NZ213468A - Benzopyran compounds as intermediates - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number £13468 213463 Priority Date(s): ^ I 43; S3.- Complete Specification Filed: Class: <&1Q$U "ft 1' 'APR M6 Publication Date: P.O. Journal, No: £(%m nil! m Under the provisions of Regular ion 23 m (I) che ..

/ - Specification has been ante-dated1, tO .—<*! JL.Ctkfei&yzdkS:. 19<£2„ H itlals NEW ZEALAND PATENTS ACT, 1953 No.

Divided frcm No. 201984 Date COMPLETE SPECIFICATION INTERMEDIATE COMPOUNDS /?' {K ' ' '--.v // \ Ji'M "'-A r 29 JAM 1985;'.' $ %■? / ••X ^ . <Ti .'/ F f vj r.^'' We, BEECHAM GROUP p.l.c, a British Company of Beecham House, Great West Road, Brentford, Middlesex TW8 9BD, England, hereby declare the invention for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement : 213468 2 INTERMEDIATE COMPOUNDS The present invention relates to intermediates for use in the preparation of novel benzopyrans having pharmacological activity.

Our New Zealand Patent Specification No. 201984 describes and claims a class of benzopyrans having blood pressure lowering activity. Such compounds are characterised by the presence of an oxo group in the nitrogen-containing ring which substitutes the benzopyran in the 4-position.

Accordingly, the Patent Specification No. 201984 provides a compound of formula (I): where in: one of Rj. and R2 is hydrogen and the other is selected from the class of alkylcarbonyl, alkoxycarbonyl, alkylcarbonyloxy, alkylhydroxymethyl, nitro, cyano, chloro, trifluoromethyl, alkylsulphiny1, alkylsulphony 1, alkoxysulphinyl, alkoxysulphonyl, alkylcarbonylamino, alkoxycarbonylamino or aminosulphinyl, aminosulphonyl or aminocarbonyl, the N (I) amino moiety being optionally substituted by one or two alkyl groups, or alkylsulphinylamino, alkylsulphonyl-a.nino, alkoxysulphinylamino or alkoxysulphonylamino or ethylenyl terminally substituted by alkylcarbonyl, nitro or cyano, or -C ( alky 1 )NOH or -C (alky 1) NNH2 , the alkyl groups or alkyl moieties of alkyl-containing groups having from 1 to 6 carbon atoms; one of R3 and R4 is hydrogen or alkyl having from 1 to 4 carbon atoms and the other is alkyl having from 1 to 4 carbon atoms, or R3 and R4 together with the carbon atom to which they are attached are spiroalkyl having from 3 to 6 carbon atoms; R5 is hydrogen, alkyl having from 1 to 3 carbon atoms or acyl having from 1 to 8 carbon atoms; and n is 1 or 2; the lactam group being trans to the OR5 group.

The other of and R2, when one of them is hydrogen, is preferably selected from the class of alkylcarbonyl, alkoxycarbonyl, alkylcarbonyloxy, alkylhydroxymethyl, nitro or cyano.

The alkyl groups or alkyl moieties of alkyl-containing groups, in respect of the other of R^ and R2, are preferably methyl or ethyl.

R3 and R4 are preferably both alkyl having from 1 to 4 carbon atoms. In particular they are both methyl or ethyl, preferably both methyl.

When R5 is alkyl, preferred examples thereof include methyl, ethyl and n- propyl, of which methyl is most preferred. When R5 is acyl, a preferred class is unsubstituted carboxylic acyl, such as aliphatic acyl or benzoyl. R5 however is preferably hydrogen.

UL 02 0 3 0 4 0 5; 06 0 V.

OB ft 1 L 12 13 t 16 17 13 19 21 2 2 2 3 2 4 26 27 • 29 31 32 • J 4 3 5 3 6 37 38 39 ,/h /? //.. 4 Within formula (I) is a sub-group of preferred compounds of formula (II): wherein one of and R2 is hydrogen and the other is selected from the class of alkylcarbonyl, alkoxycarbonyl, alky lcarbonyloxy, alkylhydroxymethyl, nitro or cyano, the alkyl groups or alkyl moieties of alkyl containing groups being methyl or ethyl, and n is 1 or 2.

