HK1064388B - Synthesis of silyl camptothecins and silyl homocamptothecins - Google Patents

Description

Synthesis of silyl camptothecins and silyl homocamptothecins

Benefits of government

The invention was carried out with the funding of the National Institutes of Health under the funding number RO1GM 33372. The government has certain rights in this invention.

Background

The present invention relates to the synthesis of silyl camptothecins and silyl homocamptothecins, and in particular to the synthesis of silyl camptothecins and silyl homocamptothecins via a semi-synthetic route from camptothecins and homocamptothecins.

References mentioned herein may assist in understanding the invention or the background of the invention. However, the inclusion of a reference herein is not intended and does not imply that such reference appears as prior art to the present invention.

The structures of camptothecin 1a and homocamptothecin 10a are shown in figure 1. The core structure of camptothecin molecules has five fused rings, a-E. Standard substituents include hydroxy and ethyl at C20, and other positions of the camptothecin ring core may also be substituted. Homocamptothecins have the same a-D ring as camptothecin, but the E ring contains an additional methylene group (C20 a). The A-B ring system of camptothecin and homocamptothecin is quinoline, and this part of the ring system is particularly important because substituents on the quinoline portion of the molecule often confer useful properties, as detailed below.

Generally, camptothecin and homocamptothecin (sometimes collectively referred to herein as camptothecin or camptothecin family) are, for example, DNA topoisomerase I inhibitors that are useful as anti-cancer drugs. Analogues of the natural product camptothecin are the most important class of compounds available for the treatment of solid tumors. Topotatan (tpt) and CPT-11 were the first two members of the camptothecin family to receive full approval from the U.S. food and drug administration (Topotatan was used in 1996 as a second line therapy for advanced epithelial ovarian cancer, Topotatan was used in 1998 for the treatment of small cell lung cancer, and CPT-11 was used in 1998 as a first line therapy for colon cancer).

Lavergne et al have demonstrated that expanding the E ring of camptothecin to produce "homocamptothecins" increases the solution stability of camptothecin while maintaining its anti-cancer activity. Lavergne, 0., Lesueur-Ginot, L., Rodas, F.P., Kasprzyk, P.G., Pommer, J., Demarquay, D., Prevost, G., Ulibarri, G., Rolland, A., Schiano-Liberore, A., M., Harnet, J., Pons, D., Camara, J., Bigg, D., "Homocamptothecins: synthesis and antagonist Activity of novel-Ring Modified Cattothecin Analogs, J Med. chem., 41, 5410-; and Lavergne, O., Lesueur-Ginot, L., Rodas, F.P., and Bigg, D., "An E-Ring Modified Camptothecin With Point inhibition and Toposiisomerease I inhibition Activity", bioorg.Med.chem.Lett.7, 2235-. In Lavergne et al, modifications of the E ring included insertion of a methylene spacer between the carbon bearing the 20-OH functionality and the carboxyl group of the naturally occurring six-membered ring α -hydroxylactone of camptothecin. It has been found that the introduction of a new 7-membered β -hydroxy lactone ring into camptothecin improves the solution stability of the agent. Despite structurally similar to camptothecin, homocamptothecin behaves very differently under physiological conditions. In general, standard camptothecin analogs are kinetic drugs because their lactone rings open rapidly and reversibly under physiological conditions. In general, the lactone ring opening of homocamptothecin is relatively slow and irreversible.

7-silyl camptothecin 2 and 7-silyl homocamptothecin 11 shown in FIG. 1 (sometimes referred to as cilatekan (silatecans) and homocil (homosilatekans)) are an important class of lipophilic camptothecin analogs, see, e.g., a) Josien, H.H., Bom, D.D., Curran, D.P., Zheng, Y.H., Chou, T.C.Bioorg.Med.Chem.Lett.7, 3189 (1997); b) pollack, i.f., Erff, m., Bom, d., Burke, t.g., Strode, j.t., Curran, d.p., Cancer Research, 59, 4898 (1999); bom, d., Du, w., Garbarda, a., Curran, d.p., chanan, a.j., Kruszewski, s., Zimmer, s.g., Fraley, k.a., bingcag, a.l., Wallace, v.p., Tromberg, b.j., Burke, t.g., clinical Cancer Research, 5, 560 (1999); bom, d., Curran, d.p., chanan, a.j., Kruszewski, s., Zimmer, s.g., Fraley, k.a., Burke, t.g.j med.chem., 42, 3018 (1999). Many of the most interesting cetuximab and high cetuximab contain one or more additional substituents (e.g., hydroxy or amino groups) in the a ring, and the combination of these substituents can provide significant improvements over any of the corresponding monosubstituted analogs. For example, 7-tert-butyldimethylsilyl-10-hydroxycamptothecin 2a (DB-67) is currently in the final stage of preclinical development. DB-67 and other sillimanimes and high sillimanimes exhibit a number of attractive features including high activity against a broad spectrum of solid tumors, low binding to blood proteins, resistance to lactone ring opening, high lipophilicity and potential oral availability, among others.

DB-67 and other Cinchonan and Gaoshima have been prepared by total synthesis using a cascade free radical addition (cascade radial ligation) route. See, for example, U.S. patent application nos. 09/007,872, 09/212,178, and 09/209,019, U.S. patent nos. 6,150,343 and 6,136,978, Curran, d.p., Ko, s.b., Josien, h.angelw.chem., iht.ed.eng., 34, 2683(1995), and Josien, h.k., Ko, s.b., bom.d., Curran, d.p.chem.eur.j, 4, 67 (1998). These full syntheses are highly flexible and allow the preparation of a variety of sillimani and gazelman analogs via conventional and parallel routes. However, the total synthesis of cetuximab and high cetuximab via cascade free radical ring-extension requires thirteen or more steps and proceeds with an overall yield of about 2%.

It would be desirable to develop improved synthetic routes for the preparation of silyl camptothecins and silyl homocamptothecins.

Disclosure of Invention

The present invention provides a semi-synthetic route to synthesize silylcamptothecin and silylhomocamptothecin from camptothecin and homocamptothecin through silyl addition to them.

In one aspect, the invention provides a method of synthesizing a compound of the formula

The method generally comprises the steps of:

reacting a compound of the formula

With silyl precursors to form silyl SiR¹R²R³Under the conditions of (1), wherein R¹、R²And R³E.g. identical or different, and independently of one another is C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, aryl, - (CH)₂)_mR¹¹Radical or SiR¹²R¹³R¹⁴Wherein m is an integer of 1 to 1O, R¹¹Is hydroxy, alkoxy, amino, alkylamino, dialkylamino, F, Cl, cyano, -SR^cOr nitro, and wherein R¹²、R¹³And R¹⁴Are the same or different and are independently an alkaneA radical or an aryl radical. Preferably, R¹、R²And R³The same or different, and independently is an alkyl group or an aryl group.

R⁴And R⁵E.g., the same or different, and independently hydrogen, -C (O) R^fWherein R is^fIs alkyl, alkoxy, amino OR hydroxy, alkyl, alkenyl, alkynyl, alkoxy, aryloxy, acyloxy, -OC (O) OR^dWherein R is^dIs alkyl, -OC (O) NR^aR^bWherein R is^aAnd R^bAre the same or different and are independently H, -C (O) R^fAlkyl or aryl, F, Cl, hydroxy, nitro, cyano, azido, formyl, hydrazino, amino, -SR^cWherein R is^cIs hydrogen, -C (O) R^fAlkyl or aryl; or R⁴And R⁵Together form three or four radicals selected from the group CH, CH₂O, S, NH or NR¹⁵A chain of members of (1), wherein R¹⁵Is C₁-C₆An alkyl group. R⁴And R⁵May be taken together, for example, to form the formula-O (CH)₂)_jA group of O-, wherein j represents an integer of 1 or 2.

R⁶Is, for example, H, F, Cl, nitro, amino, hydroxy or cyano; or R⁵And R⁶Together form three or four radicals selected from the group CH, CH₂O, S, NH or NR¹⁵A chain of members of (a). R⁵And R⁶May be taken together, for example, to form the formula-O (CH)₂)_jA group of O-, wherein j represents an integer of 1 or 2.

