ES2798324B2 - Derivatives of 1,3-oxazin-2-ones that incorporate a bromine atom in their structure, procedure for obtaining and using - Google Patents

Description

DESCRIPTION

Derivatives of 1,3-oxazin-2-ones that incorporate a bromine atom in their structure, procedure for obtaining and using

TECHNICAL SECTOR

The present invention is encompassed in the chemical and pharmaceutical field. More specifically, it refers to a new procedure for the preparation of brominated derivatives of 1,3-oxazin-2-ones and their uses as chemical compositions and in Organic Chemistry as key synthesis intermediates for pharmaceutical products.

BACKGROUND OF THE INVENTION

The 1,3-oxazin-2-one skeleton is present in various natural and non-natural products that possess biological activity for the treatment of different diseases. Among the non-natural 1,3-oxazinones, benzoxazinones are of great importance, among which is Efavirenz®. This compound is a commercial drug used in the treatment of HIV due to its activity as an inhibitor of the reverse transcriptase enzyme.

On the other hand, oxazinones have also been shown to be useful as intermediates in Organic Synthesis (Kuznestov, N. et al. Eur. J. Org. Chem. 2012 , 334; Shapk-Kraievskyi, B. et al. Tetrahedron. 2012 , 60 , 2179). For example, the synthesis of metofolin, an analgesic of the isoquinoline family, has been carried out starting from a tricyclic 1,3-oxazinan-2-one (Richter, H. et al. Angew. Chem. Int. Ed. . 2012, 51, 8784).

Due to their biological activity in the treatment of diseases and their usefulness in Organic Synthesis, oxazinones are currently being studied and different synthesis methods have been proposed.

Thus, recently, a compound derived from 1,3-oxazinan-2-one has been synthesized effective in the fight against diabetes, since it is capable of inhibiting the enzyme 11-B-hydroxysteroid dehydrogenase type 1 (11-B-HSD1 ), implicated in this disease (Xu, Z. et al. J. Med. Chem. 2011 , 54, 6050).

An interesting approach is the synthesis from the reaction of N-Boc-3-butyn-1-amines catalyzed by a gold salt (Robles-Machin, R. et al. J. Org. Chem. 2006 , 51, 5023 ).

The synthesis of oxazinones from allenic carbamates has also been described. More specifically the synthesis of 1,3-oxazinan-2-ones by oxycyclization of alenylcarbamates catalyzed by gold, with a complete control of regioselectivity (Alcaide, B. et al. Beilstein J. Org. Chem. 2013 , 9, 818) .

The cyclization of allenes with a nucleophilic substituent has the disadvantage of regioselectivity. For this reason, the development of new methods to control regioselectivity is of interest. On the other hand, the only method described in the literature for the synthesis of oxazinones from N-alenylcarbamates does not allow the incorporation of a bromine atom in its structure, which would present a synthetic advantage since it would allow the subsequent functionalization of these substrates. in order to obtain functionalized oxazinones with potential biological and / or pharmacological activity.

EXPLANATION OF THE INVENTION

In a first aspect, the present invention refers to derivatives of 1,3-oxazin-2-ones that incorporate in their structure a bromine atom of Formula (II) where R is an aromatic group, an alkyl or a heterocycle:

II

In a preferred embodiment, the 1,3-oxazin-2-one derivatives that incorporate a bromine atom of Formula (II) in their structure are the compounds from formulas (2a) to (2e):

Another object of the present invention is a synthesis method of 1,3-oxazin-2-ones that incorporate in their structure a bromine atom, of Formula II (where R can be aromatic, alkyl or heterocyclic groups) through a reaction of cyclization of alenyl-carbamates of general formula (I) promoted by CuBr ² so that it is possible to control the cyclization mode and obtain potentially interesting molecules from the biological point of view.

The cyclization reaction of the alenyl-carbamates of formula I is carried out following the reaction of Scheme 1 under different conditions, using different promoters, solvents and temperatures.

As starting substrates, the W-alenylcarbamates of formula (1a) to (1e) are used, which are easily prepared following the procedure described in the literature (Alcaide, B. et al. Beilstein J. Org. Chem. 2013 , 9, 818):

The abbreviations used in this document are as follows:

Ph phenyl functional group

Boc tert-butyloxycarbonyl

(Boc) _2nd di-tert-butyl dicarbamate

Me methyl

MeO methoxy

PMP p-methoxyphenyl

t.a. room temperature

T Temperature

t time

The cyclization reaction of the W-alenylcarbamates of formula (1a) to (1e) is carried out using different promoters, solvents and temperatures.

Copper bromide (CuBr ² ) is used as promoter in the presence of a solvent.

In a preferred embodiment, the solvent is MeCN or MeNO2 and the cyclization is carried out at room temperature or at a temperature up to 70 ° C for a reaction time of between 1.5 and 24 hours. Most preferably, the solvent is refluxing MeNO2.