Compounds of formula (II), wherein one of Rj, and R2 is hydrogen and the other is nitro or cyano, are greatly preferred. Additionally, compounds of formula (II), wherein R2 is hydrogen and Ri is one of the su'ostituents as defined hereinbefore, are preferred. Consequently the most preferred compounds are those wherein R^ is nitro or cyano and R2 is hydrogen.

The compounds of formula (I) and (II) cover both a piperidone substituent (when n=2) and a pyrrolidone substituent (when n=l).

(II) 3 It is preferred that the compounds of formula (I) and (II) are in substantially pure.form. 2 1346 The compounds of formulae (I) and (II) have asymmetric centres and therefore exist in optically active forms.

Patent Specification No. 201984 also provides a process for the preparation of a compound of formula (I) , which comprises cyclising a compound of formula (III) or, when R5 is hydrogen, a metal salt thereof: HN(CH2)n+2COLl wherein one of Rj_~ and R2" is hydrogen or a group or atom convertible into hydrogen and the other is one of the class of substituents as defined hereinbefore for the other of Rj^ and R2 or a group or atom convertible thereto, R3 to R5 and n are as defined hereinbefore, is a leaving group; and wherein the substituted amino group is trans to the OR5 group; in the case when one of Rj^and R2' is a group or atom convertible into hydrogen, converting the group or atom into hydrogen; in the case when the other of R]_~ and R2" is a group or atom convertible into one of the class of substituents as defined hereinbefore for the other of R^ and R2, converting the group or atom into one of the class of substituents as defined; and, in the case when R5 is hydrogen in the compound of formula (I), optionally alkylating or acylating with an alkylating agent having from 1 to 3 carbon atoms or an acylating agent having from 1 to 8 carbon atoms.

I Oi 02 0 3 O-i 0 5 0 6 07 03 09 • II 12 13 14 • 16 17 18 19 21 22 23 24 26 27 28 • 31 32 33 •* 36 37 38 39 2 1 346 8 The leaving group is a group that is displaceable by a secondary amino nucleophile.

Preferred examples of such groups include hydroxy and, in particular, C]_-4 alkoxy, such as ethoxy.

The cyclisation is normally carried out by heating the compound of formula (III) under reflux in an inert solvent, such as xylene or toluene.

When a metal salt of formula (III) is used, the sodium salt is preferred. However, it is even more preferred not to use a metal salt at all, especially as any elimination side reactions are thereby avoided.

Conversions of an aromatic group or atom into one of the class of substituents as defined hereinbefore for the other of Rj[ and R2, when one of them is hydrogen, are generally known. For example, it is preferred, when carrying out the reaction, to protect any unsubstitutea terminal amino moieties, such as when the other of R_l and R2 is aminosulphinyl, amino-sulphonyl or aminocarbonyl, with a protecting agent. Examples of protecting agents include acyl groups, such as acetyl. Protection of the unsubstituted terminal amino moiety is carried out by reacting a compound of formula (III), wherein one of R]_~ and R2' is hydrogen and the other is aminosulphinyl, aminosulphonyl or aminocarbonyl, with, for example, an acyl chloride. Removal of the acyl protecting agent is carried out by base hydrolysis after the cyclising reaction.

Conversions of an aromatic group or atom into one of the class of substituents as defined hereinbefore for the other R^ and R2, when one of them is a group or atom convertible into hydrogen, are generally known as well. For example, a hydrogen atom may be replaced by ' a nitro group by nitrating in a known manner a compound of formula (III), wherein one of Rj' and R2" is 0 1 0 2 O.l !M 0 5 06 • ° 7 oa 09 # 11 12 13 14 • 16 17 18 19 21 22 23 24 26 2 7 28 » JO 31 32 3 i * 3 5 3 6 37 3b 39 7 hydrogen and the other is acetamido, followed by hydrolysing the compound, converting the resulting amine into a diazonium salt, and finally decomposing it, leaving a compound of formula (I), wherein one of and R2 is hydrogen and the other is nitro.

It is however preferred that any conversions are carried out at an earlier stage as mentioned hereinafter.

Preferably, the alkylating agent is an alkyl iodide, the reaction being carried out in an inert solvent, such as toluene, in the presence of a base,such as potassium t-butoxide.

Preferably, the acylating agent is a carboxylic acid or a derivative thereof, such as an anhydride, the reaction being carried out in a non-hydroxylic solvent in the presence of a condensation promoting agent, such as dicyclohexyl- carbodiimide.