R⁷Is, for example, H, F, amino, C_1-3Alkyl radical, C_2-3Alkenyl radical, C_2-3Alkynyl, trialkylsilyl or C_1-3An alkoxy group. R⁷Preferably H. R⁸Is, for example, C_1-10Alkyl, alkenyl, alkynyl or benzyl. Preferably ethyl, allyl, benzyl or propargyl. Most preferably, R⁸Is ethyl. R⁹Is, for example, H, F or-CH₃And n is 0 or 1. R¹⁰Is, for example, -C (O) R^fOr H. Preferably, R¹⁰Is H or-C (O) CH₃。

Y is absent or O. In the case where Y is oxygen, the N-oxide is converted during the reaction to the corresponding silylcamptothecin or silylhomocamptothecin.

Preferred silyl precursors for use in the present invention include silanes, disilanes, silylgermanes, silylstannanes, silylboranes and acylsilanes. Several preferred silanes, disilanes, silylgermanes, and silylstannanes can be used with the general formula XSiR¹R²R³Wherein X is H, SiR respectively¹⁷R¹⁸R¹⁹、GeR¹⁷R¹⁸R¹⁹Or SnR¹⁷R¹⁸R¹⁹And wherein R is¹⁷、R¹⁸And R¹⁹E.g., the same or different, and independently is an alkyl or aryl group. The preferred silyl boranes and acylsilanes may also be used with the general formula XSiR¹R²R³Wherein X is X ═ B (OR)^d)₂And X ═ C (O) RⁱWherein R isⁱIs an alkyl or aryl group.

In the case of disilanes, silylgermanes, silylstannanes, silylboranes and acylsilanes, the reaction can be carried out by irradiating the reaction mixture with UV light of a wavelength suitable for directly cleaving or sensitizing the Si-X bond. Additives known in the art, such as sensitizers or (photo-) electron transfer agents, may facilitate the desired reaction.

In the case of disilanes, the reaction can be chemically completed by generating reactive radicals that will homoscission (by homoscission substitution of silicon) the silicon-silicon bond to generate a silyl group. Preferred reactive radicals for this process are hydroxyl, alkoxy or acyloxy radicals, and preferred methods for generating these radicals are pyrolysis or photolysis of hydrogen peroxide, alkyl hydroperoxides, dialkyl peroxides, alkyl acyl peroxides or diacyl peroxides. Other methods such as pyrolysis or photolysis of alkyl subnitrites (hyponitrietes) to generate alkoxy groups are also suitable.

Silanes (XSiR) can also be chemically completed by the formation of reactive radicals¹R²R³X ═ H), which will homoscission (by homoscission replacing hydrogen) silicon-hydrogen bonds to form silyl groups. Preferred reactive radicals for this process are hydroxyl, alkoxy or acyloxy radicals, and preferred methods for generating these radicals are pyrolysis or photolysis of hydrogen peroxide, alkyl hydroperoxides, dialkyl peroxides, alkyl acyl peroxides or diacyl peroxides. Other methods such as pyrolysis or photolysis of alkyl nitrite suboxides to form alkoxy groups are also suitable.

Other silyl precursors and methods of generating silyl groups are well known to those skilled in the art. See, e.g., c.chatgiliologiclu, chem.rev.1995, 95, 1229, the disclosure of which is incorporated herein by reference. Essentially any of these precursors or methods can be used in the present invention.

On the other hand, the present invention generally provides a method for producing a silyl group SiR by reacting quinoline with a silyl group generator and a silyl group precursor¹R²R³Under conditions to synthesize a silyl-substituted quinoline (e.g., at position C4 of the quinoline structure). Quinoline is represented by the formula:

the silyl quinoline of the present invention is represented by the following formula;

in a preferred embodiment of the silyl addition to substituted quinolines, the present invention generally provides a process for 7-silylcamptothecin and 7-silylhomocamptothecin comprising the steps of: camptothecin having a hydrogen at the C7 positionOr the homocamptothecin with a silyl group generator and a silyl group precursor to form a silyl group SiR¹R²R³Under the conditions of (1) and (2).

The camptothecin precursors in the reactions of the invention can be obtained from natural sources, can be obtained by total synthesis by one of several methods, or can be obtained by modification of existing synthetic or natural camptothecin analogs. The homocamptothecin precursors in the reactions of the invention can likewise be obtained, for example, by semi-synthesis from camptothecin, by total synthesis, as described by Lavergne et al, or by modification of existing homocamptothecin analogs.

Substituents (e.g., R) on the camptothecin and homocamptothecin precursors of the invention⁴、R⁵、R⁶、R⁷、R⁸、R⁹And R¹⁰) Essentially any substituent known in the art may be used. However, the substituents on the camptothecin and homocamptothecin rings preferably do not react rapidly with the silyl groups of the present invention. In general, the reaction of a substituent with a silyl group of the present invention may result in undesirable by-products that may be difficult to separate from the desired product. Examples of suitable substituents include, but are not limited to, R as described above⁴、R⁵、R⁶、R⁷、R⁸、R⁹And R¹⁰. Examples of substituents that react rapidly with silyl groups and are preferably avoided include bromine and iodine.

Many groups, such as amino and hydroxyl groups, may be protected with protecting groups well known in the art prior to addition of the silyl group. Preferred hydroxyl protecting groups include, but are not limited to, acetate and trimethylsilyl. Preferred amino protecting groups include, but are not limited to, t-butyloxycarbonyl, formyl, acetyl, benzyl, p-methoxybenzyloxycarbonyl, trityl. Other suitable protecting Groups known to those skilled in the art are disclosed in Greene, t., Wuts, p.g.m., Protective Groups in organic Synthesis, Wiley (1991), the disclosure of which is incorporated herein by reference. These protecting groups can be reacted after the addition of the silyl group using conditions well known in the art to provide the desired substituent (e.g., hydroxyl or amino). In general, the protecting groups used in the methods of the invention are preferably selected so that they can be selectively removed without affecting other substituents on the camptothecin ring. In general, the 7-silyl substituent on camptothecin (including homocamptothecin) has been found to be very stable under a number of conditions.

The solvent for the reaction may be selected from a variety of conventional organic reaction solvents. Aromatic solvents (e.g., benzene and toluene) are less preferred because addition of silyl groups to the solvent can be a competitive side reaction. Chlorinated organic solvents like chloroform and tetrachloromethane are also less preferred because the abstraction of chlorine from the solvent by the silyl group may be a competitive side reaction. However, less reactive chlorinated organic solvents, such as 1, 2-dichloroethane, are more preferred. Other preferred solvents include ethers (e.g., Tetrahydrofuran (THF), diethyl ether, dioxane, etc.), alcohols (methanol, ethanol, etc.), and dipolar aprotic solvents (CH)₃CN, DMF, DMSO, etc.). Water need not be removed from the reaction and may even be used as a co-solvent.

Preferred reaction conditions for the formation of silyl groups from silanes include the addition of an organothiol (R)¹⁶SH, wherein R¹⁶Is, for example, alkyl or trialkylsilyl). For example, one set of reaction conditions includes heating camptothecin or a homocamptothecin analog, a silane (R) in an organic solvent¹R²R³SiH), peroxides (e.g., di-t-butyl peroxide), and mercaptans (e.g., t-butane mercaptan or triisopropyl silane mercaptan). The preferred amount of silane is about 1 to 20 equivalents, more preferably about 2 to 10 equivalents, relative to the camptothecin analog. The preferred amount of mercaptan is about 0.2 to 5 equivalents, with about 1 to 3 equivalents being more preferred. The preferred amount of peroxide is about 1 to 20 equivalents, with about 2 to 5 equivalents being more preferred. Preferred reaction solvents are as discussed above, and preferred reaction temperatures are about 60 to 130 ℃. Lower reaction temperatures may cause a decrease in product conversion, while higher temperatures may increase the amount of another product in which the silyl group is added to C12 of the camptothecin precursor (if this is doneR⁷H). The preferred solvent for these reaction conditions is p-dioxane, and the preferred temperature for the reaction in this solvent is at or near the reflux point of p-dioxane. The reaction time is preferably 0.5 to 5 days, and more preferably 1 to 2 days. Preferred mercaptans include, for example, alkanethiols such as dodecanethiol and tert-butanethiol, and trialkylsilane-or triarylsilane-thiols such as triisopropylsilane-thiol. Trialkylsilylthiol or triarylsilane thiols are generally more preferred.

Thiols are sometimes used in the radical chain reaction of silanes to aid in chain extension of the chain reaction in a process commonly referred to as "polarity inversion catalysis". The silyl addition found herein does not appear as a chain reaction, but the inventors have found that thiols can promote the reaction. In the case of camptothecin and homocamptothecin precursors bearing, for example, acid-labile substituents or protecting groups, the generally mild reaction conditions using thiols are advantageous.

