which was placed in CDCl3 (2 ml). After treatment with 10% trifluoroacetic acid in CDCl3 (20 μl), the formation of the cyclization product 8 was monitored by NMR (90 MHz). After 8.5 h at ambient temperature the solution was stirred with NaHCO3 (25 mg), filtered and evaporated to give 17 mg of a yellow oil which was purified by PTLC on silica gel. After developing with 5% EtOAc / CHCl3, the main component was separated off and reapplied to PTLC plates and developed in 35% EtOAc / hexane. In this way (+/-) 13,14-desmethylartemisinin (1, Fig. 8) was isolated as white needles, which were recrystallized with EtOAc / hexane to give 4.8 mg, melting point 130-130.5 ° C.

<1> H-NMR (400 MHz): delta 5.90 (s, 1H, H5), 3.18 (dd, 1H, J = 18.3, 7.1 Hz, H11), 2.42 (dt, 1H, J = 13.5, 3.8 Hz, H1), 2.25 (dd, 1H, J = 18.3, 1.3 Hz, H11 beta), 2.02 (ddd, 1 H, J = 15.3, 4.9, 2.7 Hz, H3), 1.96-1.48 (m, 10H), 1.44 (s, 3H, -CH3). <1> <3> C-NMR: delta 168.7, 105.4, 93.2, 78.1, 43.9, 38.4, 36.0, 32.1, 31.6, 30.2 , 26.6, 25.5, 25.4, 24.7. IR (KBr) 2925, 1735, 1210, 1005 cm <-> <1>. CIMS (<+> NH4) m / e 272 (M + <+> NH4), 255 (M + <+> H).

Example 21

1-t-butyldimethylsilyloxymethylcyclohexene (5)

A solution of 1-hydroxymethylcyclohexene 4 (Fig. 6) (46.6 ml, 44.8 g, 400 mmol) in dry dichloromethane (250 ml) at 0 ° C. under argon gas was given N, N-diisopropylethylamine (76.6 ml , 440 mmol), followed by a solution of t-butyldimethylchlorosilane (66.3 g, 440 mmol) in dry dichloromethane (100 ml). The mixture was stirred at room temperature for 2 h and was then poured into ice-cold saturated ammonium chloride solution (100 ml). The organic layer was separated and washed with saturated ammonium chloride solution (100 ml) and brine (100 ml). The aqueous layers were re-extracted with dichloromethane (100 ml). The combined organic layers were dried (K2CO3) and evaporated in vacuo to give 89.7 g of raw material. This was fractionated under reduced pressure to give product 5 (Fig. 6) (81.8 g, 90%) as a colorless liquid , Boiling point 94-100 ° C / 6 mmHg. IR (thin film): 3000 (m), 2950 (s), 2930 (s), 2880 (s), 2855 (s), 1680 (w) cm <-> <1>. NMR (CDCl3): delta 5.62 (1H, m), 3.97 (2H, s), 1.93 (4H, m), 1.56 (4H, m), 0.88 ( 9H, s), 0.03 (6H, s). MS (m / e): 226 (M <+>), 211 (M-Me).

Example 22

1- (t-butyldimethylsilylhydroxymethyl) cyclohexene (6)

The silyl ether (5, Fig. 6) (26.0 ml, 22.6 g, 100 mmol) in dry THF (250 ml) at -78 ° C under argon gas was dry TMEDA (24.0 ml, 160 mmol), followed by s-BuLi (154 ml of a 1.3 M solution in cyclohexane, 200 mmol) was added. The mixture was stirred at -30 ° C. for 3 h and then cooled back to -78 ° C. A mixture of acetic acid (20 ml) and THF (80 ml) was slowly added. The mixture was poured onto ice-cold saturated sodium hydrogen carbonate solution (200 ml), which was extracted with dichloromethane (2 x 300 ml). The organic extracts were washed with brine (200 ml), dried (MgSO4) and evaporated in vacuo to give 26.7 g of crude material. This was purified by thin layer chromatography on 267 g of Kieselgel 60 (230-400 mesh), eluting with EtOAc / hexane (5; 95) → (7:93) to give the product 6 (Fig. 6) (11.65 g, 52%) as colorless IR (thin film): 3580 (w), 3460 (m, wide), 3040 (w), 2940 (s), 2900 (s), 2870 (s), 1670 (w ) cm <-> <1>. NMR (CDCl3): delta 5.53 (1 H, m), 3.92 (1 H, s), 1.97 (4 H, m), 1.58 (4 H, m), 0.94 ( 9H, s), -0.01 (3H, s), -0.11 (3H, s). MS (m / e): 226 (M <+>), 225 (M-H).

