WO2002042285A1

WO2002042285A1 - Novel process for the preparation of 4-benzoylamino chroman derivatives

Info

Publication number: WO2002042285A1
Application number: PCT/GB2001/005133
Authority: WO
Inventors: John Morris Evans; Graham Richard Geen; Inderjit Singh Mann; Mervyn Thompson
Original assignee: SmithKline Beecham Ltd
Current assignee: SmithKline Beecham Ltd
Priority date: 2000-11-23
Filing date: 2001-11-21
Publication date: 2002-05-30
Anticipated expiration: 2003-05-23
Also published as: AU2002223852A1; GB0028697D0

Abstract

A process for the preparation of a compound of formula (I), which process comprises converting the epoxide of formula (VI) to the cis-oxazoline of formula (V) by reaction with the cyano-compound of formula (VII) in the presence of an acid, then converting the compound of formula (V) in situ to the cis-amine of formula (III) or a salt thereof and thereafter reacting the cis-amine of formula (III) or salt thereof with an acid chloride of formula (IV) to give the cis-compound of formula (I).

Description

NOVEL PROCESS FOR THE PREPARATION OF 4-BENZOYLAMINO CHROMAN DERIVATIVES

This invention relates to a new synthetic process to compounds having pharmacological activity.

WO 94/13657 and WO 95/34545 (SmithKline Beecham PLC) describe compounds of formula (I) or pharmaceutically acceptable salts thereof including solvates such as hydrates having anti-convulsant activity indicated to be useful in the treatment of epilepsy and also believed to have utility in the treatment or prevention of anxiety, mania, depression, disorders associated with a subarachnoid haemorrhage or neural shock, the effects associated with withdrawal from substances of abuse, Parkinson's disease, psychosis, migraine with and without aura, cerebral ischaemia, Alzheimer's disease, schizophrenia, obsessive compulsive disorder (OCD) and/or panic and/or aggression:

(I) wherein: either Y is N and R2 is hydrogen, or Y is C-Rj where: either one of R\ and R2 is hydrogen and the other is selected from the class of hydrogen, C3..8 cycloalkyl, C\. alkyl optionally interrupted by oxygen or substituted by hydroxy, \_ alkoxy or substituted aminocarbonyl, C\._β alkylcarbonyl, Cj.g alkoxycarbonyl, Cj.g alkylcarbonyloxy, C\. alkoxy, nitro, cyano, halo, trifluoromethyl, CF3S, or a group CF3-A-, where A is -CF2-, -CO-, CH₂-, CH(OH), SO₂, SO, CH₂-O, or CONH, or a group CF₂H-A'- where A' is oxygen, sulfur, SO, SO2, CF2 or CFH; trifluoromethoxy, C\. alkylsulfinyl, perfluoro C2.6 alkylsulfonyl, C\. alkylsulfonyl, C\. alkoxysulfinyl, C\. alkoxysulfonyl, aryl, heteroaryl, arylcarbonyl, heteroarylcarbonyl, phosphono, arylcarbonylfr^^heferoarylcarbonyloxy, arylsulfinyl, heteroarylsulfinyl, arylsulfonyl, heteroarylsulfonyl in which any aromatic moiety is optionally substituted, C . alkylcarbonylamino, C\.β alkoxycarbonylamino, C\.β alkyl-thiocarbonyl, C\.β alkoxy-thiocarbonyl, C\.β alkyl-thiocarbonyloxy, 1- mercapto C2-7 alkyl, formyl, or aminosulfinyl, aminosulfonyl or aminocarbonyl, any amino moiety being optionally substituted by one or two C\. alkyl groups, or C 1 _g alkylsulfmylamino, C \ _ alkylsulfonylamino,C j _g alkoxysulfinylamino or C\. alkoxysulfonylamino, or ethylenyl terminally substituted by C g alkylcarbonyl, nitro or cyano, or -C(C|_6 alkyl)NOH or -C(Cι_6 alkyl)NNH2, or one of R and R2 is nitro, cyano or C 1.3 alkylcarbonyl and the other is methoxy or amino optionally substituted by one or two C\_β alkyl or by C2-7 alkanoyl; or R and R2 together are -(CH2)4~ or -CH = CH-CH = CH-, or form an optionally substituted triazole or oxadiazole ring; one of R3 and R4 is hydrogen or C 1.4 alkyl and the other is C 1.4 alkyl, CF3 or CH2 X^a where X^a is fluoro, chloro, bromo, iodo, Cι_4 alkoxy, hydroxy, Cι_4 alkylcarbonyloxy, -S-C1.4 alkyl, nitro, amino optionally substituted by one or two Cι_4 alkyl groups; cyano or Cj_4 alkoxycarbonyl or R3 and R4 together are C2.5 polymethylene optionally substituted by C 1.4 alkyl;

