CA1262139A - Process for the preparation of 2,3- dihydrobenzopyranone derivatives - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
Disclosed herein is a process for producing a 2,3-dihydro-[4H]-1-benzo-pyran-4-one of the formula wherein each of R1 and R2, being the same or different, is hydrogen or C1-C10 alkyl; or R1 and R2, taken together, form a C5-C7 cycloalkyl ring;
R3 is hydrogen, C1-C10 alkyl or phenyl;
R4 is hydrogen or C1-C6 alkyl;
R5 is -OR9 or -SR9, wherein R9 is hydrogen or C1-C6 alkyl; each of R6, R7 and R8, being the same or different is hydrogen, C1-Cl2 alkyl or phenyl; and the salts thereof with bases; which is useful as medicine for central nervous system as well as intermediate for producing other medicines, the process comprising:
reacting a compound of the formula with a compound of the formula or a reactive derivative thereof to obtain an intermediate of the formula

Description

6 2 ~ FC 160 "PROCESS FOR THE PREPARATION OF 2,3-DIHYDROBENZOPYRANONE
DERIVATIVES"

2,3-Dihydrobenzopyran derivatives, in particular 5-hydro-xy-2,3-dihydro-~4H~-1-be~zopyran-~-ones~ are known to be useful as such or as intermedlates for the preparation both of other useful compounds (US Patent 3,467,676, UR published Patent Applica~io~ GB 212024iA, US Patent

3,636,058 and Belgian Patent 844943) and of natural prod-ucts ~J. Am. Chem. Soc., 89 (23), 5934 (1967 ~ .
They are generally prepared by reacting suitable resorcinols with ~ unsaturated carboxylic acids, in the presence of an acid or a Lewis acid catalyst, e.g. boron trifluoride etherate, or ~lCl3, without a solvent or in a solvent, e.g.
diethyl ether, carbon disulphide or nitroben~ene, at a temperature ranging from about 20C to about 180C.
Although Friedel Crafts acylation is the most used react-ion for the ~ynthesis of these compounds, the yields obtained are unsatisfactory: in fact the reaction e.g. of olivetol (A) with 3-methylcrotonic acid (B), in the ~20 presence of boron trifluoride etherate at 125c, leads to the synthesis~of several products, from which, in particu-lar, two products may be .isolated, i.e. compound ~0~, 50 yield and co~pound (D~, 22~o yield,. the remaining 20-25~o being undesired secondary products.

OH

~ ~H
C5H11 OH ~OOH

~A) (B) C~H ~ 3 H

(C) (D) : ~- The ratio of these products depends clearly on the react-ion tempe~ature, in fact it can be reversed by using boron .5 trifluoride etherate at Z5C, so obtaining compound (C) : with 23% yield and compou~ (D)~with 63% yield. Moreover : the subsequent separation of compound (C) ~rom the isomeric compound (~) and especially from the undes;red secondary :
produc~s is d;ff;cult and yields are low.
: ~ ~ IO The present ;nvention relates to a new process for the preparation of 2,3-dihydrobenzopyran derivatives and also to certain new 2,3,7,8-tetrahydro-L4~ benzopyran-

-4~5 L6~/-diones, useful as intermediate products for their synthesis~
' ~ ' , ~ `.... . .

The new process of this invention has the important advantage over the prior art of ~llowing to obtain the desired products in ver~ good yields (fro~ abaut 53%
to about 8~%) without any need of separation of iso-S meric compounds and especially of separ~ingthem fromthe considerable amount of by~p~cts.
. Furthermr~re the ~ew process i5 very cheap, since all the starting compounds are either commercially available products or easily obtainable by simple methods, known in o~ganic chemistry, The 2,3-dihydrobe~zopyran derivatives, which can be obtained through the new process are, i~ particular, compounds having formula ~I) ~ ~ 2 (I) wherein each of R1 and R2, ~ein~ the same or diferent, is hydrogen or C1-C10 alkyl.; or R1 and R2, taken together, form a C5-C7 cycloalkyl ring;
R3 is hydrogen, C1-C10 alkyl or phenyl;
R4 is hydrogen or C1 C6 alkyl;
R5 is -ORg or -SRg, wherein Rg is hydrogen or C1-C6 alkyl;
each o R6, R7 and R8, being the same or different is hydrogen, C1-C12 alkyl or phenyl; and the salts thereof with bases;

