ES2245592B1 - New spiro lactams useful for preparing bioactive molecules e.g. conduritols, aminoinositols or their analogues - Google Patents

Abstract

Spiro lactams or its salts, complex or solvates are new. Spiro lactams of formula (I), or its salts, complex or solvates are new. R 1- R 4alkyl, aryl, heterocyclyl, alkoxy, aryloxy or amino (all are optionally substituted), H, OH, halo, OPR, =O or cyano; R 5+R 6(=O) or -O-(CH2) m-; m : 1 - 5; R 5H, OH or OPR; R 6alkyl, cycloalkyl, alkenyl, alkinyl, aryl, heterocyclyl (all are optionally substituted), H or cyano; PR : hydroxyl protecting group; a : single or double bond; Z : -(CR aR b) n, -CH 2-(CR aR b)-, -(CR aR b)-CH 2-, CH 2-(CR aR b)-CH 2-, -(CH 2) 2-(CR aR b)- or -(CR aR b)-(CH 2) 2; n : 1 - 3; R aand R balkyl, cycloalkyl, alkenyl, aryl, heterocyclyl, alkoxy, aryloxy, amino (all are optionally substituted), H or halo; Y : O, S, NR aor C(O);and W : at least one aryl, heterocyclyl or alkenyl (all are optionally substituted). Provided that (1) at least one of R 1- R 5is alkoxy or aryloxy (both are optionally substituted), OH or OPR; and (2) when both R 1and R 2or R 3and R 4are H; then a is double bond. An independent claim is included for preparation of (I). [Image].

Description

New spirolactams and their synthesis.

Field of the Invention

The present invention relates to new Spirolactam compounds, synthetic procedures and intermediate compounds for their preparation and for use as UV absorbers

Background of the invention

Lactams are compounds of great interest due to their biological activities, for example, well-known β-lactams such as some penicillins, cephalosporins and carbapenemic drugs have antibacterial activity

Spirolactams are a particular kind of lactams that have shown interesting biological properties. Be has described that some spirocondensed azetidinones have antibacterial activity, see US 4,680,388, or hypocholesterolemic properties, see for example WO 94 17038. Also, if these compounds have the functionality suitable, they are valuable intermediate compounds in different Compound families The spirolactamic ring is the equivalent of an alpha-amino or hydroxy-amino acid and opens up many possibilities in the  diastereo and / or enantioselective synthesis.

There are few synthetic procedures available for this class of compounds. WO 96 27587 describes the catalytic enantioselective synthesis of certain spirolactams that It includes a large number of stages. Document 5,734,061 also describes a procedure for the preparation of lactams N-substituted spirocyclic with a substituent of tertiary amine US 4,680,388 describes procedures to obtain N-sulfate substituted spirolactams. These procedures and the intermediate compounds used in they are directed to very particular compounds and therefore lack of a wider applicability due to the absence of groups functional reagents.

Miyazawa, E. et al . in Heterocycles , vol 59, 1: 149-160 "Synthesis of spirofused nitrogen heterocyclic compounds via N-methoxy-N-acylnitrenium ions using phenyliodine (III) bis (trifluoroacetate) (III) in trifluoroethanol" describes another procedure for obtaining functionalized spirolactams, including some spirodienones.

Glover, SA et al . in Tetrahedron , 1987, 43: 2577-2592 "N-alkoxy-N-acylnitrenium ions in intramolecular aromatic addition reactions" describe the synthesis with low yield of benzolactams by cyclization of N-alkoxy-N-acylnitrenium ions.

Kawase, M. et al . in J. Org. Chem ., 1989, 54: 3394-3403 "Electrophilic aromatic substitution with N-methoxy-N-acylnitrenium ions generated from N-chloro-N-methoxyamides: syntheses of Nitrogen heterocyclic compounds bearing a N-methoxyamide group" describe, among others, the synthesis of spiro-benzodienone-lactams by ipso amidation with a nitrenium ion.

These procedures present serious inconveniences in relation to their yields and with the limited stability of the spirocondensed lactams obtained. Therefore, any effective method for producing compounds of high performance functionalized spirolactam, with various functionalities, such as a benzodienone group, and if it is necessary with stereospecificity, it would be a good contribution received for the technique.

Summary of the invention

The invention provides for azetidinones very stable spirocondensed that are useful as compounds intermediates in the preparation of a variety of structures highly functionalized chemicals, including, if necessary, diasterean and / or enantioselective procedures.

In one aspect, the invention provides a compound of formula I:

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Formula I

one

in which R_ {1} and R2_ are independently selected from H, halogen, protected hydroxyl or unprotected, protected or unprotected silyloxy, alkyl or substituted or unsubstituted cycloalkyl, alkoxy or aryloxy substituted or unsubstituted, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, nitro, amino, mercapto or alkylthio;

R_ {3} and R_ {4} are selected independently of H, substituted alkyl, alkoxy or aryloxy substituted or unsubstituted, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl;

Z is - (CRaRb) n - where n is a selected number of 1, 2, 3 and Ra and Rb are each selected regardless of hydrogen, alkyl substituted or not substituted, substituted or unsubstituted cycloalkyl, alkenyl substituted or unsubstituted, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkoxy substituted, substituted or unsubstituted aryloxy, substituted amino or unsubstituted, or halogen;

Y is selected from -O-, -S-, -N (RaRb) - or -C (0) -, in which Ra and Rb are as defined previously and do not form a cyclic ring;

W is a group with sufficient density electronics to stabilize the compound through interactions ? (pi) with the remainder of benzodienone;

or a salt, complex or solvate thereof.

