WO2000063186A1

WO2000063186A1 - Process and intermediates for preparing benzodiazepines

Info

Publication number: WO2000063186A1
Application number: PCT/EP2000/003260
Authority: WO
Inventors: Jerome Francis Hayes
Original assignee: Smithkline Beecham Plc
Priority date: 1999-04-15
Filing date: 2000-04-12
Publication date: 2000-10-26
Also published as: GB9908662D0; AR023478A1; CO5180551A1; AU4295100A

Abstract

A new process and intermediates for preparing 1,4-benzodiazepines of formula (I) is disclosed: wherein, R1 is H, OH, Br, I, NR5R6, CO2R7, CF3SO3, C1-4alkoxy, or (4,4'-bipiperidinyl) carbonyl; R2 is alkyl, optionally substituted by CO¿2R?7 or CONR?5R6; R3 and R3'¿ are independently H, Ar or C¿1-6? alkyl optionally substituted by OH, NO2, NH2, NR?5R6¿, halogen, CO¿2?R?7, CONR5R6¿ or Ar, or together R?3 and R3'¿ are =O; R4 is H or C¿1-4? alkyl, optionally substituted by OH, NO2, NH2, NR?5R6¿, halogen, CO¿2?R?7, CONR5R6¿, or Ar; R?5 and R6¿ are independently H, Ar, C¿1-6?alkyl, HCO, C1-6alkyl-CO, Ar-CO, C1-6alkyl-SO2, or Ar-SO2; and R?7¿ is a carboxylic acid protecting group.

Description

PROCESS AND INTERMEDIATES FOR PREPARING BENZODIAZEPINES

Field of the Invention This invention relates to processes and intermediates for preparing benzodiazepine vitronectin and fibrinogen antagonists.

Background Tetrahydro-l,4-benzodiazepines form the core structure of a variety of pharmaceutically useful compounds. In particular, WO 93/00095

(PCT US92/05463), WO 94/14776 (PCT/US93/12436), and WO 95/18619 (PCT/US95/00248) disclose 7-substituted tetrahydro-l,4-benzodiazepines which are reported to be inhibitors of the fibrinogen and vitronectin receptors and are useful as inhibitors of platelet aggregation, osteoporosis, angiogenesis and cancer metastasis. These publications contain a variety of procedures for constructing the basic 1 ,4- benzodiazepine structure. The prior processes employ expensive reagents and generally require a large number of synthetic steps in the sequence.

We have now discovered new useful intermediates and a new process for preparing certain 7-substituted 1,4-benzodiazepines. The new process uses a unique cyclization step to form the diazepine ring, and is adaptable to a large scale. Teuber et al., Chem. Ber., 98, 2648 (1965), have reported an oxidative method for forming an indole, and Kraus et al., Tet. Lett., 39, 3957 (1998), have reported a cyclization for forming a 3,4-dihydro-l,4-benzodiazepine-2,5-dione, using an acyl hydroquinone and Fremy's salt. Kraus et al., Tet. Lett., 40, 2039 (1999), have also reported using Fremy's salt to promote an unusual rearrangement of a l,4-benzodiazepine-5-one, presumably through a 1-acyl quinone. The compounds of the instant invention do not possess the stabilizing acyl hydroquinone arrangement found in these compounds.

Summary of the Invention

In one aspect this invention is a new process for preparing 1,4- benzodiazepines of formula (I):

(I)

wherein R^R⁷ are as defined hereinafter, from substitued 2-hydroxy phenols of formula (II):

(II)

which comprises reacting a compound of the formula (II) with an oxidizing agent wherein R and R^R⁷ are as defined hereinafter.

In another aspect this invention comprises new compounds for preparing 1,4- benzodiazepines.

In yet another aspect this process may be used to prepare 2,3,4,5-tetrahydro- 7-( 4,4'-bipiperidinylcarbonyl)-3-oxo-4-methyl- 1 H- 1 ,4-benzodiazepine-2-acetic acid, and related active pharmaceutical agents.

Detailed Description of the Invention

Many compounds that are useful as pharmaceuticals or intermediates for preparing pharmaceuticals are given by formula (I):

(I) wherein,

R¹ is H, OH, Br, I, NR⁵R⁶, CO₂R⁷, CF₃SO₃, C alkoxy, or (4,4'- bipiperidinyl)carbonyl;

R² is alkyl, optionally substituted by CO₂R⁷ or CONR⁵R⁶; R³ and R³' are independently H, Ar or C_j.galkyl optionally substituted by OH, NO₂, NH₂, NR⁵R⁶, halogen, CO₂R⁷, CONR⁵R⁶or Ar, or together R³ and R³' are =O;

R⁴ is H or C alkyl, optionally substituted by OH, NO₂, NH₂, NR⁵R⁶, halogen, CO₂R⁷, CONR⁵R6, or Ar;

R⁵ and R⁶ are independently H, Ar, C^alkyl, HCO, C^alkyl-CO, Ar-CO, C₁.₆alkyl-SO₂, or Ar-SO₂; and

R⁷ is a carboxylic acid protecting group.

Compounds of formula (I) may be prepared by a process which comprises, reacting a compound of the formula (II) with an oxidizing agent,

(ID wherein R is OH or C^alkoxy, and R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ are as defined above, and thereafter, treating with a reducing agent. Preferably R is OH. Preferably, R¹ is H, OH, NH₂, bromo, iodo, CO₂R⁷, or C^alkoxy. More preferably, R¹ is H or OH.

