WO2004013139A2

WO2004013139A2 - Process for preparing 7-azaindoles

Info

Publication number: WO2004013139A2
Application number: PCT/GB2003/003335
Authority: WO
Inventors: Piotr Graczyk
Original assignee: Eisai Co., Ltd
Priority date: 2002-08-02
Filing date: 2003-07-31
Publication date: 2004-02-12
Also published as: AU2003248987A1; WO2004013139A3; GB0218014D0; AU2003248987A8

Abstract

The present application provides a process for the production of 7-azaindole systems by reacting a compound of formula I-1 with base

Description

PROCESS

The present application provides a process for the production of 7-azaindole systems. The present application further provides novel compounds.

The 7-azaindole system occurs in natural products such as neocryptolepine and is an important core structure present in pharmaceutical agents such as dopamrne D₄ ligands, p38 kinase inhibitors and corticotrophin-releasing hormone receptor antagonists. 7-Azaindole-containing structures have been studied as antimalarial agents, melatonin receptor ligands, antitussive agents, 5HT_2C and 5HT_2B receptor antagonists.

Previous synthetic routes to 7-azaindoles can be classified based on the type of the ring formed at the final stage of synthesis i.e. formation of the pyrrole ring or the pyridine ring.

Methods used for the synthesis of the 7-azaindole core structure by formation of the pyrrole ring start from the properly functionalised pyridine. This group of reactions include various modifications of the Madelung synthesis, Fischer indole synthesis and the Bischler reaction

The Fischer, Madelung and Reissert methods do not work well for preparation of 2-substituted 7-azaindoles. The 2-substituent may be introduced into the 7- azaindole skeleton by directed ortho lithiation but the use of this method to produce 2-substituted 7-azaindoles is limited by the number of synthetic steps involved. For the introduction of the 2-substituent by lithiation, it is necessary to have the 7-azaindole system already in place thus increasing the number of synthetic steps necessary to produce the 2-substituted 7-azaindoles. The use of lithiation also reduces the scope of substituents that can be introduced. Furthermore, the harsh conditions involved in these methods mean that the range of 7-azaindoles which can be produced by these methods are limited.

Hands et al. (Synthesis, 1996, 887) provides a method for the production of the 2-substituted 7-azaindoles utilising simple starting materials. While the yields for this method are respectable (31-84%), the final step in the synthetic scheme involves strong acidic conditions (3M HC1 at 100°C over 8h or 5.5M HC1 at 50°C over 2h). The range of substitutents on the pyridine ring is also restricted by the use of i BuLi during the formation of the intermediates.

Zhang et al. (J. Org. Chem. 2002, 67, 2345 - 2347) has indicated that the 7- azaindole system may also be accessible via Bartoli cyclization but no experimental data has been provided in support of this assertion.

Alternative methods of producing the 7-azaindoles include the use of a palladium catalysed cyclisation as indicated below.

This reaction involves the use of the expensive palladium catalyst. Furthermore the starting materials illustrated are not readily available. This method is not a viable route to the production of 7-azaindole compounds.

Methods involving the synthesis of the pyridine ring are not commonly used due to the limited availability of properly functionalised starting materials. Furthermore these methods require the use of pyrrole derivatives alkylated or arylated at the nitrogen atom.

Examples of such methods are summarised below.

Thus while there are a number of known processes for the production of the 7- azaindole compounds, these processes have a number of disadvantages including low yields, use of harsh conditions, use of expensive reagents and availability of starting materials. There is therefore required a new process which allows the production of the 7-azaindole derivatives in good yield and which allows the use of mild reaction conditions allowing a wide variety of potentially useful 7-azaindole and especially 2-substituted 7-azaindoles to be produced. The first aspect of the present invention relates to a process for the production of a compound of formula 1-2

1-2 comprising reacting a compound of formula 1-1 with base

1-1

wherein X is hydrogen or a group COR;

R and R' are independently hydrogen, halogen, branched or unbranched alkyl (optionally interrupted by one or more of 0-, -C(O)-, -N(R )-, -S(O)- and - S(0₂)-), alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, reduced arylalkyl, arylalkenyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, reduced aryl, reduced heterocyclyl, reduced heterocyclylalkyl or a substituted derivative of any of the foregoing groups, wherein the substituents are one or more independently of halogen, alkyl, halosubstituted alkyl, aryl, arylalkyl, heterocyclyl, reduced heterocyclyl, reduced heterocyclylalkyl, arylalkoxy, cyano, nitro, -C(0)R², -C0₂R², -SOR², -S0₂R², SONR³R³, NR³SO₂R², NR³C0₂R², -NR³R³, -OR², -SR², -C(0)CX^]X²NR³R³, -C(0)N(OH)R³, - C(0)NR³R³, -NR³C(0)R², -CR²(NH₂)C0₂R², -NHCX¹X²C0₂R², - N(OH)C(0)NR³R³, -N(OH)C(0)R², -NHC(0)NR³R³, -C(0)NHNR³R³, - C(0)N(OR²)R², and where:-

R² is hydrogen , Cι__]2 alkyl or aryl, optionally substituted by one or more of C₃-₄ alkyl, halogen, C ₄ haloalkyl, OR⁴, SR⁴, N0₂, CN, NR⁴R⁴, NR⁴COR⁴, NR CONR⁴R⁴, NR COR⁴, NR⁴C0₂R⁴, C0₂R⁴, COR⁴, CONR⁴ ₂, S(0)₂R⁴, SONH₂, S(0)R⁴, S0₂ NR⁴R⁴, NR⁴S(0)₂R⁴, wherein the Cj._]2 alkyl group optionally incorporates one or more insertions selected from the group consisting of -0-, -N(R⁴)-, -S(O)- and -S(0₂)-, wherein each R⁴ may be the same or different and is as defined below;

R³ is C π alkyl or aryl, optionally substituted by one or more of C_1-4 alkyl, halogen, C_1-4 haloalkyl, OR⁴, SR⁴, N0₂, CN, NR⁴R⁴, NR⁴COR⁴, NR⁴CONR⁴R⁴, NR⁴COR⁴, NR⁴C0₂R⁴, C0₂R⁴, COR⁴, CONR⁴ ₂, S(0)₂R⁴, SONH₂, S(0)R⁴, S0₂ NR⁴R⁴, NR S(0)₂R⁴, wherein the Cj_ι₂ alkyl group optionally incorporates one or more insertions selected from the group consisting of -0-, -N(R⁴)-, -S(O)- and -S(0₂)-, wherein each R may be the same or different and is as defined below;

R⁴ is hydrogen, C_1- alkyl, or Cι.₄ haloalkyl, aryl, or heterocyclyl;

I

X and X are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, arylalkyl, heterocyclylalkyl, reduced heterocyclyl or reduced heterocyclylalkyl.