Sillimanim and homosillimanim with a 10-hydroxyl group have particularly interesting biological and chemical properties. The process of the present invention is well suited for the synthesis of such 10-hydroxyciclazepam and 10-hydroxyhomocicletam. Since hydroxyl groups may interfere with silyl group formation or addition in a preceding or subsequent synthetic step, it may be desirable to use the above protecting groups, or to regenerate 10-hydroxyl group after 7-silyl group addition.

In another aspect, the invention provides a compound of the formula:

wherein R is¹-R¹⁰As defined above.

In another aspect, the invention provides that any R will be absent⁵Substituent (i.e. R)⁵Is H) to the 10-hydroxysertacol or 10-hydroxysertacol analog (i.e., R)⁵is-OH). R is to be⁵The conversion of hydrogen to-OH typically includes an oxidation step to provide the N-oxide, followed by a photolysis step. It has been found thatThe 7-silyl groups of cetuximab and homocetoman can be present under the oxidation and acidic reaction conditions employed. In a preferred embodiment of the invention, R⁴、R⁵And R⁷Is also H and the resulting product is 10-hydroxyciclazincan or homocicletan.

In this process, cilostan or gazeltan is preferably first oxidized to the N-oxide under conditions well known to those skilled in the art for such conversion. Preferred conditions are treatment of cetrimide or homocetrimide with hydrogen peroxide in the presence of a carboxylic acid, preferably acetic acid. The resulting mixture of N-oxides in the organic solvent is then irradiated with light (e.g., at the uv and visible edges of the spectrum) in the presence of an organic or inorganic acid. The preferred solvent for this reaction is an ether (e.g., p-dioxane). The wavelength of the irradiating light is preferably about 250 to 600 nm, and more preferably about 275 to 450 nm. The preferred acid used in the process is about 0.1 to 5M, preferably about 1.0M, aqueous sulfuric acid and the preferred amount of acid relative to cetrimide or homocetrimide is about 1 to 20 molar equivalents, more preferably about 1 to 2 molar equivalents.

As noted above, all compounds of the present invention, including the α -hydroxy lactone group of cilostam or the β -hydroxy lactone group of homocilostam, may exist in racemic form, enantiomerically enriched form, or enantiomerically pure form. The structural formulae of these compounds described herein encompass and/or include each form.

Unless otherwise specified, the terms "alkyl", "aryl" and other groups generally refer to both unsubstituted and substituted groups. Unless otherwise specified, alkyl is hydrocarbyl, and is preferably C₁-C₁₅(i.e., having 1 to 15 carbon atoms) alkyl, and more preferably C₁-C₁₀Alkyl, and may be branched or unbranched, acyclic or cyclic. The above definition and other definitions of alkyl also apply when a group is a substituent on another group (e.g., alkyl as a substituent of alkylamino or dialkylamino). The term "aryl" refers to phenyl or naphthyl. The term "halogen" or "halo" as used hereinBy "preferably is meant fluorine and chlorine.

The term "alkoxy" refers to-OR^dWherein R is^dIs an alkyl group. The term "aryloxy" refers to-OR^eWherein R is^eIs an aryl group. The term "acyl" refers to-C (O) R^f. The term "alkenyl" refers to a straight or branched chain hydrocarbon group having at least one double bond, preferably 2 to 15 carbon atoms, and more preferably 2 to 0 carbon atoms (e.g., -CH ═ CHR)^gor-CH₂CH＝CHR^g). The term "alkynyl" refers to a straight or branched chain hydrocarbon group having at least one triple bond, preferably 2 to 15 carbon atoms, and more preferably 2 to 10 carbon atoms (e.g., -C.ident.CR)^hor-CH₂-C≡CR^h). The terms "alkylene", "alkenylene", "alkynylene" refer to the divalent forms of alkyl, alkenyl, and alkynyl, respectively.

The above groups may be substituted with a variety of substituents to synthesize homocamptothecin analogs that retain activity. For example, alkyl groups may preferably be substituted with one or more groups including, but not limited to, benzyl, phenyl, alkoxy, hydroxy, amino (including, e.g., free amino, alkylamino, dialkylamino, and arylamino), alkenyl, alkynyl, and acyloxy. At the amino group (-NR)^aR^b) In the case of (1), preferably R^aAnd R^bIndependently hydrogen, acyl, alkyl or aryl. The acyl group may preferably be represented by (i.e. R)^fIs) alkyl, haloalkyl (e.g., perfluoroalkyl), aryl, alkoxy, amino, and hydroxy. Alkynyl and alkenyl groups may preferably be substituted with (i.e. R)^gAnd R^hPreferably) one or more of the following groups including, but not limited to, alkyl, alkoxyalkyl, aminoalkyl and benzyl.

The term "acyloxy", as used herein, refers to the group-OC (O) R^d。

The term "alkoxycarbonyloxy" as used herein refers to-OC (O) OR^d。

The term "carbamoyloxy" as used herein refers to-OC (O) NR^aR^b。

For purification, administration or other purposes, the E ring (lactone ring) may be opened with an alkali metal such as, but not limited to, sodium hydroxide or calcium hydroxide to form an E ring opened analog of the compound of formula (1) as given in the compound of formula (2). The intermediate thus obtained is more soluble in water and can be purified after treatment with acid to produce the purified form of the camptothecin analogs of the invention.

Drawings

FIG. 1 shows the chemical structures of camptothecin, homocamptothecin and several 7-silyl camptothecins and 7-silyl homocamptothecins.

FIG. 2 shows a general reaction sequence for the synthesis of 7-silylcamptothecin and 7-silylhomocamptothecin.

FIG. 3 shows the reaction of camptothecin to synthesize 7-tert-butyldimethylsilylcamptothecin and 12-tert-butyldimethylsilylcamptothecin with tert-butyldimethylsilane, di-tert-butyl peroxide and tert-butanethiol in dioxane.

FIG. 4 shows the general process for converting 7-silylcamptothecin and 7-silylhomocamptothecin to 10-hydroxy-7-silylcamptothecin and 10-hydroxy-7-silylhomocamptothecin.

FIG. 5 shows the conversion of 7-tert-butyldimethylsilylcamptothecin to 7-tert-butyldimethylsilyl-10-hydroxycamptothecin (DB-67).

Detailed Description

Substituents are typically added to the camptothecin ring by converting an existing functional group to another functional group. Introduction of new substituents by replacement of existing carbon-hydrogen bonds is more difficult. Sawada and coworkers used the Minisci reaction to replace the hydrogen with an alkyl group and a substituted alkyl group. See, Sawada, s., Okajima, s., Aiyama, r., Nokata, k., Furuta, t., Yokokura, t., Miyasaka, t.chem.pharm.bull, 39, 3183 (1991); sawada, s., Nokata, k., Furuta, t., Yokokura, t., Miyasaki, t.chem.pharm.bull, 39, 2574 (1991); and Minisci, f., viscara, e., Fontana, f.heterocycles, 28, 489 (1989). In that regard, the alkyl aldehydes are oxidized with peroxides and iron salts in the presence of camptothecin derivatives, typically under strongly acidic conditions, to provide 7-alkyl substituted camptothecin derivatives. This reaction is believed to occur via an intermediate (intermediacy) redox chain mechanism involving an acyl group that is decarbonylated to form an alkyl group. These alkyl groups then add to camptothecin.

However, the Sawada/Minisci method for the addition of alkyl groups to camptothecin C7 is not suitable for the addition of silyl groups. Essential silyl precursors, e.g. Me₃SiCHO, which is difficult to synthesize and is generally highly unstable. For example, many such precursors spontaneously ignite when exposed to air. These compounds have little or no preparative utility and cannot exist under the vigorous reaction conditions of the Sawada/Minisci pathway.

However, the present invention provides a new semi-synthetic route in which silyl groups are added to the C7 position of the quinoline or B ring of camptothecin and homocamptothecin and/or the C12 position of the A ring of camptothecin and homocamptothecin. In that regard, the inventors of the present invention have found that the important 7-silyl camptothecins and 7-silyl homocamptothecins can be prepared by reacting an existing camptothecin or homocamptothecin compound with a compound of the formula XSiR¹R²R³The known silyl precursors are synthesized by reacting under suitable reaction conditions as described above. The general reaction sequence for the synthesis of 7-silylcamptothecin and 7-silylhomocamptothecin is given in FIG. 2. The reaction mixture is worked up by standard methods (workup) and the crude reaction product is purified by, for example, chromatography, crystallization or other standard methods to provide 7-silylcamptothecin (cetuximab, n ═ 0) and 7-silylhomocamptothecin (gacet, n ═ 1).