Preferably, R² is CH₂CO₂R⁷ or CH₂CONR⁵R⁶; more preferably CH₂CO₂R⁷. Preferably, R³ and R³' are =O.

Preferaby, R⁴ is H, C^alkyl or Ar-Ci^alkyl. Methyl is especially preferred. Preferably R⁷ is C^alkyl, phenyl or benzyl. Methyl, t-butyl or benzyl is especially preferred.

Suitably, R and R¹ are each OH or OCH₃. Most preferably, R and R¹ are OH. Compounds of formula (II), wherein R, and R^J-R⁴ are as defined above, are useful for the preparation of the compounds of formula (I) and are a feature of this invention. A preferred embodiment comprises compounds of formula (II) wherein R is OH or C₁.₄alkoxy; R¹ is H, OH, Br, I, C^alkoxy.CO^⁷, CF3SO3, or (4,4'- bipiperidinyl)carbonyl, optionally protected on the basic nitrogen; R⁴ is methyl, and R⁷ is a carboxy protecting group. The condensation reaction to form the diazepine ring presumably proceeds through a Schiffs base-type intermediate, as illustrated in Scheme 1, so the oxidant used must be

Scheme 1

sufficient to promote oxidation of the aromatic hydroxyl group to a carbonyl and induce the free amino group to condense with it. Salts of ferricyanide and nitrosodisulfonate are useful, especially potassium ferricyanide and potassium mtrosodisulfonate. Agents of similar oxidation potential are also useful, such as silver (I) oxide, thallium (IN) nitrate, cerium (IN) ammonium nitrate, hypervalent iodine compounds, palladium on charcoal with a hydrogen acceptor (e.g., nitrobenzene), acid dichromate, lead tetra-acetate, and potassium periodate. Potassium nitrosodisulfonate (Fremy's salt) is a preferred reactant. Acetic acid and hydrochloric acid are preferred acids for use in the reaction, although other organic acids and mineral acids may also be suitable.

It will be apparent that when R¹ is a hydroxyl group, the reaction may proceed through a quinone-type intermediate, as indicated by the compounds of formula (III), wherein R², R³ and R⁴ are as defined in formula (I).

(IE) For instance, a preferred compound is (3S)-methyl 3-amino-4-(N-methyl-N-(l,4- benzoquinonylmethyl)carbamoyl) butanoate,

Reduction of the double bond completes the construction of the 2,3,4,5 tetrahydro-l,4-benzodiazepine ring system. Reduction may be accomplished readily by catalytic hydrogenation, such as by hydrogenation over palladium or platinum, although other means, such as transfer hydrogenation, for instance using ammonium formate and Pd/C in refluxing methanol, may be suitable.

In cases where further unsaturation is present in the ring system, tautomerisation of the Schiff s base may occur. For instance, when there is a 3-oxo group and a 2-acetic acid group, the double bond may tautomerize, as indicated in Scheme 2.

Scheme 2

Thus, 1,4-benzodiazepine ring systems that have 3-oxo, 2-acetic acid substituents tautomerize to a 2-ethylidene configuration, and compounds of formula (IN):

(IN)

wherein R¹ is H, OH, Br, I, ΝR⁵R⁶, CO₂R⁷, CF3SO3, C₁.₄alkoxy, or (4,4'- bipiperidinyl)carbonyl; R⁴ is H or C^ alkyl, optionally substituted by OH, NO , NH₂, NR⁵R⁶, halogen, CO₂R⁷, CONR⁵R⁶, or Ar; R⁵ and R⁶ are independently H, Ar, C^alkyl, HCO, C^alkyl-CO, Ar-CO, C₁.₆alkyl-SO₂, or Ar-SO₂; and R⁷ is a carboxylic acid protecting group, are useful intermediates for preparing pharmaceutically active compounds, such as those disclosed in WO 95/18619 (PCT/US95/00248); WO 93/00095 (PCT/US/92/05463) and WO 94/14776 (PCT/US93/12436). Preferably Rl is H or OH, and R⁴ is methyl. In a preferred embodiment, this invention is a process for preparing the active pharmaceutical product 2,3,4,5-tetrahydro-7-( 4,4-bipiperidinylcarbonyl)-3- oxo-4-methyl-lH-l,4-benzodiazepine-2-acetic acid, comprising reacting a compound of the formula (N):

wherein R¹ is H, OH, I, Br, CO₂R⁷, CF₃SO₂, C^lkoxy, or (4,4'- bipiperidinyl)carbonyl, optionally protected on one nitrogen; R⁴ is methyl, and R⁷ is a carboxy protecting group; with a reducing agent; and, if necessary, converting R¹ to (4,4'-bipiperidinyl)carbonyl, and, if necessary, removing any protecting groups. It will be apparent that the α,β unsaturated ester may be reduced at any point in the synthesis subsequent to the cyclization reaction. Reduction may be accomplished, for instance, using palladium or platinum on carbon. Preferably, R¹ is H or OH. In a another preferred embodiment, this invention is a process for preparing

2,3,4,5-tetrahydro-7-(4,4'-bipiperidinylcarbonyl)-3-oxo-4-methyl-lH-l,4- benzodiazepine-2-acetic acid, comprising treating the compound of formula (VI):