R I I is„ C->_M2 a „lιkι„y.lι, a ,-lτk.-y- .l.o_x„y,., ary .l1, or a gr _oup O r-vRr> 10 ;.

R¹⁰ is -₁₂ alkyl, aryl or heterocyclyl

The process of the first aspect preferably produces a compound of formula 1-2 wherein R is other than hydrogen. Preferably R is Cj-₁₂ alkyl, C₃_ι₂ cycloalkyl, phenyl, napthyl, Cj.₁₂ alkylphenyl, pyridinyl, furanyl, pyrroyl, thiophenyl, Cj._]2 alkylpyridinyl, optionally substituted with halogen, C]_₆ alkyl, CF₃, CC1₃, CH₂CH₂Br, phenyl, benzyl, pyridyl, methoxy, ethoxy, phenoxy, benzyoxy, cyano, nitro, C(O)R⁵, C0₂R⁵, SOR⁵, S0₂R⁵, SR⁵, NR⁵R⁵, CONR⁵R⁵, NR⁵C0₂R⁵; more preferably R is C . alk l or C₃_₁₂ cycloalkyl;

Preferably R' is hydrogen, C_λ„_n alkyl, C₃.ι₂ cycloalkyl, halo, phenyl, napthyl, Cj-]₂ alkylphenyl, pyridinyl, furanyl, pyrroyl, thiophenyl, C_1-12 alkylpyridinyl, optionally substituted with halogen, C_1-6 alkyl, CF₃, CC1₃, CH₂CH₂Br, phenyl, benzyl, pyridyl, methoxy, ethoxy, phenoxy, benzyoxy, cyano, nitro, C(0)R⁵, C0₂R⁵, SOR⁵, SO₂R⁵, SR⁵, NR⁵R⁵, CONR⁵R⁵, NR⁵C0₂R⁵; more preferably R' is hydrogen or phenyl optionally substituted with halogen, Cj_₆ alkyl, CF₃, CC1₃, CH₂CH₂Br, phenyl, benzyl, pyridyl, methoxy, ethoxy, phenoxy, benzyoxy, cyano, nitro, C(0)R⁵, C0₂R⁵, SOR⁵, S0₂R⁵, SR⁵, NR⁵R⁵, CONR⁵R⁵, NR⁵C0₂R⁵;

wherein R⁵ is methyl, ethyl or propyl;

R¹¹ is preferably, methyl, ethyl, propyl, butyl, pentyl, hexyl, phenyl, pyridyl or a group OR¹⁰.

Preferably R is methyl, ethyl, propyl, butyl, pentyl, hexyl, phenyl or pyridyl; X is preferably hydrogen or a group CO(CH₂)_nCH₃ or CO(CH₂)_ncycloalkyl wherein n is 0, 1, 2, 3, 4 or 5, or CO-phenyl or CO-pyridyl.

In this text, 'reduced', in the context of 'reduced heteroaryl' and the like means fully or partially saturated.

For the purposes of this invention, "alkyl" means a straight chain or branched alkyl radical of 1 to 12 carbon atoms, preferably 1 to 6 carbon atoms and most preferably 1 to 4 carbon atoms including but not limited to methyl, ethyl, n- propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl etc. The term "alkenyl" means a straight chain or branched alkylenyl radical of 2 to 12 carbon atoms, preferably 2 to 6 carbon atoms and most preferably 2 to 4 carbon atoms, and containing one or more carbon-carbon double bonds and includes but is not limited to ethylene, n-propyl-1-ene, n-proρyl-2-ene, isopropyl ene, etc.. The term "alkynyl" means a straight chain or branched alkynyl radical of 2 to 12 carbon atoms, preferably 2 to 6 carbon atoms and most preferably 2 to 4 carbon atoms, and containing one or more carbon-carbon triple bonds and includes but is not limited to ethynyl, 2-nιethylethynyl etc.. The term "cycloalkyl" means a saturated or partly unsaturated 3-12 membered cyclic alkyl group and includes but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl etc. Cycloalkyl groups may be optionally substituted or fused to one or more aryl, heterocyclyl or cycloalkyl group. "Heterocycloalkyl" means a 3-12 membered saturated or partly unsaturated cycloalkyl containing one or more hetero atom selected from N, S and O. "Haloalkyl" means an alkyl radical substituted with one or more halide atoms for example CH₂CH₂Br, CF₃ or CC1₃. "Aryl" means an aromatic 3-10 membered hydrocarbon containing one ring or being fused to one or more saturated or unsaturated rings including but not limited to phenyl, napthyl, anthracenyl or phenanthracenyl; or partially saturated bicyclic rings such as tetrahydro-naphthyl. Examples of substituents which may be present on an aryl group include one or more of halogen, amino, nitro, alkyl, haloalkyl, alkoxy, phenoxy and phenoxy substituted by one or more of halo, alkyl or alkoxy.

"Heteroaryl" means an aromatic 3-10 membered aryl containing one or more heteroatoms selected from N, O or S and containing one ring or being fused to one or more saturated or unsaturated rings and.

"Heterocyclyl" means a 3-10 membered ring system containing one or more heteroatoms selected from N, O or S and includes heteroaryl. The heterocyclyl system can contain one ring or may be fused to one or more saturated or unsaturated rings; the heterocyclyl can be fully saturated, partially saturated or unsaturated and includes but is not limited heteroayl and heterocarbocyclyl, e.g. cyclohexyl, phenyl, acridine, benzimidazole, benzofuran, benzothiophene, benzoxazole, benzoxazine, benzothiazole, carbazole, cinnoline, dioxin, dioxane, dioxolane, dithiane, dithiazine, dithiazole, dithiolane, furan, imidazole, imidazoline, fmidazolidine, indole, ndolme, indolizine, indazole, isoindole, isoquinoline, isoxazole, isothiazole, morpholine, naptbyridine, oxazole, oxadiazole, oxathiazole, oxathiazolidine, oxazine, oxadiazine, phenazine, phenothiazine, phenoxazine, phthalazine, piperazine, piperidine, pteridine, purine, pyran, pyrazine, pyrazole, pyrazoline, pyrazolidine, pyridazine, pyridine, pyrimidine, pyrrole, pyridopyrrole, pyrrolidine, pyrroline, quinoline, quinoxaline, quinazoline, quinolizine, tetrahydrofuran, tetrazine, tetrazole, thiophene, thiadiazine, thiadiazole, thiatriazole, thiazine, thiazole, thiomorpholine, thianaphthalene, thiopyran, triazine, triazole, and trithiane. A reduced heteroaryl group or moiety may be for example a fully or partially saturated derivative of the aforementioned heteroaryl groups. Examples of reduced heteroaryl groups thus include pyrrolidinyl, tetrahydrofuryl, tetrahydrothienyl and piperidinyl. Suitable substituents include one or more of halogen, oxo, amino, nitro, alkyl, haloalkyl, alkoxy, phenoxy and phenoxy substituted by one or more of halo, alkyl, haloalkyl or alkoxy.