In these cases, starting from compounds 1a to 1e, 5-bromo-1,3-oxazin-2-ones of formula (2a) to (2e) are obtained with yields greater than 50%.

These bromine derivatives are interesting from the synthetic point of view due to the possibility of functionalizing the brominated position in order to obtain products with interesting pharmacological and biological properties, through a novel radical process.

Its chemical structure allows, in another aspect of the present invention, its use in the preparation of a drug or pharmaceutical composition for the treatment and prevention of diseases such as cancer, autoimmune diseases, infectious diseases and, in general, any disease whose treatment or prevention is capable of benefiting from the biological activities shown by the compounds described in the present invention, either to a derivative thereof, or to a pharmaceutically acceptable prodrug thereof.

Another aspect of the invention relates to the use of the compounds as pesticides in the prevention and control of pests. Examples of pests in which the compounds of the present invention may have a controlling effect include acarids, insects, and small pest animals.

Another aspect of this invention refers to the use of the bromine derivatives described in supramolecular chemistry and / or in the preparation of new materials, molecular probes, fluorescent probes, optical sensors and / or chemical sensors, preferably in the preparation of polymers and / or or dendrimers and, in general, of any material whose preparation is likely to benefit from the methodology shown for the compounds described in the present invention, or to a derivative thereof.

The compounds of the present invention represented by Formula (II) can include isomers, depending on the presence of multiple bonds (eg Z, E), including optical isomers or enantiomers, depending on the presence of chiral centers. Individual isomers, enantiomers or diastereomers or mixtures thereof fall within the scope of the present invention, i.e. the term isomer also refers to any mixture of isomers, such as diastereomers, racemics, etc., even their isomers optically active ingredients or mixtures in different proportions thereof. The individual enantiomers or diastereomers, as well as their mixtures, can be separated by conventional techniques.

The term "derivative" as used herein includes both pharmaceutically acceptable compounds, that is, derivatives of compounds of Formula (II) that can be used in the manufacture of a medicine, and pharmaceutically unacceptable derivatives since these can be useful in the preparation of pharmaceutically acceptable derivatives The nature of the pharmaceutically acceptable derivative is not critical as long as it is pharmaceutically acceptable.

Also within the scope of this invention are prodrugs of compounds of Formula (II).

PREFERRED EMBODIMENT OF THE INVENTION

The present invention is illustrated by the following examples, which are not intended to be limiting of its scope.

Example 1.

This example refers to the preparation of the starting alkynyl carbamates.

Aromatic aldehydes are reacted with propargylamine in the presence of magnesium sulfate at room temperature, obtaining imines that are subsequently reduced with sodium borohydride according to scheme 2 to give amines.

15h Ar, 30 min.

Scheme 2

The protection of the NH group is carried out with di-tert-butyl dicarbamate in the presence of triethylamine as a base, obtaining the alkynyl carbamates according to Scheme 3.

Scheme 3

Table 1 shows the starting aldehydes, intermediate amines and alkynyl carbamates obtained, as well as the corresponding yields.

Example 2.

This example refers to the preparation of the alenyl carbamates.

The preparation of alenyl-carbamates is carried out from alkynyl-carbamates by the Crabbé reaction. For this, the alkynyl-carbamates are reacted in the presence of CuBr, paraformaldehyde and diisopropylamine, using 1,4-dioxane as solvent as shown in Scheme 4, thus obtaining the alenylcarbamates shown in Table 2, with good returns.

Scheme 4

^{CuBr (0.5 mmol), (CH 2} O) n (2.55 mmol) and diisopropylamine (1.8 mmol) were added to a solution of the corresponding alkyne (1 mmol) in 1,4-dioxane (5 ml) , in that order, and stirred under reflux under an argon atmosphere. When the reaction was complete (tcf), water was added and extracted with AcOEt. The organic phases were pooled and washed with brine. It was dried with MgSO ⁴ and the solvent was evaporated under reduced pressure. The products obtained were purified by column chromatography on silica gel (hexane / AcOEt).

Alenyl-carbamate 1a.

1H-NMR (300 MHz, CDCI ³ ): 1.51 (s, 9H, ³ CH ³ Boc), 3.79 (s broad, 2H, N-CH ² ), 4.48 (s, 2H, CH ² -C = =), 4.78 (dt, 2H, J = 6.6, 2.6 Hz, = = CH ² ), 5.12 (s broad, 1H, CH ==), 7.34 (m, 5H, Ar). 13C-NMR (75 MHz, CDCI ³ ): 202.1 (= =), 158.9 (C = O), 130.8 (C4ary), 128.4 (4CH Ph), 127.1 (CH Ph), 86.9 (CH = =), 80.0 ( C4ary Boc), 76.1 (= = CH ² ), 49.4 (CH ² ), 44.9 (CH ² ), 28.4 ( ³ CH ³ Boc).