which, as said above, are both drugs having central nervous system actlvity and intermediates useful for the synthesis of drugs and of natural products.
Salts of the compounds of formula (I) may be both salts with inorg~nic, e.g. alkali metal, especially lithium, sodium or potassium, bases or alkaline-earth metal, especially calcium or magnesium, bases or with organic bases, e.g. alkylamines, preferably triethylamine.
In the compounds described in the present invention the alkyl, alkoxy and alkylthio groups may be branched or straight chain groups.
When one or more of R1, R2 and R3 is C1-C10 alkyl, it is preferably C1-C7 alkyl, in particular methyl, ethyl, propyl, butyl, pentyl or hexyl.
When R1 and R2, taken together, form a C~-C7 cycloalkyl ring, it ls preferably cyclopentyl or cyclohexyl.
When the radical -ORg is Cl-C6 alkoxy, it is preferably a C1-C4 aI~oxy group, in particular methoxy, ethoxy, propoxy or isopropoxy.
20 When the radical -SRg is Cl-C6 alkylthio, it is pre~erably a Cl-C4 alkylthio group, in particular methylthio, ethyl-thio, propylthio or isopropylthio.
When one or more of R6~ R7 and R8 is Cl 12.
preferably C2-C10 alkyl and more preferably ethyl, propyl, butyl, tert-butyl, pentyl, hexyl, 1,1-dimethylheptyl or 1,2-dimethylheptyl.
.

According to the new process, which is the first object of this invention, the compounds of formula (I) can be obtained by a process compr;sing a) reacting a compound of formula (II) ~8 J J ( II) wherein R6, R7 and R8 are as defined above, with a compound of formula (III) R ~ R2 ~-R3 (III) OOH

10 wherein Rl, Rz and R3 are as defined a~ove, or a reactive derivative thereof, so obtaining a compound of formula (IV) 7 ~ 2 (IV) wherein Rl, R2, R3, R6, R7 and R8 are as defined above, and, i desired, alkylating a compound o~ ormula (IV), so obtaining a compound of ormula (V) 7 ~ ~ R2 (V) R;~--R3 o R~4 wherein Rl, R2, R3, R6, R7 and R8 are as defined above and R'4 in Cl-C6 alkyl, and then b) aromatizating a compound of formula (IV) or (V), thus obtain-ing a compound of formula (I), wherein Rl, R2, R3, R6, R7 and R8 are as defined above, R5 is hydroxy and R4, according to the starting product of formula (IV) or (V), is hydrogen or Cl-C6 alkyl, and, c) if desired, carrying out one or more of the following:
(i) alkylating a compound of formula (I) wherein R4 is hydrogen to obtain a correspondin~ compound of formula (I) wherein R4 is Cl-C6 alkyl;

(ii.) converting a compound of formula (I) wherein R5 is hydroxyl to obtain a corresponding compound of formula (I) wherein R5 is mercapto;
(iii) alkylating a compound of formula (I) wherein R5 is hydroxyl or mercapto to obtain a correspondiny compound of formula (I) wherein R5 is Cl C6 alkoxy or Cl-C6 alkylthio;
(iv) de-etherifying a compound of formula ~I) wherein R5 is Cl-C6 alkoxy to ob~ain a corresponding compound of formula (I), wherein R5 is hydroxy; and (v) converting a compound of formula (I) into a salt thereof with a base or converting a salt thereof into a free compound of formula (I).
A reactive derivative of a compound of formula (III) is for example an acid halide, an anhydride, a mixed anhydride, an azide, a reactive ester. A reactive ester may be for example a p-nitrophenyl ester~ a 2,4-dinitrophenyl ester, a pentachloro-phenyl ester, a N-hydroxysuccinimide ester or a N-hydroxyphthal-imide ester. Preferably a reactive derivative of a compound of formula (III) is an acid halide, in particular the acid chloride.
The reaction between a compound of formula (II) and a compound of formula (III), or a reactive derivative thereof, is carried out, either in a suitable organic solvent or without any solvent; in the presence of a Lewis acid, such as AlC13, TiCl4, BF3, FeC13, SnC14, ZrCl4 or ZnC12, preferably TiCl4 or SnCl4, at temperatures ranging from about 0C to about 120C, and, if necessary, under cooling to keep the reaction temperature ranging from about 15C to about 35C. Then the reaction mixture is hydrolized with water and/or a diluted inorganic acid, such as hydrochloric acid: the subsequent working up, e~g. crystallization, distillation and chromatography, is carried out according to well - 7a -known procedures. Examples of preferred solvents, in which the Friedel Crafts reaction is performed, are alkanes, alkyl halides, aromatic hydrocarbons, alkylbenzenes and nitrobenzene, more preferably aromatic hydrocarbons, in particular benzene, toluene and zylene, and alkyl halides, in particular, the chlorides, e.g.
dichloromethane, 1,2-dichloroethane and 1,1,2,2-tetrachloroethane.
The aromatization of a compound of formula (IV) or (V) may be carried out by a bromination dehydrobromination process, The bromination of a compouncl of formula (IV) or (V) may be performed through a suitable brominating agent, such as N-bromozuccinimide, in a suitable organic solvent, e.g.