Using silanes (HSiR)¹R²R³) As before the silyl groupSeveral representative studies of the body are described in the discussion of the methods of the invention herein. In the case of silanes used as silyl precursors in the process of the present invention, certain thiols (R) were found¹⁶SH) has a very beneficial effect as an additive. The results of several experiments are summarized in table 1 and fig. 3. For example, camptothecin 1a, tert-butyldimethylsilane (10 equivalents), di-tert-butylperoxide (1.7 equivalents) and tert-butanethiol (2 equivalents) were heated to reflux in dioxane for 36 hours (table 1, entry 1), followed by chromatographic separation to give (in order of elution) 7-tert-butyldimethylsilylcamptothecin 2b (20%), 12-tert-butyldimethylsilylcamptothecin 3b (10%), and recovered camptothecin 1a (57%). 7-tert-Butyldimethylsilylcamptothecin 2b was consistent with an authentic sample prepared by total synthesis. 12-tert-butyldimethylsilylcamptothecin preparation of pharmaceutical compositions¹And H NMR experiment identification.

TABLE 1 thiol-promoted^tBuSi(Me₂) Addition of H to camptothecin

Item 1234

ThiolstBuSHtC12H25SH(iPr)3SiSH(iPr)3SiSH

The temperature is 105 ℃, 160 ℃ and

yield 2b 22% 5% 23% a

Yield 3b 10% 4% 11% 22%

Recovered 1a 57% 70% 60% 20%

^aTLC analysisAnalyzing and detecting trace product

Two other thiols were also studied under similar conditions and the results are listed in table 1, entries 2-3. The results with tert-dodecyl mercaptan are generally inferior to tert-butyl mercaptan. The results with triisopropylsilanethiol were similar to tert-butanethiol.

Solvent selection is generally limited by the solubility of camptothecin. The reaction in DMSO and t-butanol was inferior to that of dioxane. Heating the reaction to 160 ℃ provided predominantly the 12-silyl isomer with a significantly reduced amount of recovered camptothecin (see, e.g., entry 4 in table 1).

Thiols are known to promote hydrogen abstraction from silanes. Although the overall mechanism of silyl addition to camptothecin and homocamptothecins is not clear, it is speculated that t-butyl peroxide decomposes to t-butyl peroxy radicals, which in turn abstract hydrogens from silanes, thiols, and/or solvents. Because the solvent is present in excess, it may react frequently. The resulting dioxanes may abstract hydrogen atoms from the mercaptans which in turn abstract hydrogen atoms from the silane during the transfer. Silyl addition then occurs competitively at the C7 and C12 positions, followed by oxidative re-aromatization. The general effectiveness of the reaction conditions of the present invention is demonstrated by heating a series of silanes with triisopropylsilane mercaptan at the reflux point of dioxane or heating a series of silanes with tert-butylmercaptan in sealed tubes at 105 ℃ or 160 ℃. Initial observations with t-butyldimethylsilane were quite common. At lower temperatures (Table 2, entries 1-6), 7-silyl isomer 2 and a lesser amount of 12-silyl isomer 3 (7-19%) were isolated in 20-30% yield. The bulk of the balance was recovered camptothecin, which was reused in subsequent experiments. At higher temperatures (Table 2, entries 7-10), little or no 7-silyl isomer 2 was observed, while 12-silyl isomer 3 was isolated in 22-37% yield, with only 10-20% of the camptothecin recovered.

TABLE 2 addition of silyl groups to camptothecin at Low (105 ℃) or high (160 ℃) temperatures

Item(s)	Silane (R)1R2R3SiH) silyl group	Temperature of	7-silyl isomer (C7 ═ silyl, C12 ═ H)		12-silyl isomer (C7 ═ H, C12 ═ silyl)		Recovery of 1
								12345678910	Et3SiiPrSi(Me)2(iPr)3SiPhSi(Me)2c-C6H11Si(Me)2Et2SiMeEt3SiiPrSi(Me)2c-C6H11Si(Me)2Et2SiMe	105℃105℃105℃105℃105℃105℃160℃160℃160℃160℃	2c2d2e2f2g2h2c2d2g2h	23％31％22％23％22％20％aaaa	3c3d3e3f3g3h3c3d3g3h	11％8％15％7％19％8％36％30％26％26％	57％61％63％65％50％67％17％19％10％10％

^aTrace product detected by TCL.

The camptothecin free radical silylation condition is established, and the semi-synthesis is applied to the synthesis of DB-67(2 a). In one study, first hydrogenation by Pt catalysis, followed by PhI (OAc)₂Oxidation of 10-hydroxycamptothecin from camptothecin. The silylation conditions described above were then applied to 10-hydroxycamptothecin. The reaction gave a 14% yield of the product mixture containing the desired DB-672a, based on comparison with the TCL of an authentic sample. However, it is difficult to separate the desired product from the product mixture.

Thus, the present invention also provides a two-step conversion of 7-silylcamptothecin or 7-silylhomocamptothecin to 10-hydroxy-7-silylcamptothecin or 10-hydroxy-7-silylhomocamptothecin, as shown in FIG. 4. The sillcan or homosillcan derivative 6 is first oxidized to the N-oxide under conditions well known to those skilled in the art for such conversion. Preferred conditions are treatment 6 with hydrogen peroxide in the presence of a low boiling carboxylic acid, preferably acetic acid. The resulting mixture of N-oxides 7 in organic solvent is then irradiated with light (e.g. at the uv and visible edges of the spectrum) in the presence of an organic or inorganic acid.

Thus, the 10-hydroxy group of DB-67 can also be added after the step of silyl addition to the unsubstituted camptothecin. Camptothecin is readily available in large quantities. Using the procedure described above, it is now readily converted to 7-tert-butyldimethylsilylcamptothecin 2b in about 20% yield and a very large amount (57%) of unreacted camptothecin is recovered. 7-tert-butyldimethylsilylcamptothecin can be converted to DB-67 according to the methods described in FIGS. 4 and 5. In that regard, oxidation of 2b with hydrogen peroxide in glacial acetic acid at 75 ℃ provided the corresponding N-oxide 4 in 81% yield. Photolysis 4 was irradiated with a high pressure mercury lamp in dioxane containing 1N aqueous sulfuric acid at room temperature to provide DB-67 in 58% yield, which was identical to the DB-67 sample prepared by total synthesis. This semi-synthesis proceeds in a total yield of about 10% of three steps, excluding the camptothecin recovered from the first step.

In general, the studies of the present invention show that the silyl addition to camptothecin in the process of the present invention occurs predominantly at the C7 or C12 position, depending on the temperature, and that it can be promoted by additives, e.g., thiols. This reaction is a key step in the short semi-synthesis of cilostan (e.g., DB-67) or homocilostan, which is significantly shorter and has higher yields than the full synthesis, e.g., the cascade free radical ring-building pathway. The increased availability of these sillimanimes and homosillimanimes should facilitate their development as antitumor agents.

Examples

Example 1a general procedure for thiol-promoted synthesis of 7-silyl camptothecin 2

To a suspension of camptothecin 1a (50 mg, 0.14 mmol) in p-dioxane (15 ml) was added the corresponding silane (0.8 ml), triisopropylsilanethiol (50 μ l, 0.23 mmol) and di-tert-butyl peroxide (50 μ l, 0.27 mmol). The mixture was then refluxed under argon for 36 hours, cooled and evaporated under reduced pressure. The brown residue was suspended in CH₂Cl₂Neutralized and applied to a silica gel column. Flash Chromatography (CH)₂Cl₂Then is used in CH₂Cl₂Acetone 5% of) in order of elution to give 7-silylcamptothecin 2, 12-silylcamptothecin 3 and unreacted camptothecin.