R5 is C\.β alkylcarbonyloxy, benzoyloxy, ONO2, benzyloxy, phenyloxy or C\. alkoxy and Rg and R9 are hydrogen or R5 is hydroxy and Rβ is hydrogen or Cι_2 alkyl and R9 is hydrogen; R7 is heteroaryl or phenyl; both of which are optionally substituted one or more times independently with a group or atom selected from chloro, fluoro, bromo, iodo, nitro, amino optionally substituted once or twice by Cι_4 alkyl, cyano, azido, Cι_4 alkyl, C1.4 alkoxy, trifluoromethoxy and trifluoromethyl; and X is oxygen or NRJQ where RJQ is hydrogen or C\. alkyl. Generally, compounds of formula (I) may be prepared from the corresponding trans-compounds, procedures for the preparation of which are generally described in prior art documents EP-0126311, EP-0376524, EP-205292, EP-0250077, EP- 0093535, EP-0150202, EP-0076075, WO/89/05808, EP-0350805, EP-0277611, EP-0277612, EP-0337179, EP-0339562, EP-0355565, EP-A-415 065 (E. Merck), EP-A-450415 (Squibb) EP-0466131, EP-A-0482934, EP-A-0296975, JO-2004- 791 and WO 89/07103.

The c/s-compounds may also be prepared by procedures generally described in or analogous to those described in prior art document EP-A-0139992.

Compounds of formula (I) may also be prepared according to the procedures described by Burrell G. et al, Tetrahedron Lett., 31, 3649-3652 (1990) or by the procedures described by Quast U. and Nillhauer E., Eur. J. Pharmacol, Molecular Pharmacology Section, 245, 165-171 (1993).

WO 94/13657 discloses a process for the preparation of a cz^'s-compound of formula (I) or a pharmaceutically acceptable salt thereof, which comprises treating the oorresponding trans-compound, in which R5 is hydroxy, with trifluoromethanesulfonic anhydride in a suitable solvent such as pyridine to furnish the c/s-oxazoline compound of formula (II);

(II) in which all of the variables are as defined in formula (I), followed by; (i) acid treatment using, for example, dilute sulfuric acid and; (ii) base treatment using, for example, sodium bicarbonate solution to give the cw-compound of formula (I). Example 17 in WO 95/34545 describes a method for the preparation of ct_s-6-acetyl-4S-(3-chloro-4-fluorobenzoylamino)-3,4-dihydro-2,2-dimethyl-2H-l- benzopyran-3S-ol from cz_y-8-acetyl-2-(3-chloro-4-fluorophenyl)-3a,9b-dihydro- 4,4-dimethyl-4H-benzo[b]pyrano[4,3-d]oxazole by hydrolysing this compound with aqueous sulfuric acid solution followed by aqueous sodium bicarbonate solution. ct__f-8-Acetyl-2-(3-chloro-4-fluorophenyl)-3a,9b-dihydro-4,4-dimethyl- 4H-benzo[b]pyrano[4,3-d]oxazole is prepared by reaction of tra«_s-6-acetyl-4S-(3- chloro-4-fluorobenzoylamino)-3 ,4-dihydro-2,2-dimethyl-2H- 1 -benzopyran-3R-ol with diethylaminosulfur trifluoride (DAST) in a dichloromethane solution. It will be appreciated that the significance of these steps is the transformation of the trans-diastereoisomer to its cz^'s-equivalent.

An alternative process for preparing the cw-compound of formula (I) has now been discovered which involves the synthesis of the cz^'s-compounds of formula (III) using a variant of the Ritter reaction. Cz^'s-compounds of formula (III) are described in prior art document EP-A-0139992. There are several advantages to this method including a shorter synthetic pathway, improved yields, and reduced material costs. This method has been found to be particularly suitable for use in stereospecific synthesis as no scrambling of the chiral centres occurs. Accordingly, the present invention provides a process for the preparation of the cw-compound of formula (I), or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable hydrate thereof, which process comprises the reaction of the cw-compound of formula (III), or a salt thereof;

(III) in which R5 is hydroxy and all other variables are as defined in formula (I) with an acylating agent of formula (IN) in which R7 is as defined in formula (I), and L is a suitable leaving group such as chloro.