~.
,.~, ~ 8 --chloroform or carbon tetrachloride, with or w;thout the presence of a radical initiator, such as dibenzoyl peroxide or bis=azodiisobutyronitr;le. Other suitable brominating agents may be, for instance bromine in acetic acid, bromine in dimethylformamide or pyridinium perbro-mide. The bromina~ion react;on is immediately followed, in the same rsaction medium, by a dehydrobromination step consisting in heating the obtained reaction mixture, ;n the presence of a suitable base, e.g. diethylaniline, dimethylaniline, collidine or triethylamine, at tempera-tures ranging from about 60~C to the reflux temperatureO
The aromatization of a compound ot formula (IV) or ~V) may be alternatively perfor~ed by heating, at tempera-tures ranging from about 150~C to about 250~C~ in a high--boiling solvent, rhosen e.g. from diethyleneglycol di-methylether, diphenylether and decalin; or by heating at refiux temperature, either in the same high-boiling solvent mentioned a~ove ~r in a hydrogen acceptor solvent, such a$ cyclohexene, in the presence of sulphur, palladium ~0 black, palladium on carbon or palladium on other sub-strates, or in the presence of another noble metal, such as rhodium or ruthenium.
Alternatively the aromat;zation of a compound of formula (IV) or (V) may be performed by heating w;th chlorany3 or dichlorodicyanobenzoquinone (DD~) or other active quin-ones in boiling benzene o~ in another suitable solvent~
e.g, dioxane, acetic acid, or toluene.

. .

Also after the aromatization of a compound o~ formula ~IY) or tV), the subsequent working upr e.g. fi Itration and evaporation o~ the ~olvent, is carried out according to well known procedures.
The compounds of formula (II) and (III) are known compounds, which are either commercially avaiiàble products or easily obtainable by simple methods well known in organic chemistry. The optional alkylation of a compound of formula (IV) to obtain a compound of formula (V), as well as the optional alkylation of a compound of formula (I), wherein R4 is hydr~gen, to obtain another compound of formula (I),.wherein R4 is C1-G6 alkyl, may be carried out in a con~entional way, for example by reaction with NaH or NaNH2 in dry dioxane or dimethylformamide or toluene and alkylating the obtained anion with an alkyl sulphate.
As exàmple of another optional conversion of a compound of formula (I) into another compound of formula (I), a compound of formula (I), wherein R5 is hydroxy may be converted into another compound of formula (I), wherein R5 is a -SH group, by following known methods, for example according to the procedure of H~ Wolfers, U.
Xraatz, F. ~orte, Synthesis, 1971, page 43.
.. _ Furthermore a compound of formula (I), wherein R5 is a -OH or -SH group, may be converted into ano-ther compound of formula ~I), wherein R5 is C1-C6 alkoxy or Cl-C6 alkyl-thio, respectively. Said etherification may be performed D