Example 1 b.7-tert-Butyldimethylsilylcamptothecin (2b)

Using general procedure 1a, 15 mg of the title compound was prepared from camptothecin (50 mg, 0.14 mmol) as a yellow solid in 23% yield. The reaction also yielded 12-tert-butyldimethylsilylcamptothecin 3b (7 mg, yield 11%) and recovered camptothecin (30 mg, 60%). [ alpha ] to]₂₀ ^D=+47.2(c 2.87，CH₂Cl₂)；IR 3357(br)，2930，2857，1750，1659，1595，1465，1378，1265，1226，1157，1047，832，728；¹H NMR(300MHz，CDCl₃)δ0.714(s，6H)，1.00(s，9H)，1.05(t，J＝7.5Hz，3H)，1.91(m，2H)，3.76(s，1H)，5.37(d，J＝16.2Hz，1H)，5.33(s，2H)，5.77(d，J＝16.2，1H)，7.63(td，J＝9.0，1.5Hz，1H)，7.68(s，1H)，7.79(td，J＝7.5，1.5Hz，1H)，8.23(d，J＝7.5Hz，1H)，8.24(d，J＝9.0Hz，1H)；¹³CNMR(CDCl₃125MHz) delta-0.6, 7.8, 19.2, 27.1, 31.6, 52.4, 66.3, 72.8, 97.7, 127.0, 129.4, 129.6, 130.8, 132.7, 136.0, 143.0, 146.4, 148.0, 150.2, 157.4, 173.9; HRMSm/z calculation C₂₆H₃₀N₂O₄Si462.1975, experimental 462.1970.

EXAMPLE 1c.7 Triethylsilylcamptothecin (2c)

Using general procedure 1a, 8.8 mg of the title compound was prepared from camptothecin (22 mg, 0.06 mmol) as a yellow solid in 30% yield. The reaction also yielded 12-triethylsilylcamptothecin 3c (3.1 mg, yield 11%) and recovered camptothecin (12.5 mg, 57%). [ alpha ] to]₂₀ ^D＝+38.1(c 0.26，CH₂Cl₂)；¹H NMR(CDCl₃300MHz) δ 0.99(t, J ═ 7.9Hz, 9H), 1.05(t, J ═ 7.5Hz, 3H), 1.13(q, J ═ 7.9Hz, 6H), 1.93(m, 2H), 3.76(s, 1H), 5.32(d, J ═ 16.2Hz, 1H), 5.33(s, 2H), 5.77(d, J ═ 16.2, 1H), 7.65(td, J ═ 7.5, 1.2Hz, 1H), 7.68(s, 1H), 7.80(td, J ═ 7.4, 0.8Hz, 1H), 8.24(d, J ═ 6Hz, 1H), 8.26(d, J ═ 7.2Hz, 1H); HRMSm/z calculation C₂₆H₃₀N₂O₄Si462.1975, experimental 462.1985.

Example 1 d.7-Isopropyldimethylsilylcamptothecin (2d)

Using general procedure 1a, 22 mg of the title compound was prepared from camptothecin (50 mg, 0.14 mmol) as a yellow solid in 31% yield. The reaction also yielded 12-isopropyldimethylsilylcamptothecin 3d (6 mg, yield 8%) and recovered camptothecin (33.2 mg, 57%). [ alpha ] to]₂₀ ^D＝+42.1(c 1.01，CH₂Cl₂)；¹H NMR(CDCl₃，300MHz)δ0.65(s，6H)，1.00(d，J＝7.4Hz, 3H), 1.02(d, J ═ 7.4Hz, 3H), 1.05(t, J ═ 7.3Hz, 3H), 1.49(hep, 7.4Hz, 1H), 1.91(m, 2H), 5.32(d, J ═ 16.2Hz, 1H), 5.33(s, 2H), 5.76(d, J ═ 16.2, 1H), 7.65(ddd, J ═ 8.4, 6.7, 1.1Hz, 1H), 7.74(s, 1H), 7.81(ddd, J ═ 8.4, 7.1, 1.1Hz, 1H), 8.23(d, J ═ 8.4Hz, 1H), 8.24(d, J ═ 8.4Hz, 1H); HRMSm/z calculation C₂₅H₂₈N₂O₄Si448.1818, experimental 448.1815.

Example 1 e.7-Tripropylsilylcamptothecin (2e)

Using general procedure 1a, 16.6 mg of the title compound was prepared from camptothecin (50 mg, 0.14 mmol) as a yellow solid in 22% yield. The reaction also yielded 12-tripropylsilyl camptothecin 3e (11.2 mg, 15%) and recovered camptothecin (63%). [ alpha ] to]₂₀ ^D＝+39.4(c0.49，CH₂Cl₂)；IR3325(br)，2956，2927，2869，1750，1659，1596，1556，1224，1157，1056，762，728；¹H NMR(CDCl₃，500MHz)δ0.98(t，J＝7.2Hz，9H)，1.03(t，J＝7.4Hz，3H)，1.15(m，6H)，1.35(m，6H)，1.91(m，2H)，3.75(s，1H)，5.32(d，J＝16.3Hz，1H)，5.33(s，2H)，5.77(d，J＝16.3，1H)，7.65(td，J＝8.2，1.3Hz，1H)，7.68(s，1H)，7.80(td，J＝8.0，0.9Hz，1H)，8.24(d，J＝6.7Hz，1H)，8.27(d，J＝7.4Hz，1H)；¹³CNMR(CDCl₃125MHz) delta 7.9, 16.7, 17.8, 18.4, 31.7, 52.0, 66.5, 72.9, 97.8, 18.2, 27.4, 128.0, 129.8, 131.2, 132.6, 135.7, 143.4, 146.6, 147.9, 150.2, 150.9, 157.6, 174.1; HRMSm/z calculation C₂₉H₃₆N₂O₄Si504.2444, experimental value 504.2467.

Example 1 f.7-Phenyldimethylsilylcamptothecin (2f)

Using general procedure 1a, 16 mg of the title compound was prepared from camptothecin (50 mg, 0.14 mmol) as a yellow solid in 23% yield. The reaction also yielded 12-phenyldimethylsilylcamptothecin 3f (4.6 mg, 7%) and recoveredCamptothecin (65%). [ alpha ] to]₂₀ ^D＝+44.9(c0.74，CH₂Cl₂)；¹H NMR(300MHz，CDCl₃) δ 0.90(s, 6H), 1.03(t, J ═ 7.5Hz, 3H), 1.88(m, 2H), 4.95(s, 2H), 5.27(d, J ═ 16.4Hz, 1H), 5.71(d, J ═ 16.4, 1H), 7.37-7.59(m, 6H), 7.74(s, 1H), 7.77(t, J ═ 7.2, 1H), 8.14(d, J ═ 8.5Hz, 1H), 8.29(d, J ═ 8.4Hz, 1H); HRMSm/z calculation C₂₈H₂₆N₂O₄Si482.1662, experimental value 482.1663.

Example 1 g.7-Cyclohexyldimethylsilylcamptothecin (2g)

Using general procedure 1a, 16.3 mg of the title compound was prepared from camptothecin (50 mg, 0.14 mmol) as a yellow solid in 22% yield. The reaction also yielded 3g (19.4 mg, 19%) of 12-cyclohexyldimethylsilylcamptothecin and recovered camptothecin (50%). [ alpha ] to]₂₀ ^D＝+27.9(c 0.48，CH₂Cl₂)；IR 3313(br)，2919，2845，1749，1658，1596，1556，1446，1256，1225，1157，1047，910，728；¹H NMR(500MHz，CDCl₃)δ0.64(s，6H)，1.05(t，J＝7.4Hz，3H)，1.21(m，6H)，1.66(m，5H)，1.88(m，2H)，3.79(s，2H)，5.31(s，2H)，5.31(d，J＝16.3Hz，1H)，5.76(d，J＝16.3，1H)，7.64(td，J＝7.3，0.9Hz，1H)，7.67(s，1H)，7.79(t，J＝7.2，1H)，8.21(d，J＝8.0Hz，1H)，8.23(d，J＝7.4Hz，1H)；¹³C NMR(CDCl₃125MHz) delta-1.4, 7.9, 26.6, 26.7, 27.5, 27.8, 31.7, 52.2, 66.5, 72.9, 97.8, 118.3, 127.3, 128.5, 129.8, 131.2, 132.4, 135.6, 143.6, 146.6, 148.0, 150.2, 150.8, 157.6, 174.1; HRMSm/z calculation C₂₈H₃₂N₂O₄Si488.2131, experimental value 488.2155.