The aryl, heteroaryl or heterocyclyl group can be optionally fused to an unsaturated, partially saturated or fully saturated five to seven membered ring containing zero to three heteroatoms, each saturated carbon in the optional fused ring is further optionally and independently substituted by =0, =S, =NNHR², NNR²R², -N-OR², =NNHCOR², =NNHC0₂R², =NNSO_zR², or

=NR , wherein each R may be the same or different and is as defined above;

Each substitutable nitrogen atom in R is optionally substituted by R³, COR², S0₂R² or C0₂R², wherein each R² and R³ may be the same or different and is as defined above;

Halogen means F, Cl, Br or I, preferably F.

In a preferred feature of the first aspect, the compound of formula 1-2 is provided wherein R and X are as defined above and R' is halide, preferably bromide or iodide, more preferably bromide. This compound can undergo a displacement reaction of the halide moiety in order to provide a different compound of formula 1-2. Examples of such displacement reactions are well known in the art and usually involve the use of a palladium catalyst. Such examples include the Suzuki coupling reaction, the Sonogashira coupling and the Stille coupling.

Compound 1-1 is converted to compound 1-2 by the addition of base. The base used must be sufficiently strong to convert compound 1-2 into an intermediate ylide as illustrated below.

1-1

Examples of such bases include sodium carbonate, butyllithium, tBuOK, sodium amide, LDA, LiHMDS, sodium hydride or sodium alkoxide. For the purposes of the first aspect, the group X can be hydrogen or a group COR where R is defined as above. Where X is a group COR, the compound of formula 1-2 is optionally deprotected to produce a compound of formula 1-3.

1-2 1-3 Removal of the group COR can be carried out using conventional conditions known in the art. In particular, the acyl group is removed using neutral to basic conditions. Some acyl groups will require the use of basic conditions such as sodium hydroxide solution, preferably incubation with a 10% sodium hydroxide solution at room temperature. More labile acyl groups can be removed using mild conditions. For example, where R is ethyl, the acyl group can be removed by incubation with silica at room temperature.

The process of the first aspect is carried out at temperatures less than 150°C, preferably less than 120°C, more preferably from approximately 90°C to 95°C. The use of low temperatures allows the use of temperature labile starting materials and therefore allows the production of a wider range of 7-azaindole compounds including temperature labile 7-azaindole compounds. This process is furthermore amenable to production of the 7-azaindole compounds in quantities in excess of 1kg due to the use of reactants which are easily available or can be synthesised from easily available starting materials. The process also allows the 7-azaindoles to be produced in high purity as the starting material I- 1 can be isolated and purified prior to its conversion to the compound 1-2.

The second aspect of the invention relates to a process for the production of a compound of formula 1-1

1-1 comprising reacting a compound of formula II-5 with a group RCOY.

Wherein the groups R', R and R¹¹ are as defined as for the first aspect of the invention, and the group Y is OH, halide or OCOR.

When the group Y is OH, the compound RCOY is activated prior to reaction with the compound of formula II-5 to form the amide of compound 1-1. Activation of the acid group can be carried out by methods known in the art. Preferably the acid group is reacted with a coupling agent to form an active intermediate which then reacts with the amine of compound II-5 to form compound 1-1. Examples of such coupling agents include dicyclohexylcarbodiimide, water soluble carbodiimide, N,N'- carbonyldimmidazole, molecular sieves, N,N,N',N- tetramethyl(succinimido)uronium tetrafluoroborate, CBMIT, benzotriazol-1-yl diethyl phosphate, BOP, and PyBOP. Alternatively the acid can be converted into an active ester. Examples of such esters include para-nitrophenyl esters, pentafluorophenyl esters, 2, 4,5-trichlorophenyl esters and succinimide esters. Such esters can be prepared by the DCC-mediated coupling of an acid RC0₂H and an appropriate ester moiety. The active esters are preferably crystalline stable materials which can be isolatied and purified prior to the amide coupling reaction. In addition, the free acid RCOOH may be converted into the acid chloride by the action of thionyl chloride or oxalyl chloride.

The second aspect may alternatively utilise a compound of formula RCOY where Y is a halide preferably chloride. Such acid halides can be produced from the corresponding acid by reaction with thionyl chloride, oxalyl chloride, phosphorus pentachloride etc. When Y is OCOR, the compound RCOY is an acid anhydride. Such acid anhydrides can be symmetrical anhydrides (i.e. where both R groups are the same) or mixed anhydrides (where the R groups are different). Symmetrical anhydrides can be produced from a variety of reagents including dicyclohexylcarbodimmide. Mixed anhydrides can be produced using acids and symmetrical anhydrides or by using reagents such as l-ethoxycarbonyl-2- ethoxy-l,2-dihydroquinoline or diphenylphosphinic acid.

The third aspect of the invention relates to a process for the production of a compound of formula II-4

II-2 II-3 II-4

comprising halogenating the methyl group to form a halomethyl derivative II-3 and reacting the compound of formula 11-3 with a P(III) compound

(R¹⁰O)(R")₂P to fomi a compound of formula II-4. The groups R¹, R¹⁰ and R¹¹ are as defined for the first aspect.

The primary amine of compound II- 1 is protected with an amino protecting group (Pr), allowing halogenation of the methyl group to form the halomethyl derivative II-3. The protecting group can be any group routinely used in the art to protect amine functionalities provided such protecting group does not require deprotection under strongly basic conditions. The protecting group must withstand the conditions of bromination. Examples of such acceptible protecting groups include benzyloxycarbonyl, t-butyloxycarbonyl, 2-(4- biphenylyl)-isopropoxycarbonyl, 9-fluorenylmethoxycarbonyl, triphenylmethyl, 2-nitrophenylsulphenyl groups. Preferably the amine group is reacted with phthalic anhydride to form an isoindole-dione derivative.

The methyl group can be halogenated with for example, NBS or Br₂. Halogenation may occur at reflux, preferably using a catalytic amount of a free radical promoter such as AIBN or benzoyl peroxide. Reaction with a group (R¹ °0)(R¹ )₂P displaces the halide to form the phosphonate of formula II-4. The halide may be refluxed with the phosphite, preferably one equivalent of phosphite or above. The halide is preferably refluxed in a neutral solvent such as toluene, benzene or xylene.

The fourth aspect of the invention provides a process for the production of a compound of formula II- 5

II-4 II-5 comprising deprotecting the amino group of compound II-4. The groups R¹, R¹⁰ and R¹¹ and Pr are as defined for the first to third aspects.