by reaction with a suitable alkyl hal.ide, in the presence of a base such as NaOH, KOH, Na2C03, K2C03, NaH, NaNH2' ~odium methoxide or sodium ethoxide in a solvent selected from the group consisting, for example, of methanol, ethanol, dioxane, acetone, dimethylformamide, hexamethyl-phosphorotriamide, tetrahydrofuran, water and their mix-tures at a temperature ranging preferably between about O~C and about 150C. Furthermore, when R5 is an etherified hydroxy g~oup, it may be convert~d into a free hydroxy group, for example by treatment with pyridine hydrochlo-ride or with a strong acid such a~ HBr or HI, or with a Lewis acid such as AlC13 or BBr3 or with an alkaline salt of a thiol.
Also the optio~al salification of a compound of formula (I) as well as the conversion of a salt into the free compound may be carried out by conventional methods.
The compounds covered by the general formuIae (IV) and (V) may be summarized by the general formula (VI) ~7 ~ (VI) 6 O ~ ~ ~ ~3 wherein R1, R2, R3, R4, R6, R7 and R8 are as defined above.
As previously stated, object of this invention are also certaln new 2,3 r 7,~-tetrahydro-~4H~-1 benzopyran-4,5-~6H~--diones ha~ing the general formula (VIa) .3~

7 ~/~ R 1 I 1~ < R2 (VLa) 6 ~ O ~ O ~ ~ 3 wherein R1, R2, R3 and R4 are as defined above and one of Rl6, R'7 and R'8 is C~-C12 alkyl or phenyl and the others, which may be the same or different, are hydrogen, C1-C6 alkyl or phenyl.

The invention also provides a process for the preparation of a compound of formula (VI), which process comprises reacting a compound of formula (II):

7 ~ ~
l l (II) R
wherein O
R6, ~ and ~ are as defined above, with a compound of formula ~III) Rl ~ 2 C~
~-R3 (III) COOH
wherein Rl, R2 and R3 are as defined a~ove, or a reactive derivative thereof, ~o obtaining a compound of for~ula (VI) in which : R4 is hydrogen, represented by the formula (IV):

R7 ~ ~ 2 ~IV) whereinRl, R2~ R3, R6~ ~ and ~ are as defined above, and, if desired, alkylating a compound of formula ~IV), so

5 obtaining a compound of formula (VI), in which R~ is Cl-C6 aIkyl, represented ~y formula (~):

~8

6 ~ ~ ~ (V~

wherein Rl,R2, ~3, R6, R7 and R8 are as de~ined above and R'4 10 is Cl-C6 aIkyl.

The following Examples illustrate ~ut do not limit the present invention9 X~71~

5-Pentyl-1 7 3-cyclohexane-1,3-d~one (2.18 g~ was added po~io~se to a solution of titanium tetrachloride (1.6ml) in dichloromethane t40 ml) ~t 0C, under nitrogen. A red oil precipitated from the solution. After 0.5 h, 3,3-dimethylacrylic acid chloride (1.72 g) was dropped and the solution was stirred ~gain for 20 h, till a yellow precipitat~ was ob*ained. The mixture was poured into a chilled 2 M HCl solution (50 ml). The phases were separat-ed, the aqueous one was extracted twice ~ith chloroform, the organic extracts were washed with water, ~ried and concentrated. The crude residue was crystallized from ethyl ether. 2,2-Dimethyl-7-pen$yl-2,3,7,8-tetrahydro--~4H~-1-benzopyran-4,5-~6HJ-dione was obtained as pale yellow needles,m.p. 88-89C, 2.06 g, 83~ yield.
By proceeding analogously the ~ollowing compounds were prepared:
2,2-dimethyl-2,3,7,8-tetrahydro-~4~-1-benzopyran-4,5--~6~-dione~m.p. 97-98C, (from toluene);
2,2,7-trimethyl-2,3,~,8-tetrahydro-f~ l-benzopyran-4,5--~6H~-dione, m.p. 134-135C;
2-methyl-2,3,7,~-tetrahydro-~4H~-1-benzopyran-4,5-~6~J-dione, m.p~ 89C;
2-methyl-7-pentyl-2,3,7,8-$etrahydro-~4H~-1-benzopyran--4,5-~6~J-dione, yellow oil: M 250; H NMR~CDC13)S~ppm) 0.9(3H,t,CH3CH2), 1.1-1.35(8H), 1.4(3H,d,CH3-2~, 1.9-2.9 (7H), 4.25-4.9(1H,m,CH-2);