Example 1 h.7-Diethylmethylsilylcamptothecin (2h)

Using general procedure 1a, 13.1 mg of the title compound was prepared as a yellow solid from camptothecin (50 mg, 0.14 mmol) in 20% yield. The reaction also yielded 12-diethylmethylsilylcamptothecin for 3h (5.2 mg, 8%) and recovered camptothecin (67%). [ alpha ] to]₂₀ ^D＝+50.0(c0.23，CH₂Cl₂)；IR3319(br)，2959，2876，1748，1658，1595，1557，1225，1157，1047，727；¹H NMR(500MHz，CDCl₃)δ0.67(s，3H)，0.95-1.19(m，13H)，1.90(m，2H)，3.77(s，1H)，5.31(d，J＝16.2Hz，1H)，5.33(s，2H)，5.76(d，J＝16.2，1H)，7.64(td，J＝8.2，1.0Hz，1H)，7.68(s，1H)，7.79(td，J＝8.2，0.9Hz，1H)，8.23(d，J＝8.7Hz，2H)；¹³C NMR(CDCl₃125MHz) delta-2.7, 7.5, 7.7, 7.9, 31.7, 52.1, 66.5, 72.9, 97.8, 118.3, 127.4, 128.1, 129.8, 131.1, 132.4, 135.7, 143.0, 146.6, 148.0, 150.2, 150.9, 157.6, 174.1; HRMSm/z calculation C₂₅H₂₈N₂O₄Si448.1818, experimental 448.1815.

Example 1i. (. + -.) 7-tert-Butyldimethylsilylhomocamptothecin

Using general procedure 1a, the title compound was prepared in 10% yield with an additional 62% recovery of (±) hCPT;¹H NMR(300MHz，CDCl₃)δ0.73(s，6H)，0.99(t，7.5Hz，3H)，1.03(s，9H)，2.05(m，2H)，3.21(d，13.6Hz，1H)，3.48(d，13.6Hz，1H)，5.23(d，19Hz，1H)，5.36(d，15.3Hz，1H)，5.39(d，19Hz，1H)，5.71(d，15.3Hz，1H)，7.46(s，1H)，7.55(m，1H)，7.65(m，1H)，7.99(d，8.6Hz，1H)，8.18(d，8.0Hz，1H)。

EXAMPLE 1j silylation of CPT-N-oxide

Using general procedure 1a, camptothecin-N-oxide (30 mg, 0.08 mmol) gave 7-tert-butyldimethylsilylcamptothecin (8 mg, 20% yield) and camptothecin (17 mg, 60%). 12-tert-butyldimethylsilylcamptothecin was observed in TLC and isolated as a mixture with other by-products.

Example 2a general procedure for the thiol-promoted synthesis of 12-silyl camptothecin

To a suspension of camptothecin 1a (20 mg, 0.057 mmol) in dioxane (2 ml) in pressure tube was added the corresponding silane (0.5 ml), followed by 20 μ l di-tert-butyl peroxide (20 μ l, 0.09 mmol) and 20 μ l triisopropylsilanethiol (20 μ l, 0.11 mmol). The pressure tube was then sealed and heated to 160 ℃ for 16 hours. After evaporation of the volatile components, the residue is chromatographed by flash chromatography (on CH)₂Cl₂Acetone 5% of) on silica gel column to give 12-silylcamptothecin 3 and recovered camptothecin.

Example 2 b.12-tert-Butyldimethylsilylcamptothecin (3b)

Using general procedure 2a, 5.8 mg of the title compound was prepared as a yellow solid from camptothecin (20 mg, 0.057 mmol) in 22% yield, additionally yielding recovered camptothecin (20%). [ delta ] is]₂₀ ^D＝+75.0(c 0.04，CH₂Cl₂)；IR 3380(br)，2927，2854，1747，1658，1602，1557，1487，1401，1247，1223，1157，1046，840，769，732；¹H NMR(500MHz，CDCl₃)δ0.56(s，6H)，0.98(s，9H)，1.06(t，J＝7.4Hz，3H)，1.94(m，2H)，3.76(s，1H)，5.31(s，2H)，5.32(d，J＝16.1Hz，1H)，5.77(d，J＝16.1，1H)，7.54(s，1H)，7.64(t，J＝7.4Hz，1H)，7.93(d，J＝7.4Hz，1H)，8.00(d，J＝7.4Hz，1H)，8.37(s，1H)；¹³C NMR(125MHz，CDCl₃) Delta-33, 7.8, 17.7, 27.7, 31.5, 50.3, 66.5, 72.8, 97.7, 118.3, 127.4, 127.9, 129.3, 131.3, 138.6, 141.1, 147.1, 150.3, 151.1, 153.3, 157.8, 174.1; HRMSm/z calculation C₂₆H₃₀N₂O₄Si462.1975, experimental 462.1972.

Example 2 c.12-Triethylsilylcamptothecin (3c)

Using general procedure 2a, 9.8 mg of the title compound was prepared as a yellow solid from camptothecin (20 mg, 0.057 mmol) in 37% yield, and recovered camptothecin was additionally obtainedBase (19%). [ delta ] is]₂₀ ^D＝+16.1(c 0.33，CH₂Cl₂)；IR 2926，2874，1744，1659，1603，1557，1463，1224，1157，908，733；¹H NMR(500MHz，CDCl₃)δ0.97(t，J＝7.5Hz，9H)，1.08(m，6H)，1.06(t，J＝7.4Hz，3H)，1.93(m，2H)，3.79(s，1H)，5.31(s，2H)，5.33(d，J＝16.2Hz，1H)，5.78(d，J＝16.2Hz，1H)，7.54(s，1H)，7.63(dd，J＝7.9，6.9Hz，1H)，7.92(d，J＝7.9Hz，1H)，7.96(d，J＝6.9Hz，1H)，8.37(s，1H)；¹³C NMR(125MHz，CDCl₃) δ 4.4, 7.8, 29.8, 31.6, 50.2, 66.5, 72.8, 97.5, 118.3, 127.5, 127.8, 128.0, 129.1, 131.4, 138.3, 140.2, 147.2, 150.3, 151.2, 153.3, 157.8, 174.0; calculated HRMSm/z

C₂₆H₃₀N₂O₄Si462.1975, experimental 462.1973.

Example 2 d.12-Isopropyldimethylsilylcamptothecin (3d)

Using general procedure 2a, 7.7 mg of the title compound was prepared from camptothecin (20 mg, 0.057 mmol) as a light yellow solid in 30% yield, yielding additionally recovered camptothecin (19%). [ alpha ] to]₂₀ ^D＝+62.5(c 0.04，CH₂Cl₂)；IR 3346(br)，2945，2863，1747，1657，1602，1558，1486，1401，1245，1223，1157，1046，1002，909，841，767，732；¹H NMR(500MHz，CDCl₃)δ0.48(s，6H)，0.98(d，J＝7.4Hz，3H)，1.0(d，J＝7.4Hz，3H)，1.06(t，J＝7.4Hz，3H)，1.49(m，1H)，1.92(m，2H)，3.78(s，1H)，5.30(s，2H)，5.32(d，J＝16.2Hz，1H)，5.77(d，J＝16.2Hz，1H)，7.52(s，1H)，7.62(dd，J＝7.9，6.8Hz，1H)，7.92(d，J＝7.9Hz，1H)，7.97(d，J＝6.8Hz，1H)，8.37(s，1H)；¹³C NMR(125MHz，CDCl₃) δ -3.8, -3.6, 7.9, 14.0, 18.1, 31.5, 50.2, 66.5, 72.8, 96.2, 118.3, 127.5, 127.8, 128.0, 129.2, 131.4, 137.8, 141.5, 147.1, 150.4, 151.1, 153.1, 157.8, 174.0; calculated HRMSm/zC₂₅H₂₈N₂O₄Si448.1818, experimental 448.1815.

Example 2 e.12-Tripropylsilylcamptothecin (3e)

This compound was isolated from the reaction described in example 1e. [ alpha ] to]₂₀ ^D＝+13.2(c 0.79，CH₂C1₂)；IR 3348，2961，2926，2873，1755，1661，1603，1491，1462，1403，1374，1333，1228，1163，1064，1005，841；¹H NMR(300MHz，CDCl₃)δ0.95(t，J＝7.1Hz，3H)，1.05-1.12(m，9H)，1.38(m，6H)，1.93(m，2H)，3.75(s，1H)，5.31(s，2H)，5.33(d，J＝16.3Hz，1H)，5.78(d，J＝16.3Hz，1H)，7.56(s，1H)，7.62(dd，J＝8.1，6.7Hz，1H)，7.91(dd，J＝8.1，1.0Hz，1H)，7.95(dd，J＝6.7，1.3Hz，1H)，8.36(s，1H)；¹³C NMR(125MHz，CDCl₃) δ 7.8, 16.5, 17.9, 18.8, 31.6, 50.3, 66.5, 72.8, 97.6, 118.3, 127.5, 127.8, 128.0, 129.1, 131.3, 137.9, 141.1, 147.1, 150.3, 151.2, 153.3, 157.85, 174.2; HRMSm/z calculation C₂₉H₃₆N₂0₄Si504.2444, experimental value 504.2450.