The stability of these compounds by selecting a suitable W group.

As an additional advantage, the compound adopts a preferred conformation in which group W blocks one of the benzodienone faces, targeting additional reactions on the free face of the rest of benzodienone.

Additionally, we have found that these Compounds have interesting UV absorbing properties that They can be modulated according to the substituents used.

Preferably, W is a group with groups unsaturated or aromatic, preferably selected from substituted or unsubstituted arylalkyl, heterocyclylalkyl substituted or unsubstituted and substituted or not alkenyl replaced.

The invention also provides a method for producing a compound of formula I comprising a step (a) of react a compound of formula III:

Formula III

2

in which R_ {1}, R2_, R 3, R 4, Z, Y, W are as defined previously,

R 5 is hydrogen or alkyl replaced or not replaced;

Hal is F, Cl, Br, I or -SO 2 CF 3;

with an ion forming agent N-acylnitrenium to produce a compound of formula I.

Preferably, the method comprises the additional step (b) of preparing a compound of formula III by reacting a compound of formula IV:

Formula IV

3

in which R_ {1}, R2_, R 3, R 4, R 5, Z, Y, W are as defined previously,

with an amide halogenating agent Weinreb type; preferably a hypochlorite selected agent alkyl, alkyl hypobromite, sodium bromite, hypochlorite sodium, benzyltrimethylammonium trihalide, N-Halophthalimide, N-halosuccinimide or Phenyodo (III) bis (trifluoroacetate) (PIFA). The more preferred is hypochlorite of sodium.

In addition, the invention provides compounds intermediates useful in the production of a compound of formula such as defined above, such as compounds III and IV.

Detailed description of the invention

The compounds described above, such like spiro-benzodienone N-methoxysubstituted, are poorly stable and tend to revert to structurally related compounds with the starting products during their synthesis or purification, due to to an easily triggered reduction process:

4

In addition, during their synthesis or during their purification, and depending on the substitution of the phenylacetamide raw materials, other aromatic heterocycles tend to occur due to their greater stability (see, J. Org. Chem , 1989, 54 : 2294-3403, scheme I):

5

A new class of compounds has been found that contain the spirolactam group and that present a benzodienone functionality, which are extraordinarily stable and They open a large number of possibilities for further use. The stability is present during the synthesis processes and also in those of purification. In these compounds the reactions mentioned above.

Without sticking to any theory, it is believed that the stability is facilitated by the interactions \ pi between the group W attached to the hydroxylamino and benzodienone functionalities. This configuration has an additional advantage in that the W group covers a face of the benzodienone group, which acts as a protective group for one of the faces and that directs the reagent attack additional to the other side.

In the above definition of compounds of formula (I) and in the description, the following terms have the indicated meanings:

"Alkyl" refers to a chain radical hydrocarbon, linear or branched, consisting of atoms of carbon and hydrogen, which does not contain saturation, which has from one to eight carbon atoms, and that is attached to the rest of the molecule by a single bond, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, n-pentyl, etc. The alkyl radicals may be optionally substituted by one or more selected substituents regardless of the group consisting of halogen hydroxyl, alkoxy, carboxyl, cyano, carbonyl, acyl, alkoxycarbonyl, amino, nitro, mercapto and alkylthio.

"Alkoxy" refers to a radical of the formula -ORa in which Ra is an alkyl radical, such as defined above, for example, methoxy, ethoxy, propoxy, etc. "Aryloxy" refers to a radical of the formula -ORb in the that Rb is an aryl radical as defined below.

"Amino" refers to a radical of the formula-NH2, -NHRa, -NRaRb.

"Aryl" refers to a phenyl radical, naphthyl or anthracil. The aryl radical may optionally be replaced by one or more of the substituents selected from the group consisting of hydroxyl, mercapto, halogen alkyl, phenyl, alkoxy, haloalkyl, nitro, cyano, dialkylamino, aminoalkyl, acyl and alkoxycarbonyl, as defined herein document.

"Aralkyl" refers to an aryl group attached to an alkyl group, such as benzyl and phenethyl.

"Cycloalkyl" refers to a ring saturated carbocyclic having from 3 to 8 atoms of carbon.

"Heterocycle" refers to a radical of heterocyclyl. The heterocycle refers to a stable ring of 3 to 15 members consisting of carbon atoms and from one to five heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, preferably a 4 to 8 ring members with one or more heteroatoms, more preferably a ring 5 or 6 members with one or more heteroatoms. For the purposes of this invention, the heterocycle can be a ring system monocyclic, bicyclic or tricyclic, which may include systems of condensed ring; and the nitrogen, carbon or sulfur atoms in the heterocyclyl radical may be optionally oxidized; he nitrogen atom may be optionally quaternized; and the heterocyclyl radical may be partially or completely saturated or be aromatic. Examples of such heterocycles include, but not limited to, azepines, benzimidazole, benzothiazole, furan, isothiazole, imidazole, indole, piperidine, piperazine, purine, quinoline, thiadiazole, tetrahydrofuran.