(NI)

wherein R¹ is H, OH, I, Br, CO₂R⁷, CF3SO3, C_Malkoxy, or (4,4'- bipiperidinyl)carbonyl, optionally protected on the basic nitrogen; R⁴ is methyl; and R⁷ is a carboxy protecting group; with an oxidizing agent, and, in any order, treating with a reducing agent and, if necessary, converting R¹ to (4,4'-bipiperidinyl)carbonyl; and, if necessary, removing any protecting groups. Preferably, R¹ is H or OH, and the product is converted to 2,3,4,5-tetrahydro-7-(4,4'-bipiperidinylcarbonyl)-3-oxo-4-methyl-lH-l,4- benzodiazepine-2-acetic acid via a palladium catalyzed aminocarbonylation. It will be understood that one may use a variety of functional groups in the process for R¹, and subsequently transform such groups to the (4,4'- bipiperidinyl)carbonyl sidechain. For instance, one may convert a hydroxyl group at R¹ to a triflate group, and add the bipiperidinylcarbonyl group via a palladium catalyzed aminocarbonylation reaction, as described in WO 97/24336

(PCT/IB96/01502). It will of course be evident that an alkoxy substituent may be converted to a hydroxy substituent, such as by hydrolysis, and further transformed by similar means to the desired 4,4'-bipiperidinylcarbonyl group. One may also use an aminocarbonylation reaction to convert the bromo or iodo group to the bipiperidinylcarbonyl amino group. Additionally, a hydrogen at R¹ may be converted to bromo or iodo group, as described for instance in WO 97/24336 (PCT/TB96/01502), and converted via an aminocarbonylation reaction to the bipiperidinylcarbonyl group. An ester group may be hydrolyzed to a carboxyl group and reacted with the bipiperidinyl group using conventional amide bond forming reagents, such as dicyclohexylcarbodiimide or via an acid chloride.

As is apparent from the foregoing, compounds according to formula (VI), are useful for preparing compounds of formula (V), and constitute a part of this invention.

Scheme 3 illustrates some of the representative methods for preparing 2,3,4,5-tetrahydro-7-( 4,4'-bipiperidinylcarbonyl)-3-oxo-4-methyl-lH-l,4- benzodiazepine-2-acetic acid.

Scheme 3

R = R¹ =OMe R = R¹ =OMe R = RI =OMe 1

R = R1 =OH R = R1 =OH R = R^I =OH 21

R = OH, R¹ = H R = OH, R1 = H R = OH, R¹ = H 31

R = OH 5, 24 R¹ = H 34

Rⁱ = OH R¹ = H (a) MeNH₂ (8.03M solution in EtOH), toluene (b) 10% Pd-C, EtOH, H₂ (c) N-Cbz- aspartic acid β-methyl ester, DCC, optionally HOBT; (d) ammonium cerium(IV) nitrate, MeCN, H₂O; (e) H₂, 10% Pd-C, ethanol; (f) potassium mtrosodisulfonate chloroform, acetic acid, HCI; (g) H₂, 10% Pd-C, ethanol; (h) potassium nitrosodisulfonate chloroform, acetic acid, HCI; (i) H₂, 10% Pd-C, ethanol, H₃PO₄

The meaning of any substituent at any one occurrence in formulas (I)-(VI) or any sub formula thereof is independent of its meaning, or any other substituent's meaning, at any other occurrence, unless specified otherwise. Abbreviations and symbols commonly used in the chemical arts are used herein to describe the compounds, reactions and reagents of this invention.

Certain radical groups are abbreviated herein. t-Bu refers to the tertiary butyl radical, Boc refers to the t-butyloxycarbonyl radical, Ph refers to the phenyl radical, CBZ or Z refers to the benzyloxycarbonyl radical, Bn refers to the benzyl radical, Me refers to methyl, Et refers to ethyl, and Ac refers to acetyl.

Certain reagents are abbreviated herein. DCC refers to dicyclohexylcarbodiimide, DMAP refers to dimethylaminopyridine, DIEA refers to diisopropylethylamine. THF refers to tetrahydrofuran, DMF refers to dimethyl formamide, Pd-C refers to a palladium on carbon catalyst, TEA refers to triethylamine, TFA refers to trifluoroacetic acid.

Cj_₄ alkyl as applied herein is meant to include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and t-butyl. Ci-galkyl additionally includes pentyl, n- pentyl, isopentyl, neopentyl and hexyl and the simple aliphatic isomers thereof. Any C^al-kyl or Ci^alkyl group may be optionally substituted by halo, -OR', SR', -CN, -NR'R', -NO₂, -CF₃, CF₃S(O)_r-, -CO₂R', -CONR'₂, C₃.₆cycloalkyl, or Ar, unless otherwise indicated, where R' is H or C . alkyl. A substituent on a C . alkyl may be on any carbon atom which results in a stable structure, and is available by conventional synthetic techniques.

Ar, or aryl, as applied herein, means phenyl or naphthyl, or phenyl or naphthyl substituted by one to three moieties. In particular, such moieties may be C^alkyl, Ci^alkoxy, Ci^alkylthio, trifluoromethyl, OH, F, Cl, Br or I.

The reactive functional groups of each synthetic fragment are suitably protected as known in the art. Suitable protective groups are disclosed in Greene, PROTECTIVE GROUPS IN ORGANIC CHEMISTRY, John Wiley and Sons, New York, 1981. For example, the Boc, Cbz, phthaloyl or Fmoc group may be used for protection of an amino (or the nitrogen of a piperidinyl). The Boc or Cbz group is generally preferred for protection of an amino group, such as on the basic nitrogen of a 4,4'-bipiperidinyl group. The term the basic nitrogen of the 4,4'-bipiperidinyl group, as used herein, indicates the nitrogen which is not attached to the benzodiazepine nucleus via a carbonyl group. A methyl, ethyl, t-Bu, cHex, benzyl, substituted benzyl, (pivaloyl)methyl or

(2-methyl-2-methoxypropanoyl)methyl ester may be used for the protection of the carboxyl group. A suitably substituted carbobenzyloxy group or benzyl group may be also be used for the hydroxyl group or amino group. Suitable substitution of the carbobenzyloxy or benzyl protecting groups is ortho and/or para substitution with chloro, bromo, nitro, methoxy or methyl, and is used to modify the reactivity of the protective group. Cj-galkoxy, phenyl and benzyl are conventional carboxy protecting groups.