Example 2 f.12-Dimethylphenylsilylcamptothecin (3f)

This compound was isolated from the reaction described in example 1f. [ alpha ] to]₂₀ ^D＝+11.3(c 0.53，CH₂Cl₂)；IR 3365，2973，2961，1750，1666，1604，1559，1492，1251，1234，1155，1110，1049，830；¹H NMR(300MHz，CDCl₃)δ0.83(s，6H)，1.09(t，J＝7.4Hz，3H)，1.94(m，2H)，3.80(s，1H)，5.24(s，2H)，5.32(d，J＝16.3Hz，1H)，5.76(d，J＝16.3Hz，1H)，7.37(m，3H)，7.53(s，1H)，7.59(dd，J＝7.5，7.4Hz，1H)，7.78(m，2H)，7.89(m，2H)，8.30(s，1H)；¹³C NMR(125MHz，CDCl₃)δ-1.3，7.9，31.6，33.9，50.2，66.5，72.8，97.7，118.4，127.6，127.8，128.1，129.0，129.6，131.3，134.5，138.0，139.1, 141.0, 146.9, 150.3, 151.2, 152.9, 157.8, 174.1; HRMSm/z calculation C₂₈H₂₆N₂O₄Si482.1662, experimental value 482.1684.

Example 2 g.12-Cyclohexyldimethylsilylcamptothecin (3g)

Using general procedure 2a, 7.3 mg of the title compound was prepared from camptothecin (20 mg, 0.057 mmol) as a light yellow solid in 26% yield, additionally yielding recovered camptothecin (10%). [ alpha ] to]₂₀ ^D＝+33.3(c 0.09，CH₂Cl₂)；IR 3363(br)，2918，2845，1745，1657，1602，1558，1486，1401，1245，1223，1157，1046，909，837，768，732；¹H NMR(500MHz，CDCl₃)δ0.46(s，6H)，1.07(t，J＝7.3Hz，3H)，1.18(br，6H)，1.67(br，5H)，1.94(m，2H)，3.76(s，1H)，5.30(s，2H)，5.32(d，J＝16.2Hz，1H)，5.77(d，J＝16.2Hz，1H)，7.56(s，1H)，7.62(t，J＝7.4Hz，1H)，7.91(d，J＝7.4Hz，1H)，7.95(d，J＝7.4Hz，1H)，8.36(s，1H)；¹³C NMR(125MHz，CDCl₃) Delta-3.4, 7.8, 26.4, 27.1, 28.1, 28.4, 31.5, 50.3, 66.5, 72.8, 97.6, 118.3, 127.5, 127.8, 128.0, 129.1, 131.3, 137.7, 141.6, 147.1, 150.3, 151.1, 153.1, 157.8, 174.2; HRMSm/Calculation C₂₈H₃₂N₂O₄Si488.2131, experimental value 488.2133.

Example 2 h.12-Diethylmethylsilylcamptothecin (3h)

Using general procedure 2a, 7 mg of the title compound was prepared from camptothecin (20 mg, 0.057 mmol) as a light yellow solid in 26% yield, which additionally yielded the recovered camptothecin (10%). [ alpha ] to]₂₀ ^D＝+50.0(c 0.05，CH₂Cl₂)；IR 3389(br)，2953，2874，1746，1659，1602，1555，1486，1402，1223，1157，1046，1004，908，838，787，732；¹H NMR(500MHz，CDCl₃)δ0.48(s，3H)，0.9-1.1(m，13H)，1.96(m，2H)，3.79(s，1H)，5.31(s，2H)，5.33(d，J＝16.2Hz，1H)，5.78(d，J＝16.2Hz，1H)，7.53(s，1H)，7.63(t，J＝7.4Hz，1H)，7.92(d，J＝7.4Hz，1H)，7.97(d，J＝7.4Hz，1H)，8.37(s，1H)；¹³C NMR(125MHz，CDCl₃δ -4.5, 6.5, 7.9, 31.6, 50.2, 66.5, 72.8, 97.4, 118.3, 127.5, 127.8, 128.0, 129.2, 131.4, 137.8, 141.0, 147.2, 150.4, 151.1, 153.2, 157.8, 174.0; HRMSm/z calculation C₂₅H₂₈N₂O₄Si448.1818, experimental 448.1824.

Example 3.7-tert-Butyldimethylsilylcamptothecin N-oxide (4)

To a solution of 7-tert-butyldimethylsilylcamptothecin (50 mg, 0.11 mmol) in glacial acetic acid (10 ml) was added 30% H₂O₂(0.8 ml, 7 mmol). The solution was then gently heated at 75 ℃ for 3 hours and evaporated to dryness under reduced pressure. The orange residue was chromatographed by flash chromatography (on CH)₂Cl₂15% acetone) on silica gel to give 40.3 mg of 7-tert-butyldimethylsilylcamptothecin-N-oxide as a pale orange powder in 81% yield. [ alpha ] to]₂₀ ^D＝+10.0(c 0.46，CH₂Cl₂)；IR3342(br)，2933，2884，2857，1750，1654，1596，1557，1499，1464，1258，1224，1160，1090，821；¹H NMR(CDCl₃，300MHz)δ0.71(s，6H)，1.00(s，9H)，1.06(t，J＝7.2Hz，3H)，1.88(m，2H)，5.28(d，J＝16.8Hz，1H)，5.32(s，2H)，5.72(d，J＝16.8，1H)，7.69(t，J＝7.7Hz，1H)，7.79(t，J＝7.8Hz，1H)，8.26(d，J＝8.4Hz，1H)，8.40(s，1H)，8.84(d，J＝8.4Hz，1H)；¹³C NMR(CDCl₃125MHz) delta-0.2, 0.0, 8.2, 19.8, 27.5, 32.1, 53.4, 66.4, 73.0, 103.1, 119.7, 129.0, 130.2, 130.4, 131.3, 134.9, 136.2, 138.3, 141.0, 141.4, 150.8, 157.2, 173.8, 207.5; HRMSm/z calculation C₂₆H₃₀N₂O₅Si478.1924, experimental 478.1902.

EXAMPLE 4 preparation of 10-hydroxy-7-tert-butyldimethylsilylcamptothecin by photolysis (2a)

A 100 ml pyrex glass round bottom flask was charged with 7-tert-butyldimethylsilylcamptothecin-N-oxide (36 mg, 0.075 mmol) and degassed dioxane (30 ml). Then 1N H was added to the solution₂SO₄Aqueous solution (80 μ l, 0.08 mmol). The resulting solution was photolyzed for 80 minutes by a high pressure mercury lamp. The reaction mixture was then evaporated to dryness and chromatographed by flash chromatography (on CH)₂Cl₂20% acetone) on silica gel to give a mixture of 9.8 mg of 7-tert-butyldimethylsilylcamptothecin and unreacted 7-tert-butyldimethylsilylcamptothecin-N-oxide, and 20.7 mg of the title compound in 58% yield as a yellow powder. [ alpha ] to]₂₀ ^D＝+22.8(c 1.89，CH₂Cl₂/MeOH 4∶1)；¹HNMR(CDCl₃，300MHz)δ0.68(s，6H)，0.96(s，9H)，1.03(t，J＝7.2Hz，3H)，1.88(m，2H)，3.77(br，1H)，5.31(d，J＝16.2Hz，1H)，5.31(s，2H)，5.75(d，J＝16.2，1H)，7.47(dd，J＝9.0，1.8Hz，1H)，7.61(d，J＝1.8Hz，1H)，7.78(s，1H)，8.22(d，J＝9.0Hz，1H)；HRMS(-CO₂) Calculated m/z value C₂₅H₃₀N₂O₃Si434.2026, experimental 434.2009.

While the invention has been described in detail in connection with the above embodiments, it is to be understood that such detail is solely for that purpose and that variations can be made therein by those skilled in the art without departing from the spirit of the invention except as it may be limited by the claims.

Claims (39)

1. A process for the synthesis of 7-silylcamptothecin and 7-silylhomocamptothecin, said process comprising the steps of: camptothecin or homocamptothecin having hydrogen at C7 position, a silyl group generator and a silyl group precursor are reacted to generate a silyl group SiR¹R²R³Under the conditions of (1) wherein R¹、R²And R³Independently is C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, aryl, - (CH)₂)_mR¹¹Or SiR¹²R¹³R¹⁴Wherein m is 1An integer of to 10, and R¹¹Is hydroxy, alkoxy, amino, alkylamino, dialkylamino, F, Cl, cyano, -SR^cOr nitro, and wherein R¹²、R¹³And R¹⁴The same or different, and independently is an alkyl group or an aryl group.