References in this document to substituted groups in the compounds of the present invention are refer to the specified remainder that can be substituted in one or more positions available by one or more suitable groups, for example, halogen such as fluorine, chlorine, bromine and iodine; cyano; hydroxyl; nitro; azido; alkanoyl such as an alkanoyl group C1-6 such as acyl and the like; carboxamide; groups alkyl including those groups that have 1 to approximately 12 carbon atoms or from 1 to about 6 carbon atoms and, more preferably, 1-3 carbon atoms; alkenyl and alkynyl groups including groups that have one or more unsaturated links and from 2 to about 12 carbon atoms or from 2 to about 6 carbon atoms; alkoxy groups having one or more oxygen bonds and from 1 to about 12 atoms carbon or from 1 to about 6 carbon atoms; aryloxy such as phenoxy; alkylthio groups including those remains that have one or more thioether bonds and from 1 to about 12 carbon atoms or from 1 to about 6 carbon atoms; alkylsulfinyl groups including those residues that have one or more sulfinyl bonds and from 1 to approximately 12 carbon atoms or from 1 to about 6 carbon atoms; alkylsulfonyl groups including those residues that have one or more sulfonyl bonds and from 1 to about 12 carbon atoms or from 1 to about 6 carbon atoms; aminoalkyl groups such as groups that have one or more atoms of N and from 1 to about 12 carbon atoms or from 1 to about 6 carbon atoms; carbocyclic aryl having 6 or more atoms of carbon, particularly phenyl or naphthyl and aralkyl such as benzyl Unless otherwise indicated, a group optionally substituted can have a substituent on each replaceable position of the group, and each substitution is independent of the other.

Unless stated otherwise, the Compounds of the invention also refers to which include compounds that differ only in the presence of one or more atoms Isotopically enriched. For example, the compounds that have the present structures, except for the replacement of a hydrogen by a deuterium or by tritium, or the replacement of a carbon by a carbon enriched in 13 C or 14 C or a nitrogen enriched in 15 N, are within the scope of this invention.

The salts of the compounds of the invention are synthesized from the original compound that contains a residue basic or acid by conventional chemical methods. Generally, such salts are prepared, for example, by making react the base or free acid forms of these compounds with a stoichiometric amount of an appropriate base or acid in water or in an organic solvent or in a mixture of both. Generally, non-aqueous media such as ether, acetate are preferred. ethyl, ethanol, isopropanol or acetonitrile. Examples of salts of acid addition include mineral acid addition salts such such as, for example, hydrochloride, hydrobromide, iodhydrate, sulfate, nitrate, phosphate and organic acid addition salts such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate and p-toluenesulfonate.

The compounds of the invention may be in crystalline form as free compounds or as solvates (for example, hydrates) and it is intended that both forms are within the Scope of the present invention. Solvation methods are generally known in the art.

The compounds of the present invention represented by the formula (I) described above may include enantiomers, depending on the presence of centers chiral, or isomers, depending on the presence of bonds multiple (for example, Z, E). Isomers, enantiomers or individual diastereoisomers and mixtures thereof fall within the scope of the present invention.

In the compound of formula I, R 3 and R 4 they are preferably H. Other substituents, such as halogen or unsubstituted alkyl are more difficult to produce due to the formation of the indole type of the compounds instead of the lactam

In the compound of formula I, the R 1 and R 2 substituents should not be strongly electrophilic because during synthesis and depending on the method used, they could hinder the attack of the nitrenium ion. Preferably each is independently selected from hydrogen, halogen, substituted aryl, more preferably, both are hydrogenated.
no.

In the compounds of formula I, the group Z gives place a ring of 4, 5 or 6 members. The replacement in the Z position creates a stereogenic center that could induce the selective functionalization of the rest of benzodienone. In a Preferred embodiment Z is - (CH 2) n -. Although 5 or 6 rings are also within the scope of the invention, in one embodiment, the ring is preferred β-lactam (n = 1) due to uses Additional that may be given to such compounds.

The Y group in the compounds of formula I, plays a role in stability and conformation and also during its synthesis. In one embodiment, Y is preferably -O-, although other atoms are not excluded, provided that the final product be stable

As already mentioned, the W group is important for the stabilization of the compound of formula I. preferably it has unsaturated or aromatic groups for increase interactions \ pi. Groups are preferred aralkyl and alkenyl groups since they provide the best stability. In a particular embodiment, W is -CRaRb-Q or -SiRaRb-Q since the conformation stability is further improved by the presence of a binding group -CRaRb- or -SiRaRb- between Y and the substituent Q that has interactions π (pi) with the rest of benzodienone The binding group is preferably -CHRa-. In this In this case, a stereogenic center is introduced that allows selectivity or specificity of any additional reaction, differentiating the two double bonds of benzodienone. This will open advantageously the route for diastereo synthesis and / or enantioselective, in addition to the selection of a face that mentioned above. Depending on the size of Ra you can modulate the interactions \ pi and therefore modulate properties as UV absorption.

In one embodiment, W is an aralkyl group. Among the substituted or unsubstituted aryl groups, preferred phenyl and naphthyl. Groups are also conceived heterocyclylalkyl.

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In one embodiment, the compounds are preferred. of formula II:

Formula II

6

In which W is as defined previously. A particularly stable compound according to the Formula II has W = benzyl.

The compounds of formula (I) defined previously they can be obtained by synthetic procedures available. Some examples of these procedures are described. in the documents mentioned above. Results are obtained particularly good forming the spirolactamic ring by the reduction of an aromatic compound by an ion N-acylnitrenium.

Therefore, in one aspect, the invention is refers to a process of preparing a compound of formula I as defined above, comprising the step (a) of reacting a compound of formula III:

Formula III

7

in which R_ {1}, R2_, R 3, R 4, Z, Y, W are as defined above; R 5 is hydrogen or substituted or unsubstituted alkyl; Hal is F, Cl, Br, I or eventually -SO 2 CF 3;

with an ion forming agent N-acylnitrenium to produce a compound of formula I.