g~ , 2-pentyl-2,3,7,8-tetrahydro-~4H~ benzopyran-4,S-~6~--dione, oil;
2,2-dimethyl-7-phenyl-2,3,7,8-tetrahydro-~4~-1-benzo-pyran-4,5~C6~J-dione, m.p. 96-97C (from toluene);
2-methyl-7-phenyl-2,3,7,3-tetrahydro-~4~-1-ben~opyran--4,S-~6~J-dione; and 2-pentyl-7-methyl-2,3,7,8-tetrahydro-~4~J-l-benzopyran--4,5-~6~-dione.

Example 2 2,2-Dimethyl~-phenyl~2,3,7,8-tetrahydro-~4~J-l-benzopyran--4,5-~5H~-dione (~ ~) was rcfluxed for 7 h in 20 ml of diethyleneglycol dimethylether in the presence of 50 mg of 10% Pd/C. The cold mixture was filtered, diluted with ethyl acetate and washed several times with water. After column chromatography, 2,2-dimethyl-5-hydroxy-7-phenyl--2,3-dihydro-~4~-1-benzopyran-4-one was obtained as a yellow solid,m.p. 126-128~, 0.52 g.
By proceeding analogously the following compounds w~re obtained:
2,2-dimethyl-5-hydroxy-2,3-dihydro-~4HJ-l-benzopyran--4-~ne, m.p. 75-77C; .
2, 2, 7-tr i methy~ hydrox~3-dihydro-~4H~ -benzopyran-4-one, m.p. 23-25C; 30C;
: 2-methyl-5-hydroxy-2,3-dihydro-~4H~-l-benzopyran-4-one,m.p./
2-methyl-5-hydroxy-7-pentyl-2,3-dihydro-~4~-1-benzopyran--4-onet oil, N 248; HNMR(CDC13): ~(ppm) 0.9(3H~t,CH3), 1.0-1.7(6H), 1.5l3H,d,J6,CH3-2~, 2.4-2.8(6H), 4.3-4.8(1H,m,~-2), 6.2-6.4(2H,H6 and H-8), 11.6~1H,s,OH);
2-pentyl-5-hydroxy-2,3-dihydro-~4H~-l-benzopyran-4-one;
2-methyl-5-hydroxy-7-phenyl-2,3-dihydro-~4~-1-benzopyran--4-one;
2-pentyl-5-hydroxy-7-methyl-2~3-dihydro-~4HJ-l-benzopyran -4-one, yellow oil; and 2,2-dimethyl-5-hydroxy-7-pentyl-2,3-dihydro-~4~-1-benzo-pyran-4-one, b.p. 100-l05C (O.01 mmHg).

IS
:

-- 16 _ 2,2-Dimethyl-7-pentyl-2,3,7,8-tetrahydro-~4~ benzo-pyran-4,5-~6H~-dione (2.4 g), N-bromosuccinimide (2 g) and dibenzoyl per~xide (100 mg) were re~luxed for 2 h in carbon tetrachloride (25 ml). The solution was filtered and concentrated. The crude residue was added with N,N-cliethylaniline ( 3 ml j and warmed for 3 h on a steam bath.
The mixture was diluted with ethyl acetate and wash~d with 5N HCl, then with water. After dryin~ and evaporat~
ion of the solvent, 2~2-dimethyl-5-hydroxy-7-pentyl-2~3-dihydro-~4~ benzopyran-4-one was obtained by distillat-tion,b.p~100-105C ~0.01 mmHg), 2.3~, 98% yield.
By pr~ceeding analogously the following compounds were obtained:
2,2-dimethyl-5-hydroxy-7-phenyl-2,3-dihydro-~4 ~ -1-benzo-pyran-4-one,m.p. 126-128C;
2~2~7-trimethy~ hydroxy~2~3-dihydro-~4~ -1-benzopyran-4--one, m.p. 23-25C;
2,2~-dimethyl-5-hydroxy-2,3-dihydro-~4H~-l-benzopyran-4-one, ~I.p~5~C; 30C;
2-methyl-5-hydroxy-2,3-dihydro-~4H~-l-benzopyran-4-one,m.p./
2-methyl-5-hydroxy-7-pentyl-2,3-dihydro-~4~J-1-benzopyran--4-one, oil;

2 pentyl-5-hydroxy-2,3-dlhydro-~4H7-1-benzopyran-4-one;
2-methyl-5-hydroxy-7~phenyl-2,3-dihydro-/4H7-1-benzopyran--4-one; and 2-pentyl-5-hydroxy-7-methyl-2,3-dihydro-~4H7-1-benzopyran--4-one, yellow oil.