The conditions for the amine deprotection will depend on the protecting group used. As discussed above, any conditions can be used to deprotect the amine group with the exception of strong base which will result in the formation of the ylide and potentially in the intramolecular reaction of II-4.

The amine group is preferably protected with phthalimide. Removal of the phthalimide protection can be achieved by the action of hydrazine in alcoholic medium at room (or elevated) temperatures.

The fifth aspect of the invention provides a compound of formula 1-4

1-4 Wherein the groups R', and R^{1 ]} are as defined for the first aspect and the group Z is hydrogen or a protecting group selected from benzyl oxycarbonyl, t- butyoxycarbonyl, 2-(4-biphenylyl)-isopropoxycarbonyl, 9- fluorenylmethoxycarbonyl, triphenylmethyl, and 2-nitrophenylsulphenyl groups. Preferably Z with the nitrogen atom is an isoindole-dione derivative.

The sixth aspect of the invention provides a compound of formula 1-1

1-1

Wherein the groups R, R', R¹¹ and X are as defined for the first aspect.

The invention will now be illustrated by the following non-limiting examples. Examples

Synthesis of example 2-substituted 7-azaindole derivative 8 is presented in Scheme 3.

Scheme 3

2-(3-Methyl-pyridin-2-y])~isoindole-l,3-dione (2)

Following the method of Moorman et al. (Synth. Commun. 1987, 17, 1695- 1699) 2-amino-3-picoline (32.44 g, 0.30 mol) and phtalic anhydride (44.44 g, 0.30 mol) were heated at 190 °C for 5 h. The product was dissolved in CH₂C1₂ (600 mL), and the solution was washed with water (200 mL), dried MgS0 , and concentrated. The semisolid residue was triturated with ether. Solid product was filtered off and dried in vacuum to afford 2 (66.66 g, 93%) as white powder. 1H NMR (400 MHz, DMSO-c/₆) δ 2.19 (s, 3H), 7.49 (dd, J= 7.6, 4.6 Hz, 1H), 7.90 (d, J= 7.6 Hz, 1H), 7.91-7.97 (m, 2H), 7.98-8.03 (m, 2H), 8.46 (d, J = 4.6 Hz, 1H).

[2-(l,3-Dioxo-l,3-dihydro-isoindol-2-yl)-pyridin-3-ylmethyl]-phosphonic acid diethyl ester (4)

2 3 4

A mixture of 2 (23.81 g, 0.1 mol) and NBS (19.58 g, 0.11 mol) in CC1₄ (270 mL) was refluxed by heating with two sun lamps (250 W each). The bromination reaction was initiated by addition of AIBN in 50 mg portions. Progress of the reaction was followed by TLC. Total of 200 mg of AIBN was added over 2 h. After this period the reflux was discontinued and the mixture allowed to cool to r.t. overnight. Solid, which formed, was filtered off, and the filtrate was concentrated to dryness in vacuum to afford crude 3 (30.19 g, containing also unreacted 2 and the relevant dibromide) as tan solid. A mixture of this solid (28.48 g) and triethyl phosphite (15.4 mL, 89.8 mrnol) in toluene (120 mL) was refluxed under N₂ for 17 h. The crude reaction mixture was applied on a column (40 mm o.d., length 30 cm) loaded with silicagel (Kieselgel 60, 230-400 mesh) in CH₂C1₂, and the product was isolated by gradient elution with CH₂Cl₂:AcOEt followed by crystallization from benzene.hexane. Obtained 4 (16.21 g, 46% from 2) as white crystalline solid. 1H NMR (400 MHz, CDC1₃) δ 1.16 (t, = 7.1 Hz, 6H), 3.17 (d, J= 21.7 Hz, 2H), 3.88-4.01 (m, 4H), 7.40 (dd, J= 7.8, 4.7 Hz, 1H), 7.78-7.83 (m, 2H), 7.93- 7.99 (m, 3H), 8.58 (dt, J= 4.1, 1.9 Hz, 1H).

(2-Amino-pyridin-3-ylmethyl)-phosphonic acid diethyl ester (5)

Hydrazine hydrate (3.26 mL, 57.7 mmol) was added to a solution of 4 (14.40 g, 38.5 mmol) in absolute EtOH (300 mL). The white suspension, which formed, was stirred at r.t. overnight. The solid was filtered off and the filtrate was concentrated in vacuum. The semisolid residue was extracted with CH₂C1₂ (4x100 mL). Combined organic solutions were extracted with 5% HC1 (3x40 mL). The combined acidic extracts were basifϊed to pH 10 with 50% aqueous NaOH (about 9.0 mL; external ice bath cooling) and the product was extracted with CH₂C1₂ (4x50 mL). The extracts were dried (MgS0₄) and concentrated in vacuum to afford 5 (9.03 g, 96%) as colourless oil. 1H NMR (400 MHz, CDC1₃) δ 1.26 (t, J- 7.1 Hz, 6H), 3.04 (d, J- 21.0 Hz, 2H), 3.98-4.12 (m, 4H), 5.08 (bs, 2H), 6.66 (ddd, J= 7.3, 5.0, 1.0 Hz, 1H), 7.28 (dt, J= 7.3, 2.3 Hz, 1H), 8.02 (dt, J= 5.0, 2.1 Hz, 1H).

(2-Dipropionylamino-pyridin-3-ylmethyl)-phosphonic acid diethyϊ ester (6)

Propionyl chloride (352 μL, 4.05 mmol) was added dropwise to a stirred and cooled (0 °C) solution of 5 (329.5 mg, 1.35 mmol) and Et₃N (753 μL, 5.40 mmol) in CH₂C1₂ (10 mL). After overnight stirring the mixture was diluted with AcOEt (1 0 mL) and washed with saturated NaHC0₃ solution (2x10 mL). The organic layer was dried (MgS0₄), concentrated and separated by silicagel chromatography (SGC) with AcOEt as eluent to afford 6 (370.2 mg, 77%) as colourless oil. ^]H NMR (400 MHz, CDC1₃) δ 1.12 (t, /= 7.2 Hz, 6H), 1.29 (t, J = 7.1 Hz, 6H), 2.57 (dq, J= 17.9, 7.1 Hz, 2H). 2.69 (dq, J= 17.9, 7.2 Hz, 2H), 2.98 (d, J= 21.8 Hz, 2H), 4.02-4.15 (m, 4H), 7.36 (dd, J= 7.8, 4.6 Hz, 1H), 8.02 (dt, J= 7.8, 2.1 Hz, 1H), 8.49 (dt, J= 4.7, 1.8 Hz, 1H).