Methods for removal of the a carboxy or amino protecting group are well known in the art. For example, an alkyl or cycloalkyl ester may be removed by basic hydrolysis, for instance an alkali metal hydroxide, such as sodium, potassium or lithium hydroxide in a suitable solvent, such as aqueous alcohol. A benzyl ester is typically removed by hydrogenation over a palladium catalyst. A basic nitrogen protected by a t-butyloxycarbonyl group, or a t-butyl ester, is typically removed by acid treatment, such as by trifluoroacetic acid or hydrochloric acid, optionally diluted with a solvent, such as methylene chloride and/or dioxane. The benzyloxycarbonyl group is generally removed by hydrogenation over a palladium catalyst. A trifluoroacetyl group is typically removed by basic hydrolysis, such as by treatment with an alkali metal hydroxide in a suitable solvent. One useful synthetic method for protecting the basic nitrogen of a piperidinyl group is to carry the group through a synthesis as a pyridinyl group, which may be reduced with a platinum or palladium catalyst toward the end of the synthesis to remove the protecting group.

The simple starting materials for preparing the compounds of this invention are commercially available or prepared by routine methods well known in the art. The intermediate compounds of this invention are useful as intermediates in the preparation of pharmaceutically active compounds, in particular compounds which have fibrinogen and vitronectin antagonist properties. General

Nuclear magnetic resonance spectra were recorded at 270 MHz. CDCI3 is deuteriochloroform, DMSO-d₆ is hexadeuteriodimethylsulfoxide, and CD₃OD is tetradeuteriomethanol. Chemical shifts are reported in parts per million (δ) downfield from the internal standard tetramethylsilane. Abbreviations for NMR data are as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd = doublet of doublets, dt = doublet of triplets, app = apparent, br = broad. J indicates the NMR coupling constant measured in Hertz. HRMS indicates high resolution mass spectroscopy.

EXAMPLES

Example 1 Preparation of 2,3,4,5-tetrahydro-7-(N-CBZ-4,4'-bipiperidinylcarbonyl)-3-oxo-4- methyl-2-methoxycarbonylethylidenyl)- 1 H- 1 ,4-benzodiazepine (9)

a) Ν-(2,5-dimethoxybenzylidine) methylamine.

To a solution of 2,5-dimethoxybenzaldehyde (20.00g, 0.12 mol) in toluene (100 ml) was added methylamine (22.5 ml of an 8.03M solution in ethanol, 0.18 mol) at room temperature. The solution became cloudy within 10 min. due to the condensation of water. The reaction had gone to completion within 30 min. according to GC analysis and the solvent was then removed in vacuo to give the required product; (21.17g, 98%) as a yellow oil. δH (CDCI3, 270 MHz) 3.50 (3H, s), 3.80 (3H, s), 3.85 (3H, s), 6.80 (IH, m), 7.00 (IH, m), 7.50 (IH, m) and 8.70 (IH, s).

b) methyl (2,5-dimethoxybenzyl) amine (1)

A solution of N-(2,5-dimethoxybenzylidine) methylamine (21.17g, 0.12 mol) in ethanol (200 ml) was hydrogenated over 10% palladium on charcoal (water content 50%ι, 4.0g). The reaction had gone to completion within 2h according to GC analysis. The catalyst was filtered off and the filtrate was concentrated to dryness. The title compound was thus obtained as a yellow oil (18.00g, 85%); δH (CDC1₃,

270 MHz) 1.70 (IH, s br), 2.45 (3H, s), 3.70 (2H, s), 3.75 (3H, s) 3.80 (3H, s), 6.70 - 6.85 (3H, m). c) (3S)-methyl 3-benzyloxycarbonylamino-4-(N-methyl-N-2,5- dimethoxybenzylcarbamoyl) butanoate (2)

To a solution of methyl (2,5-dimethoxybenzyl) amine (lO.OOg, 55.2mmol) and Ν-CBZ aspartic acid β-methyl ester (17.10g, 60.9mmol) in ethyl acetate (100 ml) was added dicyclohexylcarbo diimide (12.50g, 60.7mmol) at room temperature. A thick precipitate formed within 15 min. and after lh the reaction mixture was filtered. The filtrate was concentrated to dryness to afford the crude required product as a thick oil and as a mixture of rotamers (30.73g, 100%) δH (CDCI3, 270

MHz) 2.60 - 2.85 (2H, m), 2.90 (1.5H, s), 3.10 (1.5H, s), 3.65 (2H, s), 3.70 (3H, s), 3.80 (3H, s), 4.50 - 4.75 (IH, m), 5.05 (IH, d), 5.10 (IH, s), 4.70 (0.5H, d), 5.80 (0.5H, d), 6.70 - 6.80 (3H, m) and 7.25 - 7.40 (5H, m).

d) (3S)-methyl 3-benzyloxycarbonylamino-4-(N-methyl-N-(l,4- benzoquinonylmethyl) carbamoyl) butanoate (3) To a solution of (3S)-methyl 3-benzyloxycarbonylamino-4-(N-methyl-N-2,5- dimethoxybenzylcarbamoyl) butanoate (3) (47.0g, 0.106mol) in acetonitrile (2.35L) was added cerium IV ammonium nitrate (145.5g, 0.265mol) in water (454 ml) at - 14°C -10°C. The reaction mixture became dark brown-orange immediately and the colour became lighter over lh. The temperature was allowed to rise to 5 - 10°C over 2h. and then to 12 - 15°C over 90 min. The solvent was then removed in vacuo and the residue was dissolved in dichloromethane (500 ml) and was washed with water.