2. The process of claim 1 wherein the silyl precursor is represented by the formula XSiR¹R²R³Wherein X is H, SiR¹⁷R¹⁸R¹⁹、GeR¹⁷R¹⁸R¹⁹、SnR¹⁷R¹⁸R¹⁹、-B(OR^d)₂or-C (O) RⁱWherein R is¹⁷、R¹⁸And R¹⁹Independently is aryl or alkyl, and wherein RⁱIs alkyl or aryl.

3. The method of claim 2, wherein X is H or SiR¹⁷R¹⁸R¹⁹And the radical generator is a peroxide, and the silyl group is generated in the presence of a thiol.

4. The method of claim 3, wherein the camptothecin is unsubstituted camptothecin, R¹And R²Is methyl, and R³Is a tert-butyl group.

5. The process of claim 4, further comprising the step of substituting the hydrogen at C10 of the resulting 7-tert-butyldimethylsilylcamptothecin with OH.

6. The method of claim 5, wherein the step of replacing the hydrogen at C10 with OH comprises an oxidation step to provide an N-oxide, followed by a photolysis step.

7. The method of claim 6 wherein the oxidizing step comprises adding hydrogen peroxide to the carboxylic acid.

8. The method of claim 7, wherein the photolysis step occurs in dioxane with an acid.

9. The process of claim 3 wherein the reaction temperature is from about 60 ℃ to about 130 ℃.

10. The method of claim 2, wherein R¹、R²And R³Independently is C_1-10Alkyl or aryl.

11. The method of claim 1, wherein the 7-silylcamptothecin and 7-silylhomocamptothecin are in racemic, enantiomerically enriched, or enantiomerically pure form and are represented by the following formulae:

and the camptothecin or homocamptothecin compound having a hydrogen at the C7 position is represented by the formula:

wherein R is⁴And R⁵Are the same or different and are independently hydrogen, -C (O) R^fWherein R is^fIs alkyl, alkoxy, amino OR hydroxy, alkyl, alkenyl, alkynyl, alkoxy, aryloxy, acyloxy, -OC (O) OR^dWherein R is^dIs alkyl, -OC (O) NR^aR^bWherein R is^aAnd R^bAre the same or different and are independently H, -C (O) R^fAlkyl or aryl, F, Cl, hydroxy, nitro, cyano, azido, formyl, hydrazino, amino, -SR^cWherein R is^cIs hydrogen, -C (O) R^fAlkyl or aryl; or R⁴And R⁵Together form three or four radicals selected from the group CH, CH₂O, S, NH or NR¹⁵A chain of members of (1), wherein R¹⁵Is C₁-C₆An alkyl group;

R⁶is H, F, Cl, nitro group,Amino, hydroxy or cyano; or R⁵And R⁶Together form three or four radicals selected from the group CH, CH₂O, S, NH or NR¹⁵A chain of members of (a);

R⁷is H, F, amino, C_1-3Alkyl radical, C_2-3Alkenyl radical, C_2-3Alkynyl, trialkylsilyl or C_1-3An alkoxy group;

R⁸is C_1-10Alkyl, alkenyl, alkynyl or benzyl;

R⁹is H, F or-CH₃；

n is 0 or 1;

R¹⁰is-C (O) R^fOr H; while

Y is absent or O.

12. The process of claim 11 wherein the silyl precursor is represented by the formula XSiR¹R²R³Wherein X is H, SiR¹⁷R¹⁸R¹⁹、GeR¹⁷R¹⁸R¹⁹、SnR¹⁷R¹⁸R¹⁹、-B(OR^d)₂or-C (O) RⁱWherein R is¹⁷、R¹⁸And R¹⁹Independently is aryl or alkyl, and wherein RⁱIs alkyl or aryl.

13. The method of claim 11, wherein R⁸Is ethyl, allyl, benzyl or propargyl.

14. The method of claim 11, wherein R⁸Is ethyl.

15. The method of claim 11, wherein R⁹Is H.

16. The method of claim 11, wherein R¹⁰Is H or C (O) CH₃。

17. The method of claim 12, wherein X is H.

18. The method of claim 11, wherein R⁴、R⁵、R⁶And R⁷Is H.

19. The method of claim 12, wherein R¹And R²Is methyl, R³Is tert-butyl or methyl, R⁴Is H, R⁶Is H, and R⁷Is H.

20. The method of claim 19, wherein R⁵Is H, NH₂Or OH.

21. The method of claim 12, wherein X is H and the silyl group is formed by reacting a silyl precursor with a free radical generator.

22. The method of claim 20, wherein X is H or SiR¹⁷R¹⁸R¹⁹And the free radical generator is a peroxide.

23. The method of claim 22, wherein X is H and the silyl group is generated in the presence of a thiol.

24. The method of claim 23, wherein R⁴、R⁵、R⁶、R⁷And R¹⁰Is H, and R⁸Is ethyl.

25. The method of claim 24, wherein n is 0.

26. The method of claim 25, further comprising reacting R⁵And (3) converting into OH.

27. The method of claim 26, whereinR⁵The step of conversion to OH comprises an oxidation step to provide the N-oxide, followed by a photolysis step.

28. The method of claim 27 wherein the oxidizing step comprises adding hydrogen peroxide to the carboxylic acid.

29. The method of claim 28, wherein the photolysis step occurs in dioxane with an acid.

30. The process of claim 23, wherein the reaction temperature is from about 60 ℃ to about 130 ℃.

31. A process for the synthesis of 10-hydroxy-7-silylcamptothecin or 10-hydroxy-7-silylhomocamptothecin, said process comprising the steps of: the hydrogen at the C10 position of 7-silylcamptothecin or 7-silylhomocamptothecin is converted to-OH by oxidation of 7-silylcamptothecin or 7-silylhomocamptothecin to provide the N-oxide, followed by photolysis.

32. The method of claim 31 wherein the oxidizing step comprises adding hydrogen peroxide to the carboxylic acid.

33. The process of claim 32 wherein the carboxylic acid is acetic acid.

34. The method of claim 33, wherein the photolysis step occurs in dioxane with an acid.

35. The method of claim 34, wherein the acid is sulfuric acid.

36. The method of claim 31 wherein the wavelength of the illumination light during photolysis is about 250-600 nm.

37. The method of claim 36 wherein the wavelength of the illumination light during photolysis is about 275 nm and 450 nm.

38. The method of claim 31, wherein the compound converted is 7-silyl camptothecin.

39. A compound of the formula:

wherein R is¹、R²And R³Independently is C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, aryl, - (CH)₂)_mR¹¹Or SiR¹²R¹³R¹⁴Wherein m is an integer of 1 to 10, R¹¹Is hydroxy, alkoxy, amino, alkylamino, dialkylamino, F, Cl, cyano, -SR^cOr nitro, and wherein R¹²、R¹³And R¹⁴Are the same or different and are independently alkyl or aryl;

wherein R is⁴And R⁵Are the same or different and are independently hydrogen, -C (O) R^fWherein R is^fIs alkyl, alkoxy, amino OR hydroxy, alkyl, alkenyl, alkynyl, alkoxy, aryloxy, acyloxy, -OC (O) OR^dWherein R is^dIs alkyl, -OC (O) NR^aR^bWherein R is^aAnd R^bAre the same or different and are independently H, -C (O) R^fAlkyl or aryl, F, Cl, hydroxy, nitro, cyano, azido, formyl, hydrazino, amino, -SR^cWherein R is^cIs hydrogen, -C (O) R^fAlkyl or aryl; or R⁴And R⁵Together form three or four radicals selected from the group CH, CH₂O, S, NH or NR¹⁵A chain of members of (1), wherein R¹⁵Is C₁-C₆An alkyl group;

R⁶h, F, Cl, nitro, amino, hydroxy or cyano; or R⁵And R⁶Together form three or four radicals selected from the group CH, CH₂O, S, NH or NR¹⁵To (1)A chain of members;

R⁷is H, F, amino, C_1-3Alkyl radical, C_2-3Alkenyl radical, C_2-3Alkynyl, trialkylsilyl or C_1-3An alkoxy group;

R⁸is C_1-10Alkyl, alkenyl, alkynyl or benzyl;

R⁹is H, F or-CH₃；

n is 0 or 1; while

R¹⁰is-C (O) R^fOr H.