Example 4 2,2-Dimethyl-5-hydroxy-7-pentyl-2,3-dihydro-L4H/-l--benzopyran-4-one (1 g) was dissolved in tetrahydrofurane (12 ml) and treated with the stoichiometric amount of NaH~
The reaction mixture was evaporated, leaving 2,2-dimethyl-5-hydxoxy-7-pentyl-2,3-dihydro-~4H~-~1-benzopyran-4-~ne, sodium salt, as a residue; m.p. >250C.

- 18 ~

2,2-Dimethyl-7-phenyl 2,3,7,8-tetrahydro-~H]-l-benzopyran-4,5-~H~ 1oné (1.08 g) was refluxed 1.5 h in 10 ml of *oluene in the presence of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (~.9 g~. The mixture was filtered and concentrated; After eolumn chromato~raphy,2,2-dimethyl--5-hydroxy-7.-phenyl-~4~-1-benzopyran-4-one was obtained as a yellow solid~m.p.126-128C, 0.98 g (90% yield).
The following compo~nds were analogously prepared:
10 ~,2,?-trimethyl-5-hydroxy-2,3-dihydro-~4H~ benzopyran--4-one, m.p. 23-25C;
2,2-dimethyl-5-hydroxy-2,3-dihydro-~4H~-l-benzopyran-4--one, m.p~ 7 5-77 C ; -2,2-dimethyl-5-hydroxy-7-pentyl-2,3-dihydro-~4~ benz~-15 pyran-4-one,h.p. 100-105C (0.01 mmHg);
?-methy~-S-hydroxy-2,3-dihydro-~,4~ -1-benzopyran-4-one;
2~ethyl-5-hydroxy-7-pen-yl--2,3--dihydro-~4~J-1-ben-zopyran-4-one, oiL, 2-pentyl-5-hydroxy-2,3-dihydro-L4~J-l` ben20pyran-4-one;
2-methyl-5-hydroxy-7-phenyl-2,3-dihydro-/4~ -be~-zopyran-4 one; and 2-pen~yl -5-hydroxy-7-methy1-2,3-dihydro-/4~ ben-zopyran-4-one, yellow o;l.

, - 19 -2,2-dimethyl~2,3,7,8-tetrahydro-~4H7-1-benzopyran ~4,5--dione (1 g) was dissolved in 10 ml of dry tetrahydro-furane, the mixture cooled at -20C, added with 0.5 g of sodium hydride (80% suspension in paraffine oil), the mixture left two hours at room temperature, then added with 0.75 g of methyl iodide and refluxed three hours. Evaporation, taking up with water, extraction with ethyl acetate and evaporation of the solvent gave a crude mixture. Chromatography of this product on silica gel afforded 0.24 g of 2,2,3-trimethyl-2,3,7,8-tetrahydro-~4H~--1-benzopyran ~4,5-dione, as a low melting solid.