Compounds of formula (III) can be prepared by reacting a compound of formula (IV): O (IV) R 4 wherein Ri~ and R2' and R3 and R4 are as defined hereinbefore, with a compound of formula (V): H2N-(CH2)n+2-COLi (V) wherein n and Li are as defined hereinbefore. 0 1 02 0 \ n-l 05 Otif 07 Oi? 09 • 11 12 13 14 • 16 17 19 2 L 21 23 24 2 5 2 b 27 € 3 0 31 12 • 3 5 3 6 3 7 38 40 8 - 2 1346 S The reaction is normally carried out in a solvent at low, medium or high temperature. The solvent may be an alcohol, such as methanol or ethanol.

When is hydroxy the reaction proceeds well if carried out in refluxing ethanol in the presence of aqueous sodium carbonate. When is C^-4 alkoxy, the reaction is preferably carried out in the presence of sodium hydroxide in ethanol.

Under some conditions, the compound of formula (III) spontaneously cyclises to form a compound of formula (I).

Compounds of formula (IV) can be prepared,preferably in situ, by reacting a compound of formula (VI): OH wherein R^"* and R2' and R3 and R4 are as defined hereinbefore and the hydroxy group is trans to the bromo atom, with a base, such as potassium hydroxide, in ether or aqueous dioxan.

Alternatively, compounds of formula (III) can be prepared by reacting a compound of formula (VII): NH2 1)1 02 03 0 4 O'S 06. 07 oe 09 • 12 13 14 f 17 13 19 2 Pi 21 2 2 23 24 2 5 2 6 27 23 31 32 33 3 5 3 6 3 7 3c . j9 40 2 13468 wherein R]_~, R2', R3 and R4 are as defined hereinbefore, and the amino group is trans to the hydroxy group, with a compound of formula {VIII): L2(CH2)n+2COLi (VIII) wherein n and are as defined hereinbefore and L2 is a leaving group.

The leaving group, L2, is a group that is displaceable by a primary amino nucleophile. Preferred examples of such groups include halo, such as chloro and bromo.

Compounds of formula (VII) can be prepared by a reaction of a compound of formula (IV) with ethanolic ammonium hydroxide solution. Alternatively, they can be prepared by reduction with zinc and hydrochloric acid of a compound of formula (IX): wherein Ri', R2'# R3 an<3 R4 are as defined hereinbefore and wherein the azide group is trans to the hydroxy group.

Compounds of formula (IX) can in turn be prepared from a compound of formula (IV) by reaction with sodium azide in the presence of boric acid in for example d imethy1formamide. 2 1 346 8 The Patent Specification No. 201984 provides another process for the preparation of a compound of formula (I) , which comprises oxidising a compound of formula (X), or, when Rj. is hydrogen, a metal salt thereof: wherein Ri~, ^2'' ^3' to R5 and n are as defined hereinbefore, and wherein the nitrogen-containing ring is trans to the OR5 group; in the case when one of R^~ and R2~ is a group or atom convertible into hydrogen, converting the group or atom into hydrogen; in the case when the other of Rj_~ and R2~ is a group or atom convertible into one of the class of substituents as defined hereinbefore for the other of R^ and R2, converting the group or atom into one of the class of substituents as defined; and, in the case when R5 is hydrogen in the compound of formula (I), optionally alkylating or acylating with an alkylating agent having from 1 to 3 carbon atoms or an acylating agent having from 1 to 8 carbon atoms.

The oxidation is preferably carried out in a solvent such as aqueous methanol with a metal periodate such as potassium periodate.

(X) N 4 Compounds of formula (X) can be prepared by cyclising in the presence of an acid a compound of formula (XI): 2 1346 ™<cv2)n+2c* (R6)2 (XI) wherein Rg is methoxy or ethoxy and R^' , R2 1, R3 to R^ and n are as defined hereinbefore and wherein the substituted amino group is trans to the OR^ group.