If Hal is a halogen, a precipitating agent suitable may form the nitrenium ion. In general, the salts of silver give good results; Other salts may be used.

R 5 is preferably a donor group of electrons, to promote the ipso addition of the nitrenium ion. Preferably, R 5 is alkyl such as methyl, ethyl, propyl, etc. More preferably it is methyl.

A suitably substituted amino group may be used as an alternative to the -OR5 group; in this case, the addition of the nitrenium ion will generate the iminium salt of the benzodienone that the benzodienone generates by hydrolysis. In this alternative, it is preferred that the substituents on the N atom be electron donor groups, such as a dialkylamine. Another possibility is to use a halogen group instead of -OR5, as described in J. Org. Chem ., 2003, 68: 6739-6744.

The reaction is preferably carried out in absence of light to avoid unwanted root reactions, such as the formation of the alkoxylamide raw material, in place of amidation (addition) ipso, or the decomposition of compounds of formula III.

Preferably, the solvent should be polar, such as for example trifluoroacetic acid or acetic acid. Be prefer a temperature of about -10 ° C to about 10 ° C, more preferably about 0 ° C. Reaction can carried out in an inert atmosphere if necessary. The product obtained from formula I can be purified following procedures standard such as evaporation, chromatography, phase separation (extraction). As mentioned earlier, the product is stable and can be stored for a period of time dragged on.

The compound of formula III is prepared preferably from a Weinreb type amide compound of formula IV:

Formula IV

8

in which R_ {1}, R2_, R 3, R 4, R 5, Z, Y, W are as defined above, by reaction with a halogenating agent. He halogenating agent is preferably an agent selected from alkyl hypochlorite, alkyl hypobromite, sodium bromite, sodium hypochlorite, benzyltrimethylammonium trihalide, N-halosuccinimide, N-halophthalimide or Phenyodo (III) bis (trifluoroacetate) (PIFA). It preferred sodium hypochlorite due to its low cost and its availability.

Halogenation is preferably carried out. in a nonpolar solvent, such as acetone, and at a temperature of about -10 ° C to about 10 ° C, more preferably of about 0 ° C. The reaction is preferably carried out. in the absence of light to avoid root reactions not desired.

The compounds of formula IV are either commercially available or easily prepared by following known procedures as described, for example, in the bibliography mentioned above.

The procedures described above They provide an easy and fast way (3 stages) to get the stable compounds of formula I.

The possibility of preparing new lactams, which are stable, are densely functionalized and are very suitable to control additional reactions, opens a large number of possibilities for additional use. The compounds of formula I are useful raw materials to produce a variety of chemical structures of interest. The double link can undergo electrophilic attacks with, for example, hydroxylating agents, epoxidation agents, reducing agents, as well as Michael's cycloadditions and reactions.

NMR and UV spectroscopy data (see examples section) for the compounds described by the formula I, completely agree with the presence of interactions \ pi between its part of benzodienone and the Y-X substitution for cases where electrons \ pi are oriented adequately.

Therefore, of the comparison between the data of 1 H NMR (chemical shifts and coupling constants) for compounds 3a, 3b, 3c and 3d (examples of formula IV) and compounds 5a, 5b, 5c and 5d (examples of formula I) became apparent that compounds 5c and 5d have to present the interactions ? indicated above. For the 5d compound, the great difference between the four signals assigned to the four protons on your part of benzodienone has to correlate with the interaction between this rest and its Y-X part. Further, it is proposed that this interaction is intensified by an effect Thorpe-Ingold.

In addition, the UV data for compounds 3a, 3b, 3c and 3d (examples of formula IV) and compounds 5a, 5b, 5c and 5d (examples of formula I) (see examples section) support the conclusions obtained from its 1 H NMR data. Although the spectra for 3a, 3b, 3c and 3d (examples of formula IV) they have their maximum absorptions at 276 nm (λ max) and this is regardless of its replacement Y- W or Y-X, respectively, the situation of for example the Formula I is completely different. Compounds 5a and 5b have their maximum absorbances at 243 nm (λ max), and compounds 5c and 5b at 242 and 232 nm, respectively. The variation of 11 nm at maximum absorption (λ max) between compound 5d and compound 5a is assigned to the interaction between their rest of the benzodienone part and its part Y-X

The knowledge of the structural basis (the establishment of the interactions \ pi between its part of benzodienone and Y-X substitution) for previous features extends the reach of its accessibility and applicability. From its absorption data it is clear that, both the absorption interval and the possibility of modulating this interval by selecting appropriate substituents, makes These compound materials useful as UV absorbers.

The following examples are intended for exemplify the invention and should not be construed as limiting of the description of the claimed invention.

Examples General methods and materials

All reactions described below are carried out under argon atmosphere, unless specified otherwise. The solvents used were distilled and dried under argon atmosphere before use (the CH2Cl2 and the Benzene was distilled over CaH2). Chromatography was performed ultrafast in columns loaded with silica gel 230-400 mesh Merck. CCF was carried out (thin layer chromatography) on Merck silica gel (Kieselgel 60F-254).

All raw materials were purchased commercially (Aldrich, Fluka and Merck) and used without further purification, except for N -alkoxyamine 2d, which was prepared according to a literature procedure (see below). A commercial household bleach solution Mavy® was used, which was established to have <5% NaOCl, for the preparation of t -butyl hypochlorite following the procedure described below.