2-Ethy H-pyrrolo[2-3-b]pyridine (8)

1.0 M solution of t-BuOK in THF (205 μL, 0.205 mmol) was added to a solution of 6 (61.0 mg, 0.171 mmol) in toluene (1.0 mL). Then the mixture was stirred at 105 °C for 80 min, when TLC showed that the reaction was completed. The mixture was cooled to r.t. Silicagel (1 2 mg; Kieselge] 60, 230-400 mesh) and 10% aqueous HCl (72 μL, 0.2 mmol) were added, and the mixture was stirred at r.t. for 4 days. Acid was neutralised with Et₃N (28 μL, 0.2 mmol) and the mixture was separated by means of SGC with CH₂Cl₂:MeOH (19:1, v/v) as eluent to afford 8 (18.2 mg, 73% from 6). 1H NMR (400 MHz, CDC1₃) δ 1.40 (t, J= 7.6 Hz, 3H), 2.88 (qd, J- 7.6, 0.8 Hz, 2H), 6.20 (t, J= 0.8 Hz, 1H), 7.04 (dd, J= 7.8, 4.9 Hz, 1H), 7.83 (dd, J= 7.8, 1.5 Hz, 1H), 8.19 (dd, /= 4.9, 1.5 Hz, 1H), 10.39 (bs, 1H).

The intermediate l-(2-ethyl-pyrrolo[2,3-b]pyridin-l-yl)-propan-l-one (7) can be isolated by rapid SGC using hexane:AcOEt=T :1 (v/v) as eluent. ^!H NMR (400 MHz, CDC1₃) δ 1.31 (t, J= 13 Hz, 6H), 3.14 (qd, J= 7.4, 0.9 Hz, 2H), 3.63 (q, J= 7.3 Hz, 2H), 6.35 (t, J= 0.9 Hz, 1H), 7.14 (dd, J = 7.8, 4.8 Hz, 1H), 7.76 (dd, J= 7.8, 1.6 Hz, 1H), 8.27 (dd, J= 4.8, 1.6 Hz, 1H).

Synthesis of example 2-substituted 7-azaindole derivative 8 via monoamide 9

(Scheme 4).

5 8

Scheme 4

(2-Propionylamino-pyridiπ-3-ylmethyι)-phosphonic acid diethyl ester (9)

Propionyl chloride (518 mL, 6.0 mmol) was added dropwise to a cooled (0 °C) and stirred solution of 5 (1.1662 g, 4.78 mmol) in pyridine (10 mL). Cooling bath was then removed and the mixture was stirred at r.t. overnight. Solvent was evaporated in vacuum and the residue was separated between AcOEt- saturated aqueous NaHC0₃. The aqueous layer was extracted with AcOEt (3x4 mL). Combined organic solutions were washed with saturated aqueous NaHC0₃, dried (MgS0₄), concentrated and evaporated with -xylene to remove residual pyridine. The crude product was separated by SGC with AcOEtrMeOH as eluent (in gradient, up to 5% MeOH) to afford diamide 6 (124.9 mg, 7%) and the desired monoamide 9 (996.6 mg, 69%) as colourless oil. 1H NMR (400 MHz, CDC1₃) δ 1.24 (t, J= 7.0 Hz, 6H), 1.26 (t, J= 1.6 Hz, 3H), 2.49 (q, J= 7.6 Hz, 2H), 3.12 (d, J= 21.2 Hz, 2H), 3.96-4.02 (m, 4H), 7.09 (ddd, J= 7.6, 4.8, 0.9 Hz, 1H), 7.54 (dt, J= 7.6, 2.2 Hz, 1H), 8.44 (dt, J= 4.8, 2.1 Hz, 1H), 9.33 (bs, 1H).

2-EtbyMH-pyrrolo[2,3-b]pyridine (8)

9 8

1.0 M solution of t-BuOK in THF (1.27 mL, 1.27 mmol) was added to a solution of 9 (158.9 mg, 0.529 mmol) in toluene (3.0 mL). The mixture turned into a gel, which was stirred at 93 °C for 1 h, when TLC showed that the reaction was completed. The mixture was cooled to r.t., and separated by means of SGC with CH₂Cl₂:MeOH (19:1, v/v) as eluent to afford 8 (52.2 mg, 68%), indistinguishable (1H NMR, TLC) from the product obtained from 6 (see above).

Synthesis of example 2-aryl-substituted 7-azaindole derivative 11 (Scheme 5).

10 11

Scheme 5 [2-(3-Fluoro-benzoylarnmo)-pyridin-3-ylmethyl]-phospbonic acJd diethyl ester (10)

pyridine

10

Compound 10 was obtained from 5 (244.1 mg, 1.0 mmol) and the relevant acid chloride following the method used for the synthesis of 9. Yield 304.0 mg (83%) of colourless oil. 1H NMR (400 MHz, CDC1₃) δ 1.25 (t, J= 7.1 Hz, 6H), 3.18 (d, J= 21.1 Hz, 2H), 3.97-4.14 (m, 4H), 7.17 (ddd, J= 7.5, 4.8, 0.8 Hz, IH), 7.24 (tdd, J = 8.3, 2.6, 0.8 Hz, IH), 7.46 (td, /= 8.0, 5.7 Hz, IH), 7.59 (dt, J= 7.6, 2.1 Hz, IH), 7.87 (ddd, J = 9.6, 2.4, 1.6 Hz, IH), 7.92 (ddd, J= 1.1, 1.2, 0.9 Hz, IH), 8.55 (dt, J^"= 4.8, 2.1 Hz, IH), 10.45 (bs, IH).

2-(3-Fluoro-phenyl)-lH-pyrrolo[2,3-b]pyridme (ll)

10 11 1.0 M solution of t-BuOK in THF (1.09 L, 1.09 mmol) was added to a solution of 10 (133.4 mg, 0.364 mmol) in toluene (2.0 mL). The mixture was stirred at 90 °C overnight. The mixture was cooled to r.t., and separated by means of SGC with CH₂Cl₂:MeOH (19:1, v/v) and then with AcOEt as eluent to afford recovered starting 10 (61.7 mg, 46%) and desired 11 (14.0 mg, 18%); 1H NMR (400 MHz, CDC1₃) δ 6.82 (s, IH), 7.10 (tdd, J= 8.4, 2.5, 0.9 Hz, IH), 7.14 (dd, J= 7.8, 4.9 Hz, IH), 7.48 (ddd, J= 9.9, 8.4, 5.9 Hz, IH), 7.58 (ddd, J = 9.9, 2.4, 1.7 Hz, IH), 7.64 (ddd, J- 7.7, 1.6, 0.9 Hz, IH), 7.99 (dd, J= 7.8, 1.5 Hz, IH), 8.34 (dd, = 4.8, 1.5 Hz, IH), 12.07 (bs, IH).