Compounds of formula (XI) can in turn be prepared by reacting a compound of formula (IV) with a compound of formula (XII): H2N(CH2)n+2CH(R6)2 (XII) wherein R,- and n is as defined hereinbefore. o The Patent Specification No. 201984 provides yet another process for the preparation of a compound of formula (I) , which conprises cyclising a compound of formula (XIV) CO(CH2'n+2L3 (XIV) wherein Ri", R2**/ R3 to R5 and n are as defined hereinbefore and L3 is a leaving group, and wherein the substituted amino group is trans to the OR5 group; in the case when one of Rj^and R2'is a group or atom convertible into hydrogen, converting the group or atom into hydrogen; in the case when the other of Rj[" and R2~ is a group or atom convertible into one of the class of substituents as defined hereinbefore for the other of Rj_ and R2, converting the group or atom into one of the class of substituents as defined; and, in 01 02 03 04 05 0 6 07 08 c 11 12 13 W15 16 17 18 19 21 22 23 24 26 27 ^28 29 31 32 r3 34 36 37 38 2 13468 - 12 the case when R5 is hydrogen in the compound of formula (I), optionally alkylating or acylating with an alkylating agent having from 1 to 3 carbon atoms or an acylating agent having from 1 to 8 carbon atoms.

The leaving group 1,3, is a group that is displaceable by a secondary amino nucleophile adjacent to a carbonyl function. A preferred example is chloro.

The cyclisation reaction is preferably carried out in a solvent such as dimethylformamide in the presence of a base, such as sodium hydride.

Compounds of formula (XIV) can be prepared by reacting a compound of formula (VII) with a compound of formula (XV): wherein L3 and n are as defined hereinbefore and L4 is a leaving group; and optionally alkylating or acylating with an alkylating agent having from 1 to 3 carbon atoms or an acylating agent having from 1 to 8 carbon atoms.

The leaving group, L4, is a group that, when adjacent to a carbonyl function, is displaceable by a primary amino nucleophile.

The reaction is preferably carried out in a solvent, such as chloroform or methylene chloride, in the presence of aqueous base, such as aqueous sodium hydroxide.

In the reactions with the epoxide of formula (IV), the trans isomer is specifically formed.

L3(CH2)n+2COL4 (XV) Z.I3.frC8 u W k 'v.; ' i v-. \J) Compounds of formula (VI) can be prepared in accordance with known processes, for example the process described in the United States Patent No. 4110347, New Zealand Patent Specification No. 183551 and European patent publications Nos. 9912, 28449 and 28064.

Schematically, such process can be depicted thus: (a) Room temperature; NaOH/40% benzyltrimethyl-ammonium hydroxide in methanol; (b) Heat in o-dichlorobenzene; (c) N-bromosuccinimide/dimethylsulphoxide/water; / (d) (e) Bromine in carbon tetrachloride; and Acetone/water. i 01 02 03 04 05 06 Q7 08 09 •o 11 12 13 14 • s 16 17 18 19 21 22 23 24 26 27 ^28 ^29 31 32 I'' W 34 36 37 38 39 • -i4- 2154-68 The above process can produce mixtures of compounds during reaction (b) owing to the two sites available for ring formation. It is therefore advisable to remove any of the undesired compound by, for example, chromatography, before reaction (c) or or (d).

Instead of carrying out the conversion of a group or atom into hydrogen or group or atom into one of the class of substituents defined for the other of Ri and R2 after cyclising a compound of formula (III) or (XIV), or after oxidising a compound of formula (X), or after reacting a compound of formula (IV) with an anion of formula (XIII), it is greatly preferred that any such conversions are carried out at an earlier stage, preferably on the chromene produced after reaction (b) above. In other words, it is preferred that, for the processes of the invention R^' and R2~ are R^ and R2 respectively.

As mentioned previously, the compounds of formula (I) exist in optically active forms, and the processes of the present invention produce mixtures of such forms. The individual isomers may be separated one from another by chromatography using a chiral phase. Alternatively, an asymmetric synthesis would offer a route to the individual form.

It is preferred that the compounds of formula (I) are isolated in substantially pure form.

The intermediates of formula (III), (IX), (XI) and (XIV) are novel and constitute the present invention.

As mentioned previously, the compounds of formula (I), and especially those of formula (II), have been /'' found to have blood-pressure lowering activity. They 2» \ ^ ^ are therefore potentially useful as a pharmaceutical in the treatment of hypertension.