Example 23

1- (1 min -t-butyldimethylsilyl-1 min -propionoxymethyl) -cyclohexene (7)

A solution of the alcohol (6, Fig. 6) (11.3 g, 50.0 mmol) in diethyl ether (100 ml) at room temperature under argon gas was added dry pyridine (8.10 ml, 100 mmol), followed by propionic anhydride (7 , 70 ml, 60.0 mmol) was added. 4-Dimethylaminopyridine (610 mg, 5.0 mmol) was added and the mixture was stirred at room temperature for 16 h. The mixture was poured into ice-cold water (100 ml) and extracted with diethyl ether (2 x 100 ml). The organic extracts were washed with saturated ammonium chloride solution (100 ml), dried (MgSO4) and evaporated in vacuo to give 18.7 g of crude material. This was purified by thin layer filtration through 100 g of silica gel 60 (230-400 mesh), eluting with 500 ml of EtOAc / hexane (7:93) to give product 7 (Fig. 6) (13.9 g, 99%) as colorless \ l.IR (thin film): 3030 (w), 2925 (s), 2885 (m), 2850 (s), 2770 (w), 1740 (s), 1660 (w) cm <-> <1>. NMR (CDCl3): delta 5.44 (1 H, m), 5.05 (1 H, s), 2.25 (2 H, q, J 7 Hz), 1.88 (4 H, m), 1.49 (4 H, m), 1.05 (3 H, t, J 7 Hz), 0.83 (9 H, s), -0.03 (3 H, s), -0.12 ( 3 H, s). MS (m / e): 282 (M <+>), 253 (M-Et), 225 (M-EtCO).

Example 24

1- (1 min - (carboxyethyl) 2-t-butyldimethylsilylmethylene cyclohexane (8)

Dry cyclohexylisopropylamine (2.17 ml, 13.0 mmol) in dry THF (20 ml) at 0 ° C. under argon gas became n-BuLi (8.13 ml of a 1.6 M solution in hexane, 13.0 mmol ) added. The mixture was stirred at 0 ° C. for 10 min and then cooled down to -78 ° C. The ester (7, Fig. 6) (3.08 ml, 282 g, 10.0 mmol) was added dropwise and the mixture was stirred for 18 hours at room temperature. The mixture was poured into ice-cold saturated ammonium chloride solution (50 ml) and extracted with diethyl ether (2 x 50 ml). The organic extracts were washed with brine (50 ml), dried (MgSO4) and evaporated in vacuo to give 4.0 g of crude material. This was chromatographed on 200 g of silica gel 60 (230-400 mesh) by thin layer, eluting with ( 1% HOAc / EtOAc) / hexane (15:85) -> (20:80) purified to give the undesired isomer (161 mg, 6%) and the desired product 8 (Fig. 6) (1.70 g, 68 %) as a crystalline solid, melting point 106-109 ° C. IR (CHCl3): 3500 (w), 3030 (m, broad), 2030 (s), 2860 (s), 2650 (m, broad), 1710 (s ), 1620 (s) cm <-> <1>. NMR (CDCl3): delta 5.23 (1H, s), 2.72 (1H, m), 2.31 (3H, m), 1.64 (6H, m), 1.06 ( 3 H, d J 6 Hz), 0.88 (9 H, s), 0.07 (6 H, s). MS (m / e): 257 (M-Me), 255 (M-OH), 225 (M-Bu <t>). Analysis: Found C, 68.11; H 10.45; Si 9.56. C16H30SiO2 requires C 68.09; H 10.64; Si 9.93.