Synthesis of example 2-unsubstituted 7-azaindole 13 (Scheme 6).

.-BuOK

5 12 13

Scheme 6 (2-Formy]amino-pyridin-3-ylmetbyl)-phosphonic acid diethyl ester (12)

5 12

98% Formic acid (0.22 mL, 5.71 mmol) was added to a solution of acetic anhydride (0.54 mL, 5.72 mmol) in dry ether (5.0 mL). The solution was stirred at r.t. for 15 min. Then a solution of 5 (1.1349 g, 4.65 mmol) in ether (5.7 mL) was added over a period of 1 min. After overnight stirring at r.t., the mixture was separated between saturated aqueous NaHC0₃ - AcOEt (50 mL). The aqueous layer was extracted with AcOEt (30 mL). Combined organic solutions were washed with saturated aqueous NaHC0₃, dried MgS0 and concentrated to afford 12 (789 mg, 62%) as white solid; 1H NMR (400 MHz, CDC1₃) δ 1.26 (t, J= 7.1 Hz, 6H), 3.09 (d, J= 21.3 Hz, 2H), 3.98-4.13 (m, 4H), 7.06 (dd, J = 7.0, 5.1 Hz, IH), 7.27 (dt, = 7.6, 2.1 Hz, IH), 8.25 (bs, IH), 9.27 (bs, 2H).

lH-Pyrrolo[2,3-b]pyridine (7-azaindole, 13)

12 13

1.0 M solution of t-BuOK in THF (1.08 mL, 1.08 mmol) was added to a solution of 12 (122.4 mg, 0.450 mmol) in toluene (2.6 mL). The mixture was stirred for 30 min. at 90 °C, after which TLC showed that the reaction was completed. The mixture was cooled to r.t., and separated between water- AcOEt. The aqueous layer was extracted with AcOEt (3x). Combined organic solutions were dried (MgS0₄), concentrated, and the product was isolated by means of SGC with AcOEt as eluent to afford 13 (13.4 mg, 25%), indistinguishable (^]H NMR, TLC) from the commercially available material.

Synthesis of example 5-substituted 7-azaindole 21 (Scheme 7).

5-Bromo-3-methyl-pyridin-2-ylamine (14)

14

Bromine (15.4 mL, 0.30 mol) was added dropwise to a stirred and cooled (0-2 °C) solution of 2-amino-3-picoline (1; 32.44 g, 0.30 mol) in dry CH₂C1₂ (1000 mL) over a period of 1 h. The cooling bath was then removed, and the yellowish suspension was stirred at r.t. for 3 h 40 min. The mixture was basified to pH 9 with 2N NaOH (145 mL) followed by a mixture of saturated aqueous NaHC0₃ (100 mL) - saturated aqueous Na₂S₂0₃ (10 mL). The organic layer was separated and washed with brine, dried MgS0 and concentrated to afford 14 (56.83 g, 102%) as brown solid, which was used in the next step without purification.

2-(5-Bromo-3-methyl-pyridin-2-yl)-isoindole-l-3-dione (15)

14 15

Compound 14 (55.64 g, 0.299 mol) was converted into 15 following the protocol used for the preparation of 2. Yield 83.77 g (87%) of brownish powder. 1H NMR (400 MHz, CDC1₃) δ 2.27 (s, 3H), 7.78-7.83 (m, 2H), 7.88 (dd, J= 2.3, 0.7 Hz, IH), 7.93-7.99 (m, 2H), 8.56 (dd, 7 = 2.3, 0.4 Hz, IH).

[5-Bromo-2-(l,3-dioxo-l,3-dihydro-isoindol-2-yl)-pyridin-3-ylmethyl]- phosphonic acid diethyl ester (17)

15 16 17

A mixture of 15 (79.42 g, 0.251 mol) and NBS (49.2 g, 0.251 mol) in CC1₄ (700 mL) was refluxed by heating with two sun lamps (250 each). The bromination reaction was initiated by addition of AIBN in 100 mg portions. Progress of the reaction was followed by 1H NMR spectra of small aliquots dissolved in CDC1₃. Total of 1.05 g of AIBN was added over 7 h. The reaction mixture was concentrated to dryness in vacuum and redissolved in CH₂C1₂ (1 L). This solution was washed with IN HCl (5x400 mL). The aqueous layers were discarded and the organic layer was washed with saturated aqueous

NaHC0₃ (50 L), dried MgS0₄ and concentrated in vacuum to afford crude 16 (101.77 g; containing also unreacted 15 and the relevant dibromide) as tan solid.

A mixture of the crude 16 (100.63 g) and triethyl phosphite (28 mL, 0.163 mol) in toluene (350 mL) was refluxed for 40 h. The crude reaction mixture was applied on a column (90 mm o.d., length 24 cm) loaded with silicagel (Kieselgel 60, 230-400 mesh) in CH₂C1₂, and the product was isolated by gradient elution with CH₂C1₂: AcOEt. Obtained 17 (51.94 g, 46% from 15) as white crystalline solid. 1H NMR (400 MHz, CDC1₃) δ 1.18 (t, J= 7.1 Hz, 6H), 3.14 (d, J= 21.8 Hz, 2H), 3.93-4.02 (m, 4H), 7.78-7.83 (m, 2H), 7.94-7.98 (m, 2H), 8.09 (t, J= 2.3 Hz, IH), 8.62 (t, = 2.3 Hz, IH).

(2-Amino-5-bromo-pyridin-3-ylmethyl)-phosphonic acid diethyl ester (18)

Hydrazine hydrate (4.2 mL, 74 mmol) was added to a warm (65 °C) solution of 17 (22.60 g, 50.0 mmol) in absolute EtOH (390 mL). The white suspension, which formed, was allowed to cool to r.t. and was stirred at r.t. overnight. The solid was filtered off and the filtrate was concentrated in vacuum. The semisolid residue was extracted with CH₂C1₂ (4x100 mL). Combined organic solutions were extracted with 5% aqueous HCl (3x45 mL). The combined acidic extracts were basified to pH 10 with 50% aqueous NaOH (about 10 mL; external ice bath cooling) and the product was extracted with CH₂C1₂ (3x100 mL). The extracts were dried (MgS0 ) and concentrated in vacuum to afford 18 (15.72 g, 98%) as yellowish oil. 1H NMR (400 MHz, CDC1₃) δ 1.28 (t, J= 7.1 Hz, 6H), 2.99 (d, .7= 21-1 Hz, 2H), 4.01-4.13 (m, 4H), 5.15 (bs, 2H), 7.39 (t, J= 2.5 Hz, IH), 8.04 (t, J= 2.5 Hz, IH).