The aqueous layer was back extracted with dichloromethane (500 ml). The combined organic extracts were dried (Mg SO4) and concentrated to dryness. The residue was chromatographed on silica gel using ethyl acetate as eluant. Hence the title compound was obtained as a viscous yellow oil (44.5g, 100%); δH (CDCI3,

270 MHz) 2.60 - 3.00 (2H, m), 3.25 (3H, s), 3.70 (3H, s), 3.85 (IH, m), 4.40 (2H, ABq), 5.10 (2H, m), 5.60 (IH, d br), 6.55 (IH, m), 6.75 (2H, m) and 7.40 (5H, m).

e) (3S)-methyl 3-amino-4-(N-methyl-N-(2,5-dihydroxybenzyl) carbamoyl) butanoate (4)

A solution of (3S)-methyl 3-benzyloxycarbonylamino-4-(N-methyl-N-(l,4- benzoquinonylmethyl) carbamoyl)butanoate (44.5g, O.lOOmol) in ethanol (1.50L) was hydrogenated over 10% palladium on charcoal (16.0g) at room temperature under one atmosphere of hydrogen for 16h. The catalyst was filtered off after this time and the filtrate was concentrated to dryness. (The crude product was not characterised but was used directly in the next step). δH (d-6 DMSO, 270 MHz 40°C) 2.40 (IH, dd), 2.70 (IH, dd), 2.90 (1.5H, s), 3.05 (1.5H, s), 3.30 (2H, s br), 3.60 (3H, s), 4.35 (IH, ABq), 4.50 (IH, ABq), 6.45 (2H, m) and 6.60 (IH, m).

f) 2,3,4,5-tetrahydro-7-hydroxy-3-oxo-4-methyl-2-(methoxycarbonylethylidenyl)- lH-l,4-benzodiazepine (5)

To a solution of (3S)-methyl 3-amino-4-(N-methyl-N-(2,5-dihydroxybenzyl) carbamoyl) butanoate (4) (30.30g, 0.107mmol) in water (2.08L) and acetic acid (233 ml) and chloroform (5.0L) was added hydrochloric acid (9.7 ml of an 11.0M aqueous solution, 0.107mmol) followed by Fremy's salt (63.4g, 0.237mol) in water (3.0L) at room temperature. The reaction mixture was stirred for 3h after which time the aqueous layer was separated. The chloroform layer was washed with water (1.0L) and was then concentrated to dryness. The resultant dark foamy residue was chromatographed on silica gel using ethyl acetate:hexane - 3:1 as eluant. Hence the title compound was obtained as white solid (7.29g, 26%). δH (CDC1₃, 270 MHz) 3.00 (3H, s), 3.75 (3H, s), 4.25 (2H, s br), 5.40 (IH, s), 5.80 (IH, s), 6.70 - 6.80 2H, m), 6.85 (IH, d) and 10.50 (IH, s). High Resolution Mass Spectrum (HRMS): Found M⁺H 263.1016. C₁₃Hι₅Ν₂O reqires 263.1032.

g) 2,3,4,5-tetrahydro-7-(trifluoromethanesulfonyloxy-3-oxo-4-methyl-2- methoxycarbonylethylidenyl)-lH-l ,4-benzodiazepine (6)

To a solution of 2,3,4,5-tetrahydro-7-hydroxy-3-oxo-4-methyl-2-

(methoxycarbonylethylidenyl)-lΗ-l,4-benzodiazepine (5) (l.OOg, 3.82mmol) in pyridine (3.0 ml) was added trifluoromethanesulfonic anhydride (7.06 μl,

4.21mmol) at 0°C. The reaction mixture was stirred for 90 min. after which time it was diluted with ether (100 ml) and washed with water (250 ml). The aqueous layer was extracted with further ether (ca 100 ml) and the combined organic layers were dried (MgSO4) and concentrated to dryness. The residue was chromatographed on silica gel using ethyl acetate:hexane - 2:3 as eluant. Hence the title compound was obtained as a white solid (1.10g, 73%) m z 395 [M+H]⁺, 363 [M - MeOH+H]⁺, 335 [M - HCO₂Me+H]⁺; δH (CDCI3, 400 MHz) 3.10 (3H, s), 3.75 (3H, s), 4.30 (2H, s br), 5.50 (IH, s), 7.10 (IH, d), 7.15 (IH, d), 7.20 (IH, dd) and 10.70 (IH, s); HRMS: Found 394.0431. C1 H1₃F₃N2O₆S requires 394.0446. h) 2,3,4,5-tetrahydro-7-(N-CBZ-4,4'-bipiperidinylcarbonyl)-3-oxo-4-methyl-2- methoxycarbonylethylidenyl)- 1 H- 1 ,4-benzodiazepine (7)

A 50 ml 3-necked flask containing a mixture of 2,3,4,5-tetrahydro-7- (trifluoromethanesulfonyloxy-3-oxo-4-methyl-2-methoxycarbonylethylidenyl)-lH- 1 ,4-benzodiazepine (6) (0.27g, 0.68mmol), diisopropylethylamine (1.4 ml,