The following examples relate to the preparation of the compounds of the present invention. 01 02 03 04 05 06 07 08 • 11 12 13 • 16 17 18 19 21 22 23 24 26 is 29 31 n 34 36 37 38 13468 Example 1 6-Cyano-3 , 4-dihydro-2 , 2-dimethyl-3 , 4-epoxy-2H-benzo-[b)-pyran 4-Cyanophenol (19.60g), sodium hydroxide (9.90g), 40% benzyltrimethylammonium hydroxide in methanol (34.50g) and 3-methyl-3-chlorobutyne (25.50g) were stirred in water (150ml) and dichloromethane (150ml) for 5.5 days at room temperature. After separation of the layers, the aqueous layer was extracted twice with chloroform, and the combined organic phase evaporated leaving a gum which was taken up in ether and washed three times with 10% sodium hydroxide solution and with water before drying over magnesium sulphate. Removal of drying agent and solvent gave a viscous liquid having absorptions in the IR (film) at 2100, 2220, 3290cm~l. This liquid (20.91g) was heated in o-dichlorobenzene (40ml) at reflux temperature for 1.5 hours under nitrogen. After distillation of the solvent the fraction boiling at 110-114°/0.02mmHg (16.57g) was collected, which on standing formed a low melting solid, having an IR absorption at 2230cm~l. (See M. Harfenist and E. Thom, J. Org. Chem., 841 (1972) who quote ra.p. 36-37°).

Addition to this 6-cyanochromene (16.50g) dissolved in dimethyl sulphoxide (150ml) containing water (3.24ml) of N-bromosuccinimide (31.90g) with vigorous stirring and cooling, followed by dilution with water and extraction via ethyl acetate gave a mixture which was boiled in acetone (300ml) and water (100ml) for 5 hours to hydrolyse the small amount of 3,4-dibromide present. Evaporation of solvents gave 6-cyano-trans-3-bromo-3,4-dihydro-2,2-dimethyl-2H-benzo[b]pyran-4-ol as white crystals (24.37g). A small sample had m.p. 128-128.5° from 60-80° petroleum ether, 01 - 17 - ! 346 02 nmr (CDC13)6 1.43 (3H), 1.62 (3H), 7.48 (1H, 03 exchangeable), 4.07 (1H, d, J=9), 4.87 (1H, d, J=9), 04 6.80 (1H, d, J = 8 ) , 7.43 (1H, q, J=8 , 2), 7.78 (1H, d, 05 J=2). Analysis calculated for Ci2H12N02Br:C, 51.07; H, 06 4.26; N, 4.96; Br, 28.37. Found: C, 50.95; H, 4.38; N, 07 5.03; Br, 28.39%. 08 fThe bromohydrin (24.30g) was stirred with sodium hydroxide pellets (5.00g) in water (250ml) and dioxan 11 (200ml) for 3 hours at room temperature. The solvents 12 were removed by distillation under high vacuum and the 13 residue taken up in ether and washed with water and brine before drying over magnesium sulphate. Removal of drying agent and solvent and gave crude 6-cyano-3,4- 16 dihydro-2 ,2-dimethyl-3,4-epoxy-2H-benzo[b] pyran 17 (16.02g) as a gum, having an absorption at 2230cm-^ in 18 the IR and Nmr (CC14)S 1.26 (3H), 1.54 (3H), 3.40 and 19 3.80 (each 1H, d, J=4), 6.77 (1H, d, J=8) , 7.43 (1H, q, J=8, 2), 7.58 (1H, d, J=2). 21 / 7 f 01 02 03 04 05 l 06 07 08 #9 11 12 • 2 1346 Example 2 6-Cyano-3 , 4-dihydro-2 , 2-dimethyl-trans-4-amino-2H-benzo[b]pyran-3-ol The title compound was prepared by stirring 6-cyano-3 , 4-dihydro-2 ,2-dimethyl-3,4-epoxy-2H-benzo-[bjpyran in ethanolic ammonium hydroxide solution at room temperature until thin layer chromatography showed consumption of the starting epoxide. 2 1 346 Example 3 6-Cyano-3 , 4-dihydro-2 , 2-dimethyl-trans-4-(l-keto-4-chlorobutylamino)-2H-benzo [b]pyran-3-ol _ The amino chromanol (1.40g), as obtained in Example 2, was stirred in chloroform (20ml) and water (10ml) containing sodium hydroxide pellets (0.26g) at room temperature. 4-Chlorobutyryl chloride (0.72ml) was added and the reaction stirred vigorously for 0.5 hours. Separation of the layers and washing the organic layer with water, then brine, drying over magnesium sulphate, filtration and evaporation gave the title compound as a pale yellow solid. 01 02 03 04 OS 06 0) 08 i 11 12 13 f 2 1346 Example 4 6-Cyano-3 , 4-dihydro-2 , 2-dimethyl-trans-4-( 4 ,4-diethoxy-butylamino)-2H-benzo[b]pyran-3-ol 6-Cyano-3,4-dihydro-2,2-dime thy 1-3,4-epoxy-2H-benzo[b]pyran (200mg) and 4-aminobutyraldehyde diethyl-acetal (200mg) were heated to 100°C for 1.5 hours, a clear yellow solution forming during this time. After cooling, dilution with ether, and washing successively with water and brine, drying over sodium sulphate and evaporation, the aminoacetal was obtained as a pale yellow oil (291mg). 01 02 03 04 05 06 07 08 49 wo 11 12 13 41 16 17 18 19 21 22 23 24 •26 27 ^28 29 21 2 ] 346 Example 5 (a) 6-Nitro-3 , 4-dihydro-2-methyl-3,4-epoxy-2H-benzo(b] pyran p-Nitrophenol (49.3g) , 3-bromobut-l-yne (39.Og), potassium carbonate (66g) and potassium iodide (3.1g) were heated and stirred under nitrogen for 20 hours. The mixture was cooled, filtered, and evaporated and the residue taken up'in ether and washed with sodium hydroxide solution (10%) before drying over magnesium sulphate. Filtration and evaporation gave the phenoxy-butyne as a yellow oil (39.03g). This crude phenoxy-butyne (30g) was heated in o-dichlorobenzene (1 litre) for 24 hours under nitrogen. Removal of solvent, and recrystallisation from 60-80° petroleum ether gave 2-methyl-6-nitrochromene as an oily solid. The nitro-chromene (6.10g) dissolved in dimethyl sulphoxide (50ml) containing water (1.12ml) was treated with N-bromosuccinimide (11.40g) in one portion with vigorous stirring. After 0.5 hours the reaction mixture was poured into water (500ml) and extracted with ethyl acetate to yield the bromohydrin (7.4g) as a sticky solid. Recrystallisation from ethyl acetate -petroleum ether gave a sample of ia.p. 159°. The bromohydrin (2.27g) was stirred with potassium hydroxide pellets (2.2g) in ether (500ral) for 48 hours.