Compound 18 may also be synthesized from 5 as shown below

5 18

Bromine (24 μL, 0.46 mmol) was added dropwise to a stirred solution of aminopyridine 5 (112.0 mg, 0.459 mmol) in dry CHC1₃ (2.0 mL). The mixture was then stirred for 2 h at r.t., and treated with a mixture of saturated aqueous NaHC0₃ (2.0 mL) - saturated aqueous Na₂S₂0₃ (0.2 mL). The organic layer was separated and the aqueous layer was extracted with CH C1 (3x2 mL). Combined organic solutions were dried MgS0 and concentrated to afford 18 (144.4 mg, 98%) as brown oil.

[2-Amiπo-5-(4-dimethylamino-phenyl)-pyridin-3-yl-methyl]-phosphonic acid diethyl ester (19)

18 19

A mixture of 18 (5.47 g, 17.0 mmol), 4-(N,N-dimethylamino)phenylboronic acid (4.21 g, 25.5 mmol), LiCl (2.17 g, 51.7 mmol), (PPh₃)₂PdCl₂ (0.55 g, 0.78 mmol) and 1.0 M aqueous Na₂C0₃ (42.3 mL, 42.3 mmol) in ethanol (100 mL) - toluene (100 mL) was refluxed under N₂ for 2 h 30 min. The mixture was cooled to r.t., water (100 mL) was added, the organic layer was separated and washed with brine (100 mL). Combined aqueous solutions were extracted with AcOEt (3x100 mL). The organic extracts were washed with brine, combined with the main organic layer, dried (MgS0 ), and separated by means of SGC with CH₂Cl₂:MeOH (19:1, v/v) as eluent to afford 19 (5.34 g, 87%). 1H NMR (400 MHz, CDC1₃) δ 1.27 (t, J= 7.1 Hz, 6H), 2.98 (s, 6H), 3.10 (d, J= 21.0 Hz, 2H), 4.00-4.13 (m, 4H), 5.10 (bs, 2H), 6.79 (d, J= 8.8 Hz, 2H), 7.39 (d, J= 8.8 Hz, 2H), 7.48 (t, J= 2.5 Hz, IH), 8.23 (t, J= 2.5 Hz, IH).

[5-(4-Dimethylamino-phenyl)-2-formylamino-pyridin-3-ylmethyl]- phosphonic acid diethyl ester (20)

19 20

Compound 19 (124.4 mg, 0.342 mmol) was converted into 20 following the protocol used for the preparation of 12. Yield 99.5 mg (74%) of white solid. H NMR (400 MHz, CDC1₃) δ 1.28 (t, J= 7.1 Hz, 6H), 3.01 (s, 6H), 3.14 (d, J= 21.2 Hz, 2H), 4.03-4.17 (m, 4H), 6.81 (d, J= 8.9 Hz, 2H), 7.44 (d, J= 8.9 Hz, 2H), 7.65 (t, J= 2.5 Hz, IH), 8.45 (bs, IH), 9.20-9.30 ( , 2H).

Dimethyl-[4-(lH-pyrrolo[2,3-b]pyridin-5-yl)-phenyl]-amine (21)

Compound 20 (95.3 mg, 0.244 mmol) was converted into 21 following the protocol used for the preparation of 13. Yield 12.3 mg (21%) of white solid. ^]H NMR (400 MHz, CDC1₃) δ 3.01 (s, 6H), 6.54 (dd, J= 3.4, 0.9 Hz, IH), 6.86 (d, = 8.8 Hz, 2H), 7.36 (dd, J= 3.4, 1.5 Hz, IH), 7.54 (d, J= 8.8 Hz, 2H), 8.09 (d, J= 2.1 Hz, IH), 8.54 (d, J= 2.1 Hz, IH), 9.87 (bs, IH).

Synthesis of 2,5-disubstituted 7-azaindole 23

19 22 23

[2-(2-CyclopropyI-acetylamino)-5-(4-dimethyIamino-phenyl)-pyridin-3- ylmethylj-phosphonic acid diethyl ester (22)

19 22

z-Pr₂NEt (348 μL, 2.0 mmol) was added to a solution of 19 (363.2 mg, 1.0 mmol), PyBrOP (466 mg, 1 mmol), and cyclopropylacetic acid (100 mg, 1 mmol) in CH₂C1₂ (1.0 mL). The mixture was stirred at r.t. overnight and separated by means of SGC with AcOE MeOH (in gradient, up to 19:1 , v/v) as eluent to afford 22 (210.4 mg, 47%). 1H NMR (400 MHz, CDC1₃) δ 0.29-0.34 ( , 2H), 0.64-0.70 (m, 2H), 1.16-1.24 (m, IH), 1.26 (t, J= 1.1 Hz, 6H), 2.41 (d, J= 7.2 Hz, 2H), 3.01 (s, 6H), 3.19 (d, J= 21.1 Hz, 2H), 3.98-4.12 (m, 4H), 6.81 (d, J= 8.9 Hz, 2H), 7.46 (d, J= 8.9 Hz, 2H), 7.70 (t, J= 2.5 Hz, IH), 8.67 (t, J= 2.3 Hz, IH), 9.34 (bs, IH).

[4-(2-Cyclopropylmethyl-lH-pyrrolo[2,3~b] pyridin-5-yl)-phenyl]- dimethyl-amine (23).

22 23

1.0 M solution of t-BuOK in THF (0.70 mL, 0.70 mmol) was added to a suspension of 22 (130.3 mg, 0.293 mmol) in toluene (1.7 mL). The mixture turned into a gel, which was stirred at 110 °C for 20 h. The mixture was cooled to r.t., and separated by means of SGC with CH₂Cl₂:MeOH (19:1, v/v) as eluent to afford 23 (35.5 mg, 42%) of white solid. 1H NMR (400 MHz, CDC1₃) δ 0.29-0.33 (m, 2H), 0.62-0.67 (m, 2H), 1.08-1.17 (m, IH), 2.75 (d, J= 6.9 Hz, 2H), 3.01 (s, 6H), 6.28 (dt, J= 2.1, 0.9 Hz, IH), 6.85 (d, J = 8.9 Hz, 2H), 7.52 (d, J= 8.9 Hz, 2H), 7.95 (d, J= 1.9 Hz, IH), 8.41 (d, J= 1.9 Hz, IH), 9.34 (bs, IH).