Melting points (mp) were determined in a Reichert heating microscopic device and have not corrected. The 1 H and 13 C NMR spectra were measured with a Varian Gemini-200 and Varian spectrometer Inova-300 with (CH 3) 4 Si as internal reference and CDCl3 as solvent, unless Specify otherwise. The spectral data of 1 H and 13 C NMR are reported in parts per million (δ) in relation to the residual sign of the solvent (CDCl3, 7.26 ppm and 77.0 ppm for 1 H and 13 C NMR, respectively). The 1 H and 13 C NMR denominations are: s (singlet); s a (wide singlet); d (double); t (triplet); q (quarter); m (multiplet). Infrared (IR) spectra were recorded with a FT-IR spectrometer (infrared with transformed of Fourier) from Perkin-Elmer. UV spectra are recorded with a Perkin-Elmer 402 spectrometer. Low resolution mass spectra (LRMS) were obtained with a Hewlett Packard 5973 MSD spectrometer with an input system Direct (EI) at 70 eV. The microanalytical data (A.E.) is obtained with Perkin-Elmer 240C instruments and Heraus CHN-O in the Analysis Department Instrumental of the Institute of General Organic Chemistry (C.S.I.C.).

Example 1 General procedure for the preparation of N- alkoxyamides 3a-da from 4-methoxyphenylacetyl chloride (1)

9

N -alkoxyamines 2a-c were purchased from Aldrich and Fluka, and were used without further purification. N -alkoxyamine 2d was prepared following the procedure described in Brown, DS; Gallagher, PT; Lightfoot, AP; Moody, CJ; Slawin, AMZ; Swann, E. Tetrahedron 1995, 51 , 11473-11488.

To a vigorously stirred solution of N- alkoxyamine 2a-d hydrochloride (17.87 mmol) and sodium carbonate (32.50 mmol) in a mixture of benzene (23 ml) and H2O (23 ml) with cooling in an ice water bath, 4-methoxyphenylacetyl chloride (1) was added. The mixture was stirred at room temperature for 12 h under an argon atmosphere and the progress of the reaction was monitored by TLC (hexane-AcOEt, 1: 2). Then AcOEt (50 ml) was added and the organic phase was separated. This process was repeated three times. The combined extracts were washed with brine (2 x 50 ml), dried over Na2SO4, filtered and concentrated under reduced pressure to give the corresponding N- alkoxyamide 3a-d, which was used in the Next reaction without further purification.

Example 2 N- Methoxy-4-methoxyphenylacetamide (3a)

The compound was obtained from 1 and 2a as described in Kawase, M. et al J. Org. Chem ., 1989, 54: 3394-3403 "Electrophilic aromatic substitution with N-methoxy-N-acylnitrenium ions generated from N-chloro-N-methoxyamides: syntheses of Nitrogen heterocyclic compounds bearing a N-methoxyamide group".

R f = 0.14 (TLC, hexane-AcOEt, 1: 2); yield, 99%; white solid, mp 86-87 ° C (mp bibl. 83-85 ° C); 1 H-NMR (200 MHz, CDCl 3): δ 7.88 (1H, s a., NH), 7.19 (211, d, J = 8.7 Hz, H-2 ), 6.88 (2H, d, J = 8.7 Hz, H-3), 3.81 (3H, s, OCH3), 3.71 (3H, s, NOCH3), 3.50 (2H, s, CH2); 13 C-NMR (75 MHz, CDCl 3): δ 169.1, 158.5, 130.1, 126.1, 113.9, 63.8, 55.1, 39.1 ; IR (KBr): 34 3467, 3159, 2967, 1644, 1612, 1513, 1252, 1063, 1033 cm -1; UV (MeOH) λ max 276 nm (1619 l · -1-ccm -1); LRMS (EI): m / z 195 (M +, 3), 165 (1), 160 (1), 148 (6), 135 (4), 121 (100), 91 (23), 78 (66); AE (C 10 H 13 NO 3): calculated C, 61.53; 11, 6.71; found C, 61.61; H, 6.76.

Example 3 N - ( O- Allyl hydroxy) -4-methoxyphenylacetamide (3b)

Following the same procedure as in the Example 1, but starting from 2b, compound 3b is obtained.

R f = 0.30 (TLC, hexane-AcOEt, 1: 2); yield, 99%; white solid, mp 100-101 ° C; 1 H-NMR (200 MHz, CDCl 3): δ 7.85 (1H, s a., NH), 7.18 (2H, d, J = 8.5 Hz, H-2 ), 6.87 (2H, d, J = 8.5 Hz, H-3), 5.89 (1H, m, C H = CH2), 5.31 (1H, s a., CH = C H2 , 5.25 (1H, s a., CH = C H2 ), 4.32 (2H, d, OCH2), 3.80 (3H, s , OCH 3), 3.49 (2H, s, CH 2); 13 C-NMR (75 MHz, CDCl 3): δ 169.1, 158.5, 131.9, 130.0, 126.2, 120.2, 113.8, 76.9 , 55.0, 39.2; IR (KBr): 34 3467, 2967, 1641, 1609, 1514, 1253, 1057 cm -1; UV (MeOH) λ max 276 nm (2070 1 mol -1 - \ cm -1); LRMS (EI): m / z 221 (M +, 37), 180 (3), 161 (16), 148 (33), 135 (9), 121 (100), 91 (17), 78 (31); AE (C 12 H 15 NO 3): calculated C, 65.14; H, 6.83; found C, 65.21; H, 6.89.