Filtration gave the 3,4-epoxy-2-methylchroman as a yellow crystalline solid (1.05g). / . / / 01 02 03 04 05 06 07 08 •9 11 12 13 •< 16 22 - 2 1245a (b) 6-Ni tro-3 , 4-dihydro-2-methyl-trans-4-( ethoxycarbonyl-propylamino)-2H-benzo[b]-pyran-3-ol The epoxide of Example 5 (a) (1.03g) was boiled with ethyl 4-aminobutyrate hydrochloride (0.84g) and sodium hydroxide pellets (0.20g) in ethanol (50ml) for 10 hours. Filtration and evaporation and chromatographic purification gave a gum (1.10g) which was dissolved in 2N hydrochloric acid and extracted three times with ethyl acetate. Basification of the aqueous / phase and extraction with ethyl acetate gave a crude ester which was used as such in Example 9 of New Zealand Patent Specification No. 201984. / / / / 2. 1 346 8 Example 6 7-N i tro-3 , 4-d ihydro-2 , 2-d imethyl-trans-4- ( 3-carbethoxy-propylamino)-2H-benzo[bjpyran-3-ol 7-Nitro-3 ,4-dihydro-2,2-dimethy 1-3,4-epoxy-2H-benzo[b]pyran (0.48g, the preparation of which is described in Example 3 of U.K. Patent No. 1,548,221), ethyl 4-aminobutyrate hydrochloride (0.34g) and sodium hydroxide pellets (0.08g) were refluxed in ethanol (50ml) for 12 hours. Filtration and evaporation and chromatography on a chromatotron (2mm silica gel HF254/ gradient elution with pentane-ethyl acetate) gave recovered epoxide (0.20g) and trans-4-(3-carbethoxy-propylamino)-7-nitro-2,2-diinethyl-2H-benzo [b]pyran-3-ol (0.21g) as a gum, which was used as such in Example 10 of New Zealand Patent Specification No. 201984. 01 2 13 46 $ 02 Example 7 03 0 4 6-Chioro-3 , 4-dihydro-2 , 2-dimethyl-trans-3-bromo-4- 0 5 hydroxy-2H-benzo[b]pyran 06 07 The title compound was prepared analogously to the 08 preparation of the 3-bromo-4-hydroxy compound of ^^9 Example 1 giving a crude crystalline solid. 11 NMR (CDCI3): 51.35 (3H, s) , 12 1.53 (3H, s) , 13 3.22 (1H, m), •< 4.00 (1H, d, J=9Hz), 4.77 (1H, dr J=9Hz), 16 6.51 (1H, d, J=8Hz), 17 7.03 (1H, q, J=8.2Hz) 18 7.30 (1H, narrow m). 19 134