IR (CHCI ³ ): 1955 (==), 1692 (C = O) cm -1.

HRMS (ES): Calculated M + for C ¹⁶ H ²¹ NO ² : 259.1572 Experimental: 259.1579

Alenyl-carbamate 1b.

1H-NMR (300 MHz, CDCI ³ ): 1.49 (s, 9H, ³ CH ³ Boc), 3.76 (s broad, 2H, N-CH ² ), 3.80 (s, 3H, O-CH ³ ), 4.38 ( s, 2H, CH ² -C = =), 4.75 (dt, 2H, J = 6.6, 2.8 Hz, = = CH ² ), 5.08 (s broad, 1H, CH ==), 6.86 (d, 2H, J = 8.7 Hz, Ar), 7.19 (d, 2H, J = 8.1 Hz, Ar). 13C-NMR (75 MHz, CDCI ³ ): 206.3 (= • =), 158.8 (O- C4ary), 158.8 (C = O), 130.3 (C4ary), 129.4 (2CH PMP), 113.9 (2CH PMP), 86.9 (CH = =), 79.8 (C4ary Boc), 76.1 (= = CH ² ), 55.2 (O-CH ³ ), 48.9 (CH ² ), 44.6 (CH ² ), 28.4 ( ³ CH ³ Boc).

IR (CHCI ³ ): 1954 (= =), 1692 (C = O) cm -1.

HRMS (ES): CaIcuIate M + for C ¹⁷ H ²³ NO ³ : 289.1678 ExperimentaI: 289.1675

Alenyl-carbamate 1c.

1H-NMR (300 MHz, CDCI ³ ): 1.34 (s, 3H, CH ³ ), 1.41 (s, 3H, CH ³ ), 1.45 (s, 9H, ³ CH ³ Boc), 3.39 (m, 2H, N -CH ² ), 3.67 (m, 1H, N-CHH-aliene), 3.93 (m, 2H, O-CHH N-CHH-aiene), 4.02 (dd, 1H, J = 8.3, 6.2 Hz, O-CHH ), 4.25 (s broad, 1H, O-CH), 4.77 (dt, 2H, J = 6.6, 2.8 Hz, CH = = CH ² ), 5.12 (q, 1H, J = 6.4 Hz, CH = = CH ² ). 13C-NMR (75 MHz, CDCI ³ ): 208.8 (= • =), 151.8 (C = O), 109.1 (C4ary acetonide), 87.1 (CH = = CH ² ), 79.9 (C4ary Boc), 76.3 (CH = = CH ² ), 75.3 (O-CH), 67.3 (O-CH ² ), 49.1 (N-CH ² ), 47.3 (N-CH ² -aline), 28.4 ( ³ CH ³ Boc), 26.8 (CH ³ ), 25.5 (CH ³ ).

IR (CHCI ³ ): 1957 (= =), 1694 (C = O) cm -1.

HRMS (ES): CaIcuIate M + for C ¹⁵ H ²⁵ NO ⁴ : 283.1784 ExperimentaI: 283.1786

1

Alenyl-carbamate 1d.

1H-NMR (300 MHz, CDCI ³ ): 1.49 (s, 9H, ³ CH ³ Boc), 3.35 (dd, 1H, J = 14.4, 7.2 Hz, N-CHH), 3.63 (s, 3H, O-CH ³ ), 3.74 (m, 1H, N-CHH), 3.77 (s, 3H, O-CH ³ ), 3.78 (m, 1H, CHHC = • =), 3.82 (d, 1H, J = 4.4 Hz, HC -N), 4.46 (m, 1H, CHH-C ==), 4.56 (d, 1H, J = 5.1 Hz, HC-O), 4.76 (m, 2H, = = CH ² ), 5.03 (s broad, 1H, CH ==), 6.85 (d, 2H, J = 8.3 Hz, PMP), 7.44 (m, 2H, PMP). 13C-NMR (75 MHz, CDCI ³ ): 208.5 (==), 164.5 (C = O lactam), 155.7 (C = O Boc), 130.4 (C4ary), 118.7 (2CH PMP), 114.3 (2CH PMP), 87.4 (CH ==), 82.5 (HC-O), 80.5 (O-C4ary), 79.9 (== CH ² ), 59.1 (O-CH ³ ), 55.9 (HC-N), 55.4 (O-CH ³ ), 47.4 (N-CH ² ), 45.1 (N-CH ² ), 28.4 ( ³ CH ³ Boc).

IR (CHCI ³ ): 1957 (==), 1754 (C = O), 1694 (C = O) cm -1.