Example 4 N- Benzyloxy-4-methoxyphenylacetamide (3c)

Following the same procedure as in the Example 1, but starting from 2c, compound 3c is obtained.

R f = 0.40 (TLC, hexane-AcOEt, 1: 2); yield, 99%; white solid, mp 98-99 ° C; 1 H-NMR (200 MHz, CDCl 3): δ 7.71 (1H, s a., NH), 7.34 (5H, s a., Ph), 7.11 (211 , d, J = 8.5 Hz, H-2), 6.83 (2H, d, J = 8.5 Hz, H-3), 4.86 (2H, s, OC H2 Ph ), 3.79 (3H, s, OCH3), 3.45 (2H, s, CH2); 13 C-NMR (75 MHz, CDCl 3): δ 168.9, 158.5, 135.0, 130.0, 129.01, 128.4, 128.3, 126.0 , 113.9, 77.8, 55.0, 39.3; IR (KBr): 34 3436, 3159, 2965, 1644, 1611, 1512, 1252, 1059, 1032, 726, 696 cm -1; UV (MeOH) λ max 276 nm (1558 1 mol -1 - \ cm -1); LRMS (EI): m / z 271 (M +, 14), 239 (2), 211 (6), 193 (1), 180 (2), 165 (3), 148 (5), 121 (71), 91 (100), 77 (29); AE (C 16 H 17 NO 3): calculated C, 70.83; H, 6.32; found C, 70.87; H, 6.35.

Example 5 (-) - ( S ) - N - (1-Phenylethoxy) -4-methoxyphenylacetamide (3d)

Following the same procedure as in the Example 1, but starting from 2d, the compound 3d is obtained.

R f = 0.32 (TLC, hexane-AcOEt, 1: 1); yield, 99%; white solid, mp 60-61 ° C; [α] D 20 = -168.2 ° (c 1.1, CHCl 3); 1 H-NMR (200 MHz, CDCl 3): δ 7.56 (1H, s a., NH), 7.32 (5H, m, Ph), 6.98 (2H, d , J = 7.1 Hz, H-2), 6.77 (2H, d, J = 7.1 Hz, H-3), 4.98 (1H, m, OC H (CH 3) Ph ), 3.78 (3H, s, OCH 3), 3.35 (2H, s, CH 2), 1.53 (3H, d, J = 6.6 Hz, CH 3) ; 13 C-NMR (75 MHz, CDCl 3): δ 168.5, 158.1, 140.6, 129.7, 128.0, 127.8, 126.6, 126.3 , 113.5, 82.5, 54.7, 38.8, 20.4; IR (KBr): 320 3202, 3057, 2956, 2927, 2847, 1652, 1609, 1512, 1455, 1301, 1247, 1178, 1035, 700 cm -1; UV (MeOH): λ max (ε) = 276 nm (1841 1 mol -1 - cm cm -1); LRMS (EI): m / z 285 (M +, 3), 268 (2), 181 (6), 165 (2), 148 (6), 121 (40), 105 (100), 91 (5), 77 (17); AE (C 17 H 19 NO 3): calculated C, 71.56; H, 6.71; found C, 71.62; H, 6.75.

Example 6 General procedure for the preparation of spirolactams 5a-d

First, the t -butyl hypochlorite compound was prepared following the procedure described in Mintz, MJ; Walling, C. Org. Syntheses 1969, 49 , 9-12:

10

To a vigorously stirred commercial household bleach solution (500 ml) was added, at 10 ° C in the dark and as a single portion, a solution of tert-butyl alcohol (37 ml, 0.39 mol) and glacial acetic acid ( 24.5 ml, 0.43 mol). The reaction mixture was stirred for approximately 3 min, and then poured into a separatory funnel. The lower aqueous phase was discarded and the oily yellow organic phase was washed first with 10% Na2CO3 aqueous solution (50 ml) and then with H2O (50 ml). The product was dried over CaCl2 (1 g) and filtered. The product can be stored in a refrigerator over CaCl2 in amber glass bottles. The t -butyl hypochlorite isolated by this procedure could be used in the next reaction without further purification.

eleven

To a stirred solution of N- alkoxyamide 3a-d (7.37 mmol) in CH 2 Cl 2 (30 ml) was added slowly, at 0 ° C in the dark, freshly prepared tert - butyl hypochlorite ( 9.21 mmol). Alternatively, sodium hypochlorite such as the commercial domestic bleach solution Mavy® was used at room temperature in the dark. The resulting mixture was stirred at 0 ° C (or in the case of the added lye, at room temperature) in the dark under an argon atmosphere until the disappearance of the raw material was observed by TLC (hexane-AcOEt, 1: 2) (the time required was generally less than 30 min). The solvent was evaporated in the dark under reduced pressure and the residue, N -chloro- N- alkoxyamide 4a-d as a yellow solid (Rf approx 0.83, hexane-AcOEt, 1: 2), was used in the Next reaction without further purification.

The N - Chloro - N -alcoxiamida 4a-d solid cooled to 0 ° C and under an argon atmosphere, a solution of silver carbonate (14.74 mmol) in TFA (30 ml) in the dark with shaking . The mixture was stirred until the reaction was completed, generally 30 min (monitoring by TLC, hexane-AcOEt, 1: 2), and then the solvent was removed under pressure below 35 ° C. The residue was basified with 5% Na 2 CO 3 aqueous solution (75 ml) with cooling. The precipitated silver salts were filtered through Celite in vacuo, and the pad was washed with CH2Cl2. The aqueous solution was extracted with CH2Cl2 (3 x 150 ml). The combined extracts were washed with brine (2 x 150 ml), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-AcOEt) to give the spiro-? -Lactam 5a-d.