Claims

1. A process for the production of a compound of formula 1-2

1-2 comprising reacting a compound of formula 1-1 with base

1-1

wherein X is hydrogen or a group COR;

R and R' are independently hydrogen, branched or unbranched alkyl (optionally interrupted by one or more of 0-, -C(O)-, -N(R )-, -S(O)- and - S(0₂)-), alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, reduced arylalkyl, arylalkenyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, reduced aryl,' reduced heterocyclyl, reduced heterocyclylalkyl or a substituted derivative of any of the foregoing groups, wherein the substituents are one or more independently of halogen, alkyl, halosubstituted alkyl, aryl, arylalkyl, heterocyclyl, reduced heterocyclyl, reduced heterocyclylalkyl, arylalkoxy, cyano, nitro, -C(0)R², -C0₂R², -SOR², -S0₂R², SONR³R³, NR³S0₂R², NR³C0₂R², -NR³R³, -OR², -SR², -C(0)CX¹X²NR³R³, -C(0)N(OH)R³, - C(0)NR³R³, -NR C(0)R², -CR²(NH₂)C0₂R², -NHCX^!X²C0₂R², - N(OH)C(0)NR³R³, -N(OH)C(0)R², -NHC(0)NR³R³, -C(0)NHNR³R³, - C(0)N(OR²)R², and where :-

R² is hydrogen , C j-₁₂ alkyl or aryl, optionally substituted by one or more of Cι_ alkyl, halogen, C_M haloalkyl, OR⁴, SR⁴, N0₂, CN, NR⁴R⁴, NR⁴COR⁴, NR⁴CONR⁴R⁴, NR⁴COR⁴, NR⁴C0₂R⁴, C0₂R⁴, COR⁴, CONR⁴ ₂, S(0)₂R⁴, SONH₂, S(0)R⁴, S0₂ NR⁴R⁴, NR⁴S(0)₂R⁴, wherein the C ₂ alkyl group optionally incorporates one or more insertions selected from the group consisting of -0-, -N(R⁴)-, -S(O)- and -S(0₂)-, wherein each R⁴ may be the same or different and is as defined below;

R is Ci_i₂ alkyl or aryl, optionally substituted by one or more of -₄ alkyl, halogen, C haloalkyl, OR⁴, SR⁴, N0₂, CN, NR⁴R⁴, NR⁴COR⁴, NR⁴CONR⁴R⁴, NR⁴COR⁴, NR⁴C0₂R⁴, C0₂R⁴, COR⁴, CONR⁴ ₂, S(0)₂R⁴, SONH₂, S(0)R⁴, S0₂ NR⁴R⁴, NR⁴S(0)₂R⁴, wherein the C]-₁₂ alkyl group optionally incorporates one or more insertions selected from the group consisting of -0-, -N(R⁴)-, -S(O)- and -S(0₂)-, wherein each R⁴ may be the same or different and is as defined below;

R⁴ is hydrogen, Cι_₄ alkyl, or Cι_₄ haloalkyl, aryl, or heterocyclyl;

1

X and X are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, arylalkyl, heterocyclylalkyl, reduced heterocyclyl or reduced heterocyclylalkyl;

R¹¹ is Cι_i₂ alkyl, aryl, heterocyclyl or OR¹⁰ and R¹⁰ is Cι_ι₂ alkyl, aryl, or heterocyclyl.

2. A process as claimed in claim 1 wherein R is C_M2 alkyl, C₃_]₂ cycloalkyl, phenyl, napthyl, Cμ₁₂ alkylphenyl, pyridinyl, furanyl, pyrroyl, thiophenyl, -.₁₂ alkylpyridinyl, optionally substituted with halogen, -₆ alkyl, CF₃, CCI₃, CH₂CH Br, phenyl, benzyl, pyridyl, methoxy, ethoxy, phenoxy, benzyoxy, cyano, nitro, C(0)R⁵, C0₂R⁵, SOR⁵, S0₂R⁵, SR⁵, NR⁵R⁵, CONR⁵R⁵ or NR⁵C0₂R⁵; wherein R⁵ is methyl, ethyl or propyl.

3. A process as claimed in claim 1 or claim 2 wherein R' is hydrogen, C_\._n alkyl, C₃.₁₂ cycloalkyl, halo, phenyl, napthyl, Cj_ι₂ alkylphenyl, pyridinyl, furanyl, pyrroyl, thiophenyl, C_M2 alkylpyridinyl, optionally substituted with halogen, Cι_₆ alkyl, CF₃, CC1 , CH CH₂Br, phenyl, benzyl, pyridyl, methoxy, ethoxy, phenoxy, benzyoxy, cyano, nitro, C(0)R⁵, C0₂R⁵, SOR⁵, S0₂R⁵, SR⁵,

NR⁵R⁵, CONR⁵R⁵ or R⁵C0₂R⁵

wherein R⁵ is methyl, ethyl or propyl.

4. A process as claimed in any one of claims 1 to 3 wherein R is methyl, ethyl, propyl, butyl, pentyl, hexyl, phenyl, pyridyl or a group OR¹⁰, wherein R is methyl, ethyl, propyl, butyl, pentyl, hexyl, phenyl or pyridyl.

5. A process as claimed in any one of claims 1 to 4 wherein X is hydrogen or a group CO(CH₂)_nCH₃ or CO(CH₂)_ncycloalkyl wherein n is 0, 1, 2, 3, 4 or 5, or CO-phenyl or CO-pyridyl.

6. A process for the production of a compound of formula 1-3 comprising deprotecting a compound of formula 1-2 to produce a compound of formula 1-3.

1-2 1-3

wherein R and R are as defined in any one of claims 1 to 5.

7. A process for the production of a compound of formula 1-1

comprising reacting a compound of formula II-5 with a group RCOY.

wherein the groups R', R and R¹¹ are as defined in any one of claims 1 to 5, and the group Y is OH, halide or OCOR.

8. A process for the production of a compound of formula II-4

II-2 π-3 π-4

comprising halogenating a compound of formula II-2, to form a methyl-halo derivative II -3 and reacting the compound of formula II-3 with a phosphite (R¹ °0)(R^{1 ]})₂P to form a compound of formula II-4, wherein R^{1 ]} is d.j ₂ alkyl, aryl or heterocyclyl or OR¹⁰, R³⁰ is C₁-₁₂ alkyl, aryl or heterocyclyl R¹ is as defined in any one of claims 1 to 5 and Pr is a protecting group.

A process for the production of a compound of formula II-

comprising deprotecting the amino group of compound II-4, wherein R¹¹, Pv and R¹ are as defined in claim 8.

10. A compound of formula 1-4,

wherein the groups R', and R¹¹ are as defined in any one of claims 1 to 5 and the group Z is hydrogen or a protecting group selected from enzyloxycarbonyl, t-butyloxycarbonyl, 2-(4-biphenylyl)-isoρropoxycarbonyl, 9- fluorenylmethoxycarbonyl, triphenylmethyl, 2-nitrophenylsulphenyl or isoindole-dione.

11. A compound of formula I- 1

wherein the groups R, R', Rⁿ and X are as defined in any one of claims 1 to 5.