Claims (27)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for the preparation of a compound of formula (I) (I) wherein each of R1 and R2, being the same or different, is hydrogen or C1-C10 alkyl; or R1 and R2, taken together, form a C5-C7 cyclo-alkyl ring;
R3 is hydrogen, C1-C10 alkyl or phenyl;
R4 is hydrogen or C1-C6 alkyl;
R5 is -OR9 or -SR9, wherein R9 is hydrogen or C1-C6 alkyl;
each of R6, R7 and R8, being the same or different is hydrogen, C1-C12 alkyl or phenyl, or a salt thereof with a base;
said process comprising:
a): reacting a compound of formula (II) (II) wherein R6, R7 and R8 are as defined above, with a compound of formula (III) (III) wherein R1, R2 and R3 are as defined above, or a reactive derivative thereof, thereby obtaining a compound of formula (IV) (IV) wherein R1, R2, R3, R6, R7 and R8 are as defined above, and, if desired, alkylating a compound of formula (IV), thereby obtaining a compound of formula (V) (V) wherein R1, R2, R3, R6, R7 and R8 are as defined above and R'4 is C1-C6 alkyl, and then b) aromatization a compound of formula (IV) or (V), thus obtaining a compound of formula (I), wherein R1, R2, R3, R6, R7 and R8 are as defined above, R5 is hydroxy and R4, according to the starting product of formula (IV) or (V), is hydrogen or C1-C6 alkyl, and c) if desired, carrying out one or more of the following:
(i) alkylating a compound of formula (I) wherein R4 is hydrogen to obtain a corresponding compound of formula (I) wherein R4 is C1-C6 alkyl;
(ii) converting a compound of formula (I) wherein R5 is hydroxyl to obtain a corresponding compound of formula (I) wherein R5 is mercapto;
(iii) alkylating a compound of formula (I) wherein R5 is hydroxyl or mercapto to obtain a corresponding compound of formula (I) wherein R5 is C1-C6 alkoxy or C1-C6 alkylthio;
(iv) de-etherifying a compound of formula (I) wherein R5 is C1-C6 alkoxy to obtain a corresponding compound of formula (I), wherein R5 is hydroxy; and (v) converting a compound of formula (I) into a salt thereof with a base or converting a salt thereof into a free compound of formula (I).

2. A process according to claim 1, wherein the reaction of step a) is carried out in the presence of a Lewis acid.

3. A process according to claim 2, wherein the aromatizat-ion of step b) is carried out by a bromination-dehydrobromination process: by heating with an active quinone in a solvent: or by heating from about 150°C to about 250°C in a high-boiling solvent.

4. A process according to claim 1, 2 or 3, wherein the optional alkylation of step a) is carried out using a suitable alkylsulfate in the presence of sodium hydride or sodium amide.

5. A process according to claim 1, 2 or 3, wherein the alkylation (i) of step c) is carried out using a suitable alkylsulphate in the presence of sodium hydride or sodium amide.

6. A process according to claim 1, 2 or 3, wherein the alkylation (iii) of step c) is carried out using a suitable alkyl halide in the presence of a base.

7. A process according to claim 1, 2 or 3, wherein the de-etherification (iv) of step c) is carried out using pyridine hydrochloride, a strong acid, a Lewis acid or an alkaline salt of a thiol.

8. A process for the preparation of a compound of formula (VI) (VI) wherein R1, R2, R3, R4, R6, R7 and R8 are as defined in claim 1, which process comprises reacting a compound of formula (II) (II) wherein R6, R7 and R8 are as defined in claim 1, with a compound of formula (III) (III) wherein R1, R2 and R3 are as defined in claim 1, or a reactive derivative thereof, thereby obtaining a compound of formula (VI) in which R4 is hydrogen, represented by the formula (IV):

(IV) wherein R1, R2, R3, R6, R7 and R8 are as defined in claim 1, and, if desired, alkylating a compound of formula (IV), thereby obtaining a compound of formula (VI), in which R4 is C1-C6 alkyl, represented by formula (V):

(V) wherein R1, R2, R3, R6 r R7 and R8 are as defined in claim 1 and R'4 is C1-C6 alkyl.

9. A process according to claim 8, wherein in the starting material of formula (II) R6, R7 and R8 are R'6, R'7 and R'8, respectively wherein one of R'6, R'7 and R'8 is C2-C12 alkyl or phenyl and the others which may be the same or different are hydrogen, C1-C6 alkyl or phenyl, thereby obtaining a compound of formula (VIa) (VIa) wherein R1, R2, R3 and R4 are as defined in claim 1 and one of R'6, R'7 and R'8 is C2-C12 alkyl or phenyl and the others, which may be the same or different, are hydrogen, C1-C6 alkyl or phenyl.

10. A compound of the formula:

(VIa) (wherein:
each of R1 and R2 which may be the same or different is hydrogen or C1-C10 alkyl; or R1 and R2, taken together, form a C5-C7 cycloalkyl ring;
R3 is hydrogen, C1-C10 alkyl or phenyl;
R4 is hydrogen or C1-C6 alkyl; and one of R?, R? and R? is C2-C12 alkyl or phenyl and the others which may be the same or different are hydrogen, C1-C6 alkyl or phenyl) or a salt thereof with a base.