1-Methoxy-1-azaspiro [3.5] nona-5,8-dien-2,7-dione (5th)

Flash chromatography (hexane-AcOEt, 1: 1). R f = 0.33 (TLC, hexane-AcOEt, 1: 2); yield, 43%; light brown solid, mp 107-109 ° C; 1 H-NMR (200 MHz, CDCl 3): δ 6.91 (2H, d, J = 10.2 Hz, C H = CHCO), 6.46 (2H, d, J = 10.2 Hz, CH = C H CO), 3.77 (3H, s, OCH 3), 2.97 (2H, s, CH 2); 13 C-NMR (75 MHz, CDCl 3): δ 184.2, 162.2, 145.5, 132.5, 65.5, 60.4, 43.6; IR (KBr): v 3436, 3014, 2934, 1772, 1667, 1630, 1404, 1060, 880 cm -1; UV (MeOH): λ max (ε) = 243 nm (11959 1 mol -1 - cm cm -1); LRMS (EI): m / z 179 (M +, 1), 164 (1), 151 (2), 137 (100), 106 (3), 78 (6); AE (C 9 H 9 NO 3): calculated C, 60.33; H, 5.06; found C, 60.39; H, 5.10.

1- ( O- Allyl hydroxy) -1-azaspiro [3.5] nona-5,8-dien-2,7-dione (5b)

Flash chromatography (hexane-AcOEt, 3: 2). R f = 0.40 (TLC, hexane-AcOEt, 1: 2); yield, 68%; yellow oil; 1 H-NMR (200 MHz, CDCl 3): δ 6.89 (2H, d, J = 10.1 Hz, C H = CHCO), 6.44 (2H, d, J = 10.1 Hz, CH = C H CO), 5.97-5.83 (1H, m, CH2 -C H = CH2), 5.37 (1H, m, CH2 -CH = C H2 , 5.32 (1H, m, CH2 -CH = C H2 ), 4.35 (2H, d, J = 6.3 Hz, CH_ {2 -C H = CH2), 2.96 (2H, s, CH2); 13 C-NMR (75 MHz, CDCl 3): δ 183.9, 162.6, 145.7, 131.6, 131.4, 128.7, 77.8, 60.1 , 42.9, 12.8; IR (NaCl, CCl4):? 3536, 3050, 2927, 1783, 1669, 1631, 1401, 1251, 1052, 940, 880, 839 cm -1; UV (MeOH): λ max (ε) = 243 nm (12549 1 mol -1 - cm cm -1); LRMS (EI): m / z 205 (M +, 1), 177 (3), 163 (79), 147 (34), 133 (36), 120 (8), 106 (89), 78 (100); AE (C 11 H 11 NO 3): calculated C, 64.38; H, 5.40; found C, 64.44; H, 5.44.

1-Benzyloxy-1-azaspiro [3.5] nona-5,8-dien-2,7-dione (5c)

The purity of the spirolactam 5c is related to the concentration of the household bleach solution used. The 1 H NMR spectra should be used for the determination of the spirolactam / N- alkoxyamide ratio (5c: 3c). By CCF both compounds have the same R f (0.40, hexane-AcOEt, 1: 2).

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Flash chromatography (hexane-AcOEt, 2: 1). R f = 0.40 (TLC, hexane-AcOEt, 1: 2); yield, 68%; light brown-reddish solid, mp 77-79 ° C; 1 H-NMR (200 MHz, CDCl 3): 8 7.32 (5H, m, Ph), 6.55 (2H, d, J = 10.2 Hz, C H = CHCO), 6.17 (2H, d, J = 10.2 Hz, CH = C H CO), 4.88 (2H, s, OC H2 Ph), 2.89 (2H, s, CH2 }); 13 C-NMR (75 MHz, CDCl 3): δ 183.8, 162.9, 145.0, 134.2, 130.9, 128.7, 128.6, 128.1 , 78.7, 60.0, 42.9; IR (KBr): µ 3459, 3043, 2963, 1764, 1672, 1630, 1375, 1056, 886, 841, 768, 737, 696 cm -1; UV (MeOH): λ max (ε) = 242 nm (9511 1 mol -1 - cm cm -1); LRMS (EI): m / z 255 (M +, 1), 197 (41), 121 (6), 106 (16), 91 (100), 78 (25); AE (C 15 H 13 NO 3): calculated C, 70.58; H, 5.13; found C, 70.63; H, 5.18.

(-) - ( S ) -1- (1-Phenylethoxy) -1-azaspiro [3.5] nona-5,8-dien-2,7-dione (5d)