8.05mmol), N-CBZ-4,4'-bipiperidine hydrochloride (298 mg, 0.88mmol), palladium II chloride bistriphenylphosphine (10 mg, 0.014mmol) and water (30μl, 1.66mmol) in N-methylpyrrolidinone (2.2 ml) was evacuated and filled with carbon monoxide gas several times. The reaction mixture was then heated to 90 - 95°C under an atmosphere of carbon monoxide with vigorous stirring. After 5h palladium (0) tetrakistriphenylphosphine (lOOmg) was added and the carbonylation was continued. The reaction had gone to completion according to ΗPLC analysis after 16h. A solution assay of the reaction mixture against a reference standard indicated the yield to be 18 lmg, 46%. The reaction mixture was diluted with dichloromethane (30 ml) and was filtered. The filtrate was washed with water (2 x 30 ml) and was then concentrated to dryness in vacuo. The residue was chromatographed on silica gel using ethyl acetate as eluant to give the title compound as a pale yellow foam (144mg, 37%o). This was triturated with ether (ca 4 ml) to give a purified sample as a white powder, m/z 575 [M+Η]⁺; δH (CDC1₃, 400 MHz) 1.10 - 1.45 (6H, m), 1.60 - 1.85 (4H, m), 2.75 (4H, m), 3.15 (3H, s), 3.75 (3H, s), 3.85 (IH, s v br), 4.15 - 4.30 (4H, m), 4.70 (IH, s br), 5.15 (2H, s), 5.45 (IH, s), 7.00 (IH, d), 7.30 - 7.40 (7H, m) and 10.70 (IH, s).

i) methyl 2,3,4,5-tetrahydro-7-( 4,4'-bipiperidinylcarbonyl)-3-oxo-4-methyl-lH-l,4- benzodiazepine-2-acetate (8)

A suspension of 2,3,4,5-tetrahydro-7-(N-CBZ-4,4'-bipiperidinylcarbonyl)-3- oxo-4-methyl-2-methoxycarbonylethylidenyl)-lH-l,4-benzodiazepine (7) (375 mg, 0.653mmol) in methanol (20 ml) and water (10 ml) was acidified to pH 2.5 with a 26%) aqueous solution of phosphoric acid. The resultant mixture was hydrogenated over 10% palladium on charcoal (Johnson Matthey type 87L, 375 mg) at 60 psi in a Parr Shaker at room temperature. The reaction had gone to completion within 2h according to HPLC analysis. The catalyst was filtered off and the filtrate was concentrated in vacuo to ca 5 ml. Water (10 ml) was added and the pH was then adjusted to 10 with a 35% aqueous solution of ammonia. A white precipitate formed and the suspension was cooled to 5°C for 16h. The precipitate was then filtered off and dried in the open atmosphere to give the title compound as a white powder (257mg, 89%).

j) 2,3,4,5-tetrahydro-7-( 4,4'-bipiperidinylcarbonyl)-3-oxo-4-methyl-lH-l ,4- benzodiazepine-2-acetic acid (9)

The compound of Example l(i) (0.26 mmol) was dissovled in methanol (9 ml), and 1.0 N sodium hydroxide (0.81 ml, 0.81 mmol) was added. The solution was stirred overnight at room temperature, and concentrated. The residue was dissolved in water/acetonitrile (3 ml), cooled to 0°C, acidified with HCI, and concentrated to yield the title compound.

Example 2 Preparation of 2,3,4,5-tetrahydro-7-( 4,4 -bipiperidinylcarbonyl)-3-oxo-4-methyl- lH-l,4-benzodiazepine-2-acetic acid (12)

a) N-(2,5-hydroxybenzylidine) methylamine

Using the procedure of Example 1(a), except substituting 2,5-dihydroxy- benzaldehyde for 2,5-dimethoxy-benzaldehyde, the title compound was prepared. δH (CDC1₃, 270 MHz), 3.50 (3H,S), 6.75 (lH,m), 6.85 (2H,m) and 8.25 (lH,s)

b) N-methyl, N-(2,5-dihydroxybenzyl) amine (21)

Using the procedure of Example 1(b), except substituting the compound of Example 2(a) for the compound of Example 1(a), the title compound was prepared. δH (CDCI3, 270 MHz) 2.25 (3H,S), 3.60 (2H,s) and 6.50 (3H,m).

c) (3S)-methyl 3-benzyloxycarbonylamino-4-(N-methyl-N-2,5- dihydroxybenzylcarbamoyl) butanoate (22)

Using the procedure of Example 1(c), except substituting the compound of Example 2(b), and chromatographmg the crude product over silica gel using ethyl acetate:hexane - 1 :1 - 1 :0 as eluent, the title compound was prepared (46%). δH (CDC1, 270 MHz) 2.65 (lH,dd), 2.80 (lH,dd) 2.95 (3H,s), 3.60 (3H,s), 4.35 (2H, ABQ), 5.05 (2H,m), 5.80 (lH,d), 6.65 (lH,s), 6.75 (2H,m), 7.25 - 7.50 (5H,m) and 8.60 (2H,s(br)). e) (3S)-methyl 3-amino-4-(N-methyl-N-(2,5-dihydroxybenzyl) carbamoyl) butanoate (23)