NMR spectra. The 1H-NMR and 13C-NMR spectra were performed on Bruker Avance 300 (300 MHz) instruments, using TMS as an internal reference. The chemical shifts are expressed in ppm (5) and the coupling constants in Hz. The multiplicity of the signals is expressed as follows: singlet (s), doublet (d), triplet (t), multiplet (m), doublet of doublets (dd), doublet of triplets (dt), quadruplet (q), septuplet (sept).

Mass spectrometry. High resolution electrospray (EE) mass spectra were performed at CENQUIOR (CSIC) on an AGILENT 6520 Accurate-Mass QTOF LC / MS spectrometer.

Example 3

This example concerns the optimization of the cyclization conditions of the alenylcarbamates.

Starting from the alenyl-carbamate of formula 1a, the cyclization reaction is carried out according to Scheme 5, in an inert atmosphere of argon (Ar), using CuBr ² as promoter with different solvents, temperatures and reaction times.

Table 3 shows the reaction conditions in each case and it is observed that the best performance resulted using CuBr ² as promoter, MeNO ² as solvent and reflux, at a temperature of 70 ° C; in this case, after 1.5 h of reaction, 5-bromo-1,3-oxazin-2-one (2a) was obtained as the only reaction product with a yield of 72%. This bromine derivative is interesting from the synthetic point of view due to the possibility of functionalizing this position if necessary.

Table 3

On a suspension of the alene (1 mmol) in nitromethane (5 mL), the CuBr ² (2.5 mmol) was added under argon atmosphere and it was kept stirring at reflux until the reaction was complete. When the reaction was complete (tcf), the solvent was evaporated under reduced pressure. The products obtained were purified by a silica gel column (hexane / AcOEt)

Oxazinone 2a.

1H-NMR (300 MHz, CDCh): 3.25 (dd, 1H, J = 9.0, 6.1 Hz N-CHH-CH), 3.51 (t, 1H, J = 9.1 Hz, N-CHH-CH), 4.38 (q , 2H, J = 14.9 Hz, N-CH ² ), 4.89 (dd, 1H, J = 9.0, 6.2 Hz, Br-CH), 5.59 (d, 1H, J = 5.6 Hz, = CHH), 6.03 (dd , 1H, J = 2.3, 1.1 Hz, = CHH), 7.26 (m, 5H, Ar). 13C-NMR (75 MHz, CDCh): 156.9 (C = O), 135.2 (= C), 129.0 (C4ary), 128.9 (2CH Ar), 128.1 (3CH Ar), 118.8 (= CH ² ), 74.6 (Br -CH), 48.7 (CH ² ), 48.3 (CH ² ).

IR (CHCh): 2929 (C = C), 1759 (C = O) cm -1. Melting point: 74-76 ° C.

HRMS (ES): Calculated [M + H] + for C ^ H ^ BrN O ² : 284.0105 Experimental: 284.0096

Example 4

This example refers to the cyclization of the alenyl carbamates.

Taking into account the optimal reaction conditions according to example 3, the products 2b to 2e are obtained according to Scheme 6.

Scheme 6

Table 4 shows the products and yields obtained in each case.

Table 4

1

Claims (1)

1. Derivatives of 1,3-oxazin-2-ones that incorporate in their structure a bromine atom of Formula (II) where R is an aromatic group, an alkyl or a heterocycle.

2. Derivatives of 1,3-oxazin-2-ones that incorporate in their structure a bromine atom of Formula (II), according to claim 1, of formulas (2a) to (2e).

3. Process for obtaining 1,3-oxazin-2-one derivatives that incorporate in their structure a bromine atom of Formula (II), according to claim 1, which comprises the cyclization reaction of alenyl-carbamates of general Formula ( I) using copper bromide as promoter.

Procedure for obtaining 1,3-oxazin-2-one derivatives that incorporate in their structure a bromine atom of Formula (II), according to claim 3, where the alenyl-carbamates are compounds of formula (1a) to (1e) .

Procedure for obtaining 1,3-oxazin-2-one derivatives that incorporate in their structure a bromine atom of Formula (II), according to claims 3 and 4, where the cyclization is carried out in the presence of a solvent. Procedure for obtaining 1,3-oxazin-2-one derivatives that incorporate in their structure a bromine atom of Formula (II), according to claim 5, where the solvent is MeCN or MeNO ² . Procedure for obtaining 1,3-oxazin-2-one derivatives that incorporate in their structure a bromine atom of Formula (II), according to claim 6, where the cyclization is carried out at room temperature or at a temperature higher than 70 ° C for a reaction time between 1.5 and 24 hours. 1 8. Procedure for obtaining 1,3-oxazin-2-one derivatives that incorporate in their structure a bromine atom of Formula (II), according to claim 6, where the solvent is MeNO ² at reflux. 1