Flash chromatography (hexane-AcOEt, 3: 2). R f = 0.47 (TLC, hexane-AcOEt, 1: 2); yield, 55%; brown oil; [α] D 20 = -63.6 ° (c 1.0, CHCl 3); 1 H-NMR (200 MHz, CDCl 3): δ 7.30-7.17 (5H, m, Ph), 6.67 (1H, dd, J = 10.0, 2, 9 Hz, C H = CHCO), 6.23 (1H, dd, J = 10.0, 2.0 Hz, CH = C H CO), 6.11 (1H, dd, J = 10.0, 2 , 9 Hz, C H = CHCO), 5.81 (1H, dd, J = 10.0, 2.0 Hz, CH = C H CO), 4.88 (1H, q, J = 6.6 Hz , OC H (CH 3) Ph), 2.75 (2H, s, CH 2), 1.44 (3H, d, J = 6.6 Hz, CH 3); 13 C-NMR (75 MHz, CDCl 3): S 184.2, 163.8, 145.4, 144.9, 140.1, 131.9, 130.5, 128.9, 128.6, 127.1, 85.0, 60.5, 43.4, 20.7; IR (NaCl, CCl 4): 32 3289, 2978, 2927, 1784, 1668, 1630, 1512, 1454, 1249, 1050, 700 cm -1; UV (MeOH): λ max (ε) = 232 nm (3083 1 mol -1-cm -1); LRMS (EI): m / z 269 (M +, 1), 181 (1), 165 (1), 155 (1), 148 (1), 121 (26), 105 (100), 77 (19); AE (C 16 H 15 NO 3): calculated C, 71.36; H, 5.61; found C, 71.40; H, 5.67.

Claims (23)

1. Compound of formula I: Formula I 12 in which R_ {1} and R2_ are independently selected from H, halogen, protected hydroxyl or unprotected, substituted or unsubstituted silyloxy, alkyl or cycloalkyl substituted, substituted or unsubstituted alkoxy or aryloxy, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl substituted, nitro, amino, mercapto or alkylthio; R_ {3} and R_ {4} are selected independently of H, substituted alkyl, alkoxy or aryloxy substituted or unsubstituted, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl; Z is - (CRaRb) n - where n is a selected number of 1, 2, 3 and Ra and Rb are each selected regardless of hydrogen, alkyl substituted or not substituted, substituted or unsubstituted cycloalkyl, alkenyl substituted or unsubstituted, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkoxy substituted, substituted or unsubstituted aryloxy, substituted amino or unsubstituted, or halogen; Y is selected from -O-, -S-, -N (RaRb) - or -C (O) -, in which Ra and Rb are as defined previously and do not form a cyclic ring; W is a group with sufficient density electronics to stabilize the compound through interactions ? with the remainder of benzodienone; preferably a group selected from substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocyclyl alkyl, alkenyl substituted or unsubstituted; or a salt, complex or solvate thereof. 2. Compound according to claim 1, in the that R 3 and R 4 are H. 3. Compound according to claims 1 or 2, in which R_ {1} and R_ {2} are each selected independently of hydrogen, halogen and substituted aryl. 4. Compound according to claim 3, in the that R1 and R2 are H. 5. Compound according to any one of the claims 1-4, wherein Z is - (CHRa) n, where Ra and n is as defined in the claim 1. 6. Compound according to claim 5, in the that n is 1. 7. Compound according to claim 5 or 6, in the one that Ra is H. 8. Compound according to any one of the claims 1-7, wherein Y is -O-. 9. Compound according to any one of the claims 1-8, wherein W is -CRaRb-Q, in which Ra and Rb are as defined above and Q is substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkenyl replaced. 10. Compound according to claim 9, in the that Ra and Rb are H. 11. Compound according to claim 10, in the that Q is aryl, preferably phenyl.

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12. Compound of formula II: Formula II 13 in which W is as defined in claim 1 or 9. 13. Compound according to claim 12, in the that W is -CH_ {-2}, and Q is aryl substituted or not substituted, substituted or unsubstituted alkenyl; preferably substituted or unsubstituted phenyl or vinyl. 14. Compound according to claim 13, in the that Q is phenyl. 15. Procedure for producing a compound of spirolactam according to any one of the claims 1-14, which comprises step (a) of reacting a compound of formula III: Formula III 14 in which R_ {1}, R2_, R 3, R 4, Z, Y, W are as defined in the claim one R 5 is hydrogen or alkyl replaced or not replaced; Hal is F, Cl, Br, I or -SO 2 CF 3; with an ion forming agent N-acylnitrenium to produce a compound of formula I. 16. Method according to claim 15, in the one that the ion formation agent N-acylnitrenium is a precipitating agent of halogen, preferably a silver salt. 17. Method according to claim 15 or 16, in which step (a) is carried out in the absence of light. 18. Procedure according to any of the claims 15-17, comprising the step additional (b) of preparing a compound of formula III by doing reacting a Weinreb type amide compound of formula IV:

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Formula IV fifteen with a halogenating agent; preferably an agent selected from alkyl hypochlorite, alkyl hypobromite, sodium bromite, sodium hypochlorite, benzyltrimethylammonium trihalide, N-halosuccinimide, N-halophthalimide or bis (trifluoroacetate) of phenyodode (III) (FIFA) 19. Method according to claim 18, in which the halogenating agent is alkyl hypochlorite, preferably tert-butyl hypochlorite, or sodium hypochlorite 20. Procedure according to any one of the claims 15-19 comprising the step additional (c) of producing the compound of formula IV by doing reacting a compound of formula V with a compound of formula SAW: 16 in which W, Y, Z, R_ {1}, R2, R3, R4, R5 are as defined previously Y L is a nucleophilic leaving group, preferably halogen 21. Compound of formula III:

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Formula III 17 in which R_ {1}, R2_, R 3, R 4, Z, Y, W are as defined in any one of the claims 1-14 R 5 is hydrogen or I rent; Hal is F, Cl, Br, I or SO_ {2} F_ {3}. 22. Compound of formula IV: Formula IV 18 in which R_ {1}, R2_, R 3, R 4, Z, Y, W are as defined in any one of claims 1-14 and R 5 is hydrogen or alkyl substituted or not replaced. 23. Use of a compound as defined in claims 1-14 as absorbent of UV radiation