A solution of 22 (7.82g, 18.80 mmol) in absolute ethanol 107ml was hydrogenated over 10%) palladium on charcoal (0.78g) for 20h. The catalyst was filtered off and the filtrate was concentrated to dryness. The residue was chromatographed on silica gel using ethyl acetate : dichloromethane : methanol - 4:4:2 as eluant. The title compound was obtained as a colourless foam (3.6g, 65%).

f) 2,3,4,5-tetrahydro-7-hydroxy-3-oxo-4-methyl-2-(methoxycarbonyl ethylidenyl)- lH-l,4-benzodiazepine (24)

Using the procedure of Example 1(f), except subtituting the compound of Example 2(e) for the compound of Example 1(e), the title compound was prepared.

g) 2,3,4,5-tetrahydro-7-( 4,4'-bipiperidinylcarbonyl)-3-oxo-4-methyl-lH-l ,4- benzodiazepine-2-acetic acid (9)

Using the compound of Example 2(f) and following the procedures of Examples 1(d) - l(j), the title compound is prepared.

Example 3 Preparation of 2,3,4,5-tetrahydro-7-( 4,4'-bipiperidinylcarbonyl)-3-oxo-4-methyl- 1 H- 1 ,4-benzodiazepine-2-acetic acid

a) Ν-(2-hydroxybenzylidine) methylamine

Using the procedure of Example 1(a), except substituting 2-hydroxy- benzaldehyde for 2,5-dimethoxy-benzaldehyde, the title compound was prepared. δH (CDC1₃, 270MHz) 6.80 (lH,t), 7.00 (lH,s), 7.20-7.30 (2H,m) and 8.40 (lH,s).

b) N-methyl, N-(2-hydroxybenzyl) amine (31)

Using the procedure of Example 1(b), except substituting the compound of Example 3(a) for the compound of Example 1(a), the title compound was prepared. δH (CDC1₃, 270MHz) 2.50 (3H,s), 4.00 (2H,s) 6.75 (lH,t),6.80 (lH,d), 7.00 (lH,d) and 7.20 (lH,t). c) (3S)-methyl 3-benzyloxycarbonylamino-4-(N-methyl-2- hydroxybenzylcarbamoyl) butanoate (32)

Using the procedure of Example 1(c), except substituting the compound of Example 3(b) for the compound of Example 1(b) and adding HOBT (1.1 equiv), and chromatographmg the crude product using ethyl acetate :hexane - 4:6 - 1 :0 as eluent, the title compound was prepared (82%). δH (CDC1₃, 270MHz) 2.65 (lH,dd), 2.80

(lH,dd), 3.20 (3H,s), 3.60 (3H,s), 4.40 (2H,ABQ), 5.10 (2H,m),5.70 (lH,d), 6.80 (lH,t), 6.90 (lH,d), 7.15 (lH,dd), 7.25 (lH,dt) and 9.05 (lH,s).

d) (3S)-methyl 3-amino-4-(N-methyl-N-(2-hydroxybenzyl) carbamoyl) butanoate

(33}

A solution of 32 (11.26g 28.15mmol) in absolute ethanol (78ml) was hydrogenated over 3% palladium on charcoal (2.62g) at room temperature for 2h.

The catalyst was filtered off and the filtrate was concentrated to dryness. The residue was chromatographed on silica gel using ethyl acetate: chloroform: methanol - 9:9:2 as eluant. The title compound was obtained as acolourless foam (6.90g, 92%). δH

(CDCI3, 270MHz) 2.55 (lH,dd), 2.70 (lH,dd), 3.20 (3H,s), 3.65 (3H,s), 4.15 (lH,t),

4.50 (2H,ABQ), 6.80 (lH,t) 6.95 (lH,d), 7.15 (lH,d) and 7.25 (lH,t). [M +H}⁺ 267

Using the procedure of Example 1(f), except substituting the compound of

Example 3(e), the title compound is prepared.

f) methyl 2,3,4,5-tetrahydro-3-oxo-4-methyl-lH-l ,4-benzodiazepine-2-acetate

Following the procedure of Example 4, except substuting the compound of Example 3(e), the title compound is prepared.

g) methyl 2,3,4,5-tetrahydro-7-( 4,4'-bipiperidinylcarbonyl)-3-oxo-4-methyl-lH-l,4- benzodiazepine-2-acetate (9)

Following the procedures set forth in WO 97/24336 (PCT/IB96/01502), the title compound is prepared.

Example 4 Preparation of methyl 2,3,4,5-tetrahydro-7-hydroxy-3-oxo-4-methyl-lH-l,4- benzodiazepine-2-acetate (10) A solution of the compound of Example 1(f) (1.73g, 6.6mmol) in absolute ethanol (173ml) was hydrogenated over 10% palladium on charcoal (1.73g) for 16h. at room temperature. The catalyst was then filtered off and the filtrate was concentrated to dryness. The residue was slurried in dichloromethane; ether - 1:1 and the product was then filtered off as a white solid (800mg, 46%). δH (DMSO, 270MHz) 2.60(lh, dd), 2.80(1H, dd), 2.90 (3H, s), 3.60(3H,s), 3.75(1H, d), 4.80(lH,m), 5.10(lH,d), 5.35(1H, d), 6.40(3H, m) and 8.55(1H, s).

The above description fully discloses how to make and use the present invention. However, the present invention is not limited to the particular embodiments described hereinabove, but includes all modifications thereof within the scope of the following claims. The various references to journals, patents and other publications which are cited herein comprises the state of the art and are incorporated herein by reference as though fully set forth.