Example 25

1-t-Butyldimethylsilyloxy-8-hydroperoxy-4-methyl-8-hexahydroisochroman-3-one (1)

Ozonated oxygen (0.48 bar [7.0 psi], 0.4 l / min, 70 v) was through a sintered glass frit into a solution of the carboxylic acid 8 (Fig. 6) (500 mg, 1.77 mmol) in dry Methanol (20 ml) passed at -70 ° C. for 6 min and 40 s. The mixture was evaporated in vacuo to give 651 g of crude material which was purified by thin layer chromatography on 65 g of silica gel 60 (230-400 mesh) eluting with EtOAc / -hexane (25:75) to give product 1 (Fig 4) (334 mg, 57%) as a white solid. IR (CHCl3): 3520 (m), 3340 (m, broad), 2950 (s), 2900 (m), 2890 (m), 2870 (s), 1740 (s) cm <-> <1>. NMR (400 MHz, CDCl3): delta 8.06 (1H, broad), 5.74 (1H, s), 2.99 (1H, dq, J7.7 Hz), 2.21 (1 H, ddd, J 7, 7.12 Hz), 1.91 (1H, m), 1.67 (5H, m), 1.28 (2H, m), 1.16 (3H, d, J 7 Hz), 0.92 (9H, s), 0.20 (3H, s), 0.17 (3H, s). C13 NMR (400 MHz, CDCl3): delta 173.6, 138.3, 99.5, 83.2, 41.4, 35.5, 29.2, 25.6 (3 C), 25.5 , 23.7, 23.1, 21.0, 17.9, 12.4. MS (m / e): 331 (M + H <+>), 315 (M-Me), 297 (M-O2H), 285 (M-CO2), 273 (M-Bu <t>). The stereochemistry of 1 (Fig. 6) was determined as follows:

Treatment of 1 with triphenylphosphine in THF gave alcohol 1a (Fig. 6). After careful chromatographic purification and multiple crystallizations, 1a was analyzed by means of X-ray crystallographic analysis (Crystallitics, Inc., Lincoln, Nebraska), which showed that it had the structure and relative stereochemistry according to FIG. This information can be used to infer the structure of 1 according to FIG.

Example 26

14-desmethyl-2-nor-1,2-secoartemisinin (2)

Trifluoroacetic acid (0.54 ml) was added to a solution of hydroperoxide 1 (Fig. 6) (133 mg or 0.403 mmol) in dry distilled acetone (6 ml) under argon gas. The mixture was stirred magnetically overnight at room temperature under argon gas, poured into saturated aqueous NaHCO3 and extracted with 3 × 25 ml Et2O. The combined organic layer was washed with 1 x 40 ml H2O and 1 x 40 ml saturated aqueous NaCl. The organic phase was dried over MgSO4, filtered and the solvent was evaporated in vacuo. The crude product was placed on a preparative TLC plate (1.5 mm silica gel) and eluted with 20% EtOAc / hexane to give 2 (Fig. 6, as a white solid (75 mg or 73% yield), m.p. 111-112 DEG C. IR (CCl4): 2960, 2880, 1755, 1460, 1390, 1220, 1180, 1100, 1020 cm <-> <1>. Compound 2 shows unusual NMR behavior. <1> H-NMR (CDCl3) at 25 ° C: delta 0.92 (d, J = 8.8 Hz, 2 H), 1.18 (br s, 3 H), 1.38 (br s, 3 H), 2.70 (br s, 0.5 H), 3.10 (br s, 0.5 H), 5.50 (br s, 1 H); at 60 ° C: delta 0.95 (dq, J = 4.7, 13.3 Hz, 1 H), 1.18 (d, J = 6.8 Hz, 3 H), 1.43 (br s, 3 H), 1.54 (br s, 3 H), 2, 5 (very br s, 1 H), 3.2 (br s, 3 H), 1.54 (br s, 3 H), 2.5 (very br s, 1 H), 3.2 (br s , 1 H), 5.60 (s, 1 H); at 3.5 ° C: 0.9 (m, 1.5 H), 1.60 (d, J = 7.2 Hz, 3 H) , 1.37 (s, 3H), 1.61 (s, 3H), 2.60 (d, J = 13 Hz, 0.8H), 3.09 (dq, J = 6.6, 13 Hz, 0.8 H), 3.5 (m, 0.4 H), 5.59 (s, 0.8 H), 5.68 (s, 0.2 H). <1> <3 > C-NMR (CDCl3) at 60 ° C: delta 12.0, 23.0, 23.6, 24.9, 25 , 1, 31.3, 34.0, 71.8, 76.0, 76.5, 92.9, 94.8, 172.0. MS (Dlc-NH3): 274 (M + NH4 <+>), 257 (M + H <+>), 198, 181, 170, 153.