11. A process according to claim 8, wherein the reaction of the first step is carried out in the presence of a Lewis acid.

12. A process according to claim 11, wherein the Lewis acid is titanium tetrachloride.

13. A process according to claim 11, wherein the alkylation of the second step is carried out by first treating a compound of formula (IV) with sodium hydride or sodium amide in a dry solvent and then alkylating the thus treated compound with a suitable alkyl sulphate or alkyl halide.

14. A process according to claim 12, wherein the alkylation of the second step is carried out by first treating a compound of formula (IV) with sodium hydride in dry tetrahydrofurane and then methylating the thus treated compound with methyl iodide.

15. A process according to claim 8, 11 or 13, wherein in the starting materials R1 and R2 are each hydrogen, methyl, ethyl, propyl, butyl, pentyl or hexyl, R3 is hydrogen, and R6, R7 and R8 are each hydrogen, C2-C10 alkyl or phenyl.

16. A process according to claim 8, 12 or 14, wherein in the starting materials R1 and R2 are each hydrogen, methyl or pentyl, R3 is hydrogen, R6 and R8 are hydrogen and R7 is hydrogen, methyl, pentyl or phenyl.

17. A process according to claim 2, wherein the aromatizat-ion of step b) is carried out by heating a compound of formula (IV) or (V) in a high-boiling solvent in the presence of palladium.

18. A process according to claim 2, wherein the aromatization of step b) is carried out by first brominating a compound of formula (IV) or (V) with N-bromosuccinimide in the presence of a radical initiator and then by heating the brominated product in the presence of a base to perform dehydrobromination.

19. A process according to claim 2, wherein the aromatizat-ion of step b) is carried out by heating a compound of formula (IV) or (V) with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in a boiling solvent.

20. A process according to claim 17, 18 or 19, wherein in the starting materials R1 and R2 are each hydrogen, methyl, ethyl, propyl, butyl, pentyl or hexyl, R3 is hydrogen, and R6, R7 and R8 are each hydrogen, C2-C10 alkyl or phenyl.

21. A process according to claim 17, 18 or 19, wherein in the starting materials R1 and R2 are each hydrogen, methyl or pentyl, R3 is hydrogen, R6 and R8 are hydrogen and R7 is hydrogen, methyl, pentyl or phenyl.

22. A process for producing 2,2-dimethyl-7-pentyl-2,3,7,8-tetrahydro[4H]-1-benzopyran-4,5-[6H]-dione, which process comprises reacting 5-pentyl-1,3-cyclohexane-1,3-dione and 3,3-dimethylacrylic acid or a reactive derivative thereof.

23. A process according to claim 22, wherein 3,3-dimethyl-acrylic acid chloride is used as the reactive derivative and the reaction is carried out in the presence of titanium tetrachloride.

24. 2,2-Dimethyl-7-pentyl-2,3,7,8-tetrahydro-[4H]-1-benzopyran-4,5-[6H]-dione.

25. A process for producing 2,2-dimethyl-5-hydroxy-7-pentyl-2,3-dihydro-[4H]-1-benzopyran-4-one or a base salt thereof, which process comprises:
(a) reacting 5-pentyl-1,3-cyclohexane-1,3-dione and 3,3-dimethylacrylic acid or a reactive derivative thereof to produce2,2-dimethyl-7-pentyl-2,3,7,8-tetrahydro-[44H]-1-beenzo-pyran-4,5-[6H]-dione, and then (b) aromatizating the resulting compound into the desired compound, and (c) if desired, converting the desired compound into a base salt thereof.

26. A process according to claim 25, wherein the aromatiz-ation of step b) is carried out by (i) heating in diethylenegly-col dimethylether in the presence of palladium; (ii) first brominating with N-bromozuccinimide in the presence of dibenzoyl peroxide followed by heating in the presence of N,N-diethyl-aniline or (iii) heating with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in a boiling solvent.

27. A process according to claim 26, wherein the aromatiz-ation product is converted into sodium salt thereof.