Claims

Claims:

1. A process for preparing a compound of the formula (I):

(I) wherein,

R¹ is H, OH, Br, I, NR⁵R⁶, CO₂R⁷, CF3SO3, C^alkoxy, or (4,4'- bipiperidinyl)carbonyl; R² is alkyl, optionally substituted by CO₂R⁷ or CONR⁵R⁶;

R³ and R³' are independently H, Ar or Ci-galkyl optionally substituted by OH, NO₂, NH₂, NR⁵R⁶, halogen, CO₂R⁷, CONR⁵R⁶or Ar, or together R³ and R³' are =O;

R⁴ is H or C alkyl, optionally substituted by OH, NO₂, NH₂, NR⁵R⁶, halogen, CO₂R⁷, CONR⁵R⁶, or Ar;

R⁵ and R⁶ are independently H, Ar, C^alkyl, HCO, C^alkyl-CO, Ar-CO, C_!.₆alkyl-SO₂, or Ar-SO₂; and

R⁷ is a carboxylic acid protecting group, which comprises reacting a compound of the formula (II) with an oxidizing agent,

(π) wherein

R is OH or C alkoxy, and R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ are as defined above, and, thereafter, treating with a reducing agent.

2. A process according to claim 1 wherein R² is CH₂CO₂R⁷, and together R³ and R³' are =O.

3. A process according to claim 1 wherein R¹ is H, OH or C^alkoxy.

4. A process according to claim 1 wherein the oxidizing agent is potassium ferricyanide or potassium nitrosodisulfonate.

5. A process according to claim 1 wherein the reducing agent is hydrogen in the presence of a palladium or platinum on carbon catalyst.

6. A compound of formula (III):

(in) wherein,

R² is alkyl, optionally substituted by CO₂R⁷ or CONR⁵R⁶; R³ and R³' are independently H, Ar or C^alkyl optionally substituted by OH, NO₂, NH₂, NR5R6, halogen, CO₂R⁷, CONR5R6₀Γ Ar, or together R³ and R³' are =O;

R5 and R⁶ are independently H, Ar, C_j.galkyl, HCO, C^alkyl-CO, Ar-CO, C₁.₆alkyl-SO₂, or Ar-SO₂; and

R⁷ is a carboxylic acid protecting group,

7. A compound according to claim 6 which is (3S)-methyl 3-amino-4-(N-methyl-N- (1,4-benzoquinonylmethyl) carbamoyl) butanoate.

8. A method for preparing 2,3,4,5-tetrahydro-7-( 4,4'-bipiperidinylcarbonyl)-3-oxo-

4-methyl- 1 H- 1 ,4-benzodiazepine-2-acetic acid comprising, in any order, reacting a compound of formula (V):

wherein

R¹ is H, OH, Br, I, C alkoxy, CO₂R⁷, CF₃SO₂, or (4,4'-bipiperidinyl)carbonyl, optionally protected on one nitrogen; R⁴ is methyl, and R⁷ is a carboxy protecting group; with a reducing agent, and, if necessary, converting R¹ to (4,4'- bipiperidinyl)carbonyl; and if necessary, removing any protecting groups.

9. A compound of the formula:

(V) wherein

R¹ is H, OH, I, Br, C₁.₄alkoxy, CO₂R⁷, CF₃SO₂, or (4,4'- bipiperidinyl)carbonyl optionally protected on the basic nitrogen; R⁴ is methyl, and R⁷ is a carboxy protecting group.

10. A compound according to claim 8, which is:

2,3,4,5-tetrahydro-3-oxo-4-methyl-2-(methoxycarbonyl ethylidenyl)-lH-l,4- benzodiazepine;

2,3,4,5-tetrahydro-7-hydroxy-3-oxo-4-methyl-2-(methoxycarbonylethylidenyl)-lH- 1,4-benzodiazepine;

2,3,4,5-tetrahydro-7-(trifluoromethanesulfonyloxy-3-oxo-4-methyl-2- methoxycarbonylethylidenyl)- IH- 1 ,4-benzodiazepine; or

2,3,4,5-tetrahydro-7-(N-CBZ-4,4'-bipiperidinylcarbonyl)-3-oxo-4-methyl-2- methoxycarbonylethylidenyl)-lΗ-l,4-benzodiazepine.

11. A method for preparing 2,3,4,5-tetrahydro-7-( 4,4'-bipiperidinylcarbonyl)-3- oxo-4-methyl-lH-l,4-benzodiazepine-2-acetic acid, comprising reacting a compound of the formula:

(NI)

wherein R¹ is H, OH, Br, I, C^alkoxy, CO₂R⁷, CF3SO3, or (4,4'- bipiperidinyl)carbonyl, optionally protected on one nitrogen; R⁴ is methyl, and R⁷ is a carboxy protecting group; with an oxidizing agent, and, in any order, treating with a reducing agent; and, if necessary, converting R¹ to (4,4'-bipiperidinyl)carbonyl; and removing any protecting groups.

12. A compound of the formula

(II) wherein

R is OH or C^alkoxy; R¹ is H, OH, Br, I, C₁.₄alkoxy,CO₂R⁷, CF3SO3, or (4,4'- bipiperidinyl)carbonyl, optionally protected on the basic nitrogen;; R⁴ is methyl, and R⁷ is a carboxy protecting group.

13. A compound according to claim 11, which is:

(3S)-methyl 3-amino-4-(N-methyl-N-(2,5-dihydroxybenzyl) carbamoyl) butanoate; or

(3S)-methyl 3-amino-4-(N-methyl-N-(2-hydroxybenzyl) carbamoyl) butanoate.