Example 27

The preparation of Examples 20-24 is repeated, with 400 mmol of 1-hydroxymethylcyclopentene being used in Example 20 instead of 1-hydroxymethylcyclohexene 4 (FIG. 6). This gives artemisinin analog compounds similar to compounds 2 and 3, but which have one less carbon atom in the alkylene bridge between the "1" and the "7" carbon atom.

Example 28

The preparation of Examples 20-24 is repeated, with 400 mmol of 1-hydroxy-2-ethylhex-2-ene being used in Example 20 instead of 1-hydroxymethylcyclohexene 4 (FIG. 6). This gives artemisinin analog compounds similar to compounds 2 and 3, but with an ethyl as R18 and a butyl as R19.

Example 29

Biological results

(A) Analog compound 1 (Figure 8) was sent to the Walter Reed Army Institute of Research (WRAIR) for in vitro testing against P. falciparum using modifications of the procedures of Desjardins et al., 1979, and Milhous et al ., 1985 (Desjardins, RE, CJ Canfield, DE Haynes, and JD Chulay, Antimicrob. Agents Chemother., Vol. 16, 710-713 [1979]; Milhous, WK, NF Weatherly, JH Bowdre, and RE Desjardins, Antimicrob . Agents Chemother. Vol. 27, 525-530, 1985) for evaluating the specific effectiveness of compound 1 (FIG. 8) as an antimalarial agent against known controls carried out simultaneously, such as chloroquine, mefloquine, pyrimethamine, sulfadoxine, tetracycline, Qinghaosu or quinine Some antimalarials are static rather than fatal in effectiveness, the incubation period must be extended to evaluate the effects of such drugs on parasite growth rates. To ensure exponential parasite growth and maximum radioisotope uptake during the entire extended incubation, a reduced parasite circulation in the blood (0.2%) and reduced hematocrit values (0.2%) are necessary. As a result, drugs that are actively built into erythrocytes (such as chloroquine or qinghaosu) have slightly lower 50% inhibitory concentrations than other assay systems that operate with higher hematocrit levels. With the exception of the contribution from the 10% normal human mixed plasma and added 10 <-> <1> <0> M (0.014 ng / ml) PAB, the culture medium is folate-free. The trace amount of PAB ensures the exponential growth of the sulfonamide-responsive parasite Clones without antagonistically affecting the effectiveness of antifol antimalarials. In this medium, sulfonamides and sulfones have a thousand to ten thousand times and DHFR inhibitors are 5-200 times more effective than in normal RPMI-1640 culture medium.

All test compounds are solubilized in DMSO and diluted 400-fold in the culture medium with plasma (in order to rule out a DMSO effect), so that an initial concentration of at least 12,500 ng / ml is obtained. Medicines are then diluted five-fold using the Cetus Pro / Pette system, with a concentration range of 0.8 ng / ml to 12,500 ng / ml being used. 50% inhibitory concentrations are given in ng / ml.

Table I shows the differences in the sensitivity courses of the two control clones P. falciparum (Oduola, AMJ, NF Weatherly, JH Bowdre, RE Desjardins, Thirty-second Annual Meeting, American Society of Tropical Medicine and Hygiene, San Antonio, Texas, 4.- Dec 8, 1983) and provides test results. The W-2 Indochina clone P. falciparum is resistant to chloroquine, pyrimethamine and sulfadoxine, but responds to mefloquine. The African D-6 clone P. falciparum responds to chloroquine, pyrimethamine and sulfadoxine, but is resistant to mefloquine. <TABLE> Columns = 6 Title: Table I In vitro ED50 values of selected antimalarials against two strains of P. falciparum * Head Col 01 AL = L: Antimalarial Head Col 02 AL = L: MW Head Col 03 to 04 AL = L: D-6 clone (African. Strain) Head Col 05 to 06 AL = L: W-2 clone (Indochina strain) SubHead Col 03 AL = L> x 10 <-9> M: SubHead Col 04 AL = L> ng / ml: SubHead Col 05 AL = L> x 10 <-9> M: SubHead Col 06 AL = L> ng / ml: Qinghaosu 282 10.99 3.09 7.01 1.97 Dihydroquinghaosu 284 1.68 0.47 1.37 0, 38 Arteether 312 6.00 1.87 3.96 1.23 (+) - 13-14-bisnorartemisinin (1, Fig. 8) 254 82.95 21.06 15.98 4.05 Chloroquine 515 11.49 5 , 91 52.13 26.84 Mefloquine <SDO NM = Drawings>