Claims (10)

WHAT WE CLAIM IS:

1. A compound of formula (XIV): "iCOtCH2W3 (XIV) wherein : one of Ri and R2 is hydrogen and the other is selected from the class of alkylcarbonyl, alkoxycarbonyl, alkylcarbonyloxy, alkylhydroxymethyl, nitro, cyano, chloro, trifluoromethyl, alkylsulphinyl, alkylsulphonyl, alkoxysulphinyl, alkoxysulphonyl, alkylcarbonylamino, alkoxycarbonylaraino, or aminosulphinyl, aminosulphonyl or aminocarbonyl, the amino moiety being optionally substituted by one or two alkyl groups, or alkylsulphinylamino, alkylsulphonyl-amino, alkoxysulphinylamino or alkoxysulphonylamino, or ethylenyl terminally substituted by alkylcarbonyl, nitro or cyano or -C(alkyl)NOH or -C(alkyl)NNH2, the alkyl groups or alkyl moieties of alkyl-containing groups having from 1 to 6 carbon atoms; one of R3 and R4 is hydrogen or alkyl having from 1 to 4 carbon atoms and the other is alkyl having from 1 to 4 carbon atoms, or R3 and R4 together with the carbon atom to which they are attached are spiroalkyl having from 3 to 6 carbon atoms; R5 is hydrogen, alkyl having from 1 to 3 carbon atoms or acyl having from 1 to 8 carbon atoms; and n is 1 or 2; and L^ is a leaving group; and wherein the substituted amino group is trans to the OR^ group. - 26 -

2 1346 A compound of formula (III): HN(CH2ln+2COLl (III) wherein R1, R^, R3 to "R5 and n are as defined in claim 1, Lj is a leaving group, and wherein the substituted amino group is trans to the OR^ group.

3. A compound of formula (IX) (IX) wherein one of R ' and R^' is hydrogen or a group or atom convertible into hydrogen and the other is one of the class of substituents as defined in claim 1 for the other of R^ and R2, or a group or atom convertible thereto and R^ and R^ are as defined in claim 1, the azide group being trans to the hydroxy group.

4. A compound of formula (XI): HN'CH2,n«CHtR6)2 (XI) 213468 - 27 - wherein R is methoxy or ethoxy and R ' , R/, R_ to 6 1 £ 3 R^ and n are as defined in claims 1 and 3, the substituted amino group being trans to the OR^ group.

5 . 6-Cyano-3,4-dihydro-2 , 2-dimethyl-trans-4-amino-2H-benzo[b]pyran-3-ol.

6 . 6-Cyano-3 , 4-dihydro-2 , 2-dimethyl-trans-4- (1-keto-4-chlorobutylamino)-2H-benzo[b]pyran-3-ol.

7 . 6-Cyano-3 , 4-dihydro-2 , 2-dimethyl-trans-4- (4,4-diethoxybutylamino)-2H-benzo[b]pyran-3-ol.

8 . 6-Nitro-3 , 4-dihydro-2-methyl-trans-4- (ethoxycarbonyl-propylamino)-2H-benzo[b]pyran-3-ol.

9 . 7-Nitro-3,4-dihydro-2,2-dimethyl-trans-4-(3-carbethoxypropylamino) -2H-benzo [b] pyran-3-ol.

10 . 6-Chloro-3 , 4-dihydro-2 , 2-dimethyl-trans-3-bromo-4-hydroxy-2H-benzo[b]pyran. <*«»»« DA A- J. park-TT"*-*-"' ^ * WON *GENR «*