R7COL

(IN)

It should be appreciated that the compound of formula (I) or a pharmaceutically acceptable salt thereof also includes solvates of such compounds, such as for example the hydrate.

Typically, the c/s-compound of formula (III), or a salt thereof, is mixed with an organic solvent, and water and an aqueous base is added. A solution of the acylating agent in an organic solvent is added to the mixture, and the mixture stirred for approximately one hour. The mixture is heated if necessary and the lower, aqueous, phase separated, filtered, and washed with organic solvent. The phases are separated and the organic phase washed with dilute mineral acid and water. The volume of the organic phase is reduced by distillation under reduced pressure and the mixture heated to achieve complete dissolution. Seed crystals of the relevant compound of formula (I) are added and the mixture cooled slowly to about 10°C, then stirred for about one hour. The product is then isolated and dried.

In a preferred aspect, the cz^'s-compound of formula (III), or a salt thereof, is mixed with toluene, and water and aqueous sodium hydroxide solution added, maintaining the temperature between 20°C and 25°C. A solution of the acylating agent in toluene is added to the mixture, maintaining the temperature between 20°C and 25°C. Toluene is added and the mixture stirred at between 20°C and 25°C for 75 minutes. The mixture is heated to between 70°C and 80°C and the lower, aqueous, phase separated, filtered, and washed with toluene, at between 70°C and 80°C. The phases are separated and the organic phase washed at between 60°C and 70°C, with dilute hydrochloric acid and water. A slurry of charcoal in toluene is added and the mixture heated preferably to between 80°C and 85°C and filtered. The volume is reduced by distillation under reduced pressure and the solution heated to between 80°C and 90°C, then cooled to 78°C. Seed crystals of the relevant compound of formula (I) are added and the mixture cooled to 25 °C over about about ten hours and then to 10°C over about one hour, then stirred at about 8°C for one hour. The product is isolated and dried as described in the Description.

The s-compound of formula (III) may be prepared from the epoxide of formula (NI) by acid hydrolysis of the intermediate oxazoline of formula (N) in situ. The epoxide of formula (NI) may be first reacted to form a compound of formula (NIII) which may be isolated and then reacted to form the oxazoline of formula (N) with hydrolysis in situ to yield the cz's-compound of formula (III). The oxazoline of formula (N) may be formed by reaction of the compound of formula (NIII) or the epoxide of formula (NI) with an organic cyanide of formula (Nil) in the presence of an strong acid or a Lewis acid. The hydrolysis of the compound of formula (N) proceeds via a two step mechanism whereby the oxazoline ring is opened under mildly acidic conditions to give the corresponding amino-ester, which is then hydrolysed by strong acid to give the amino-alcohol of formula (III), wherein R5 is hydroxy.

Alternatively, the c/s-compound of formula (III) may be prepared by hydrolysis of the intermediate compound (IX). Compound (IX) is formed from compound (N) in situ by mild acid hydrolysis to form the amino-ester as described above, but adjustment of the reaction conditions to basic pH results in the transformation of the amino-ester to the thermodynamically more stable amido-alcohol (IX). Compounds of formula (IX) are described in prior art document EP-A-0139992.

(V) (NI) (Nil)

(NIII) (IX)

wherein R]2 is hydroxy, C1-C4 alkoxy, or halogen, and R is CJ-CJO alkyl, or C3-C8 cycloalkyl optionally substituted one or more times with a group or atom selected from fluoro, chloro, bromo, iodo, nitro, amino, hydroxy, or cyano.

The Ritter reaction is described in the following references: Ritter J.J. and Minieri P.P. J. Am. Chem. Soc. 70, 4045-4050, (1948) Senanayake CH. et al Tetrahedron Lett. 36, 3993-3996, (1995) Senanayake CH. et al Tetrahedron Lett. 36, 7615-7618, (1995)

The compounds of formula (N) are novel and form an aspect of the invention. The preparation of the s-compound of formula (III) may be carried out using any of the processes A-C below. To form a salt of the compound of formula (III), process C may be used, but following process C2 described therein:

A. Typically a solution of the compound of formula (NI) is mixed with the appropriate organic solvent and appropriate acid and the mixture stirred for up to one hour at ambient temperature. The aqueous layer is separated if necessary, and the solvent removed to afford the crude compound of formula (NIII). This is then dissolved in an appropriate organic cyanide and added to a solution of a Lewis acid in the relevant organic cyanide. The mixture is heated under reflux for 0.5- 1.5 hours, cooled to about 30°C, and water added slowly. The resulting mixture is stirred for about one hour. The aqueous layer is separated and extracted with ethyl acetate. The organic cyanide solution and ethyl acetate extracts are combined and evaporated to dryness. To this is added aqueous hydrochloric acid and toluene, and the mixture heated under reflux for 3-4 hours. The aqueous is separated, washed with hot toluene, and zsσ-propyl alcohol added to the aqueous solution. The pH is adjusted to pH 9-10 by the addition of aqueous sodium hydroxide solution, the mixture cooled to 0-5°and the product compound of formula (III) isolated and dried. In a preferred aspect a solution of the compound of formula (NI) in dichloromethane is treated with aqueous sulfuric acid for 30 minutes. The organic layer is separated and the aqueous layer extracted with dichloromethane. The combined organic extracts are washed with water and then evaporated to dryness under vacuum to afford the compound of formula (NIII). This is then dissolved in acetonitrile and added to a solution of aluminium chloride in acetonitrile, and then heated under reflux for thirty minutes. On cooling to 30°C water is added and then stirred at this temperature for 30 minutes. The aqueous layer is separated and extracted with ethyl acetate and the combined organic solutions evaporated to dryness under vacuum. Aqueous HC1 and toluene are added and the mixture heated under reflux for three hours. The aqueous layer is separated while hot and then washed with hot toluene (70-80°C). isø-propyl alcohol is added to the aqueous layer and the pH adjusted to pH 9 with aqueous sodium hydroxide solution. The mixture is cooled to 0-5°C, and the product compound of formula (III) isolated and dried as described in Example A.

B. Typically, to a solution of a Lewis acid in an organic cyanide of formula (Nil) is added a solution of the epoxide of formula (VI) in the organic cyanide of formula (Nil). Water is added and the mixture stirred overnight. The solution is basified and extracted with a suitable organic solvent. The organic extract is then dried and evaporated to yield the crude compound of formula (IX), which is then purified by chromatography. Hydrolysis of the purified product with base furnishes the compound of formula (III). In a preferred aspect, aluminium chloride is added in portions to acetonitrile at 0°C with stirring under an atmosphere of argon. A solution of the compound of formula (NI) in acetonitrile is added dropwise over a period of about twenty minutes. The reaction is stirred for two hours, water carefully added, and the mixture stirred at room temperature for about twelve hours. The solution is basified with sodium bicarbonate and extracted with ethyl acetate. The organic extract is dried with anhydrous magnesium sulfate, filtered, and evaporated to yield the crude compound of formula (IX) as a gum. The crude product is purified by chromatography on silica gel with elution by ethyl acetate. Aqueous sodium hydroxide solution is added to a solution of the purified product in ethanol and the mixture heated under reflux under an atmosphere of argon for about twenty-four hours. The volume of the resulting solution is reduced by evaporation, the solution salified, and extracted with ethyl acetate. The crude extract is purified by chromatography with elution by an ethyl acetate:methanol/ethyl acetate mixture. Evaporation of the solvents then affords the compound of formula (III) as described in Example B. C Typically, a solution of an appropriate strong acid in the alkyl cyanide of formula (Nil) is heated to 60-80°C and a solution of the compound of formula (NI) in the alkyl cyanide of formula (Nil) is added to the solution. Water is then added, the temperature adjusted to about 65°C and the mixture stirred for about 90 minutes before cooling to about 30°C The solvent is removed under reduced pressure and water added. Distillation is continued- to remove the last traces of the alkyl cyanide. To form the free base, Procedure Cl is followed. To form a salt, Procedure C2 is followed: Procedure Cl : Water, acid and toluene are added and the mixture heated under reflux for 3.5 hours. The lower aqueous phase is separated and washed with further toluene at approximately 70°C Isopropanol is then added to the aqueous phase and the pH of the mixture adjusted to pH 9-10 with sodium hydroxide solution. The mixture is cooled to 0-5°C and stirred for 12-18 hours. The product is then isolated and dried.

Procedure C2: Water and alcohol are added followed by the complementary acid of the desired salt and the mixture stirred under reflux for about three and a half hours. The mixture is allowed to cool and seeded with crystals of the desired salt of the compound of formula (III). The mixture is cooled to about 5°C over 8 hours and stirred for one hour. The product is then isolated.

In a preferred aspect, a solution of trifluoromethanesulfonic acid in acetonitrile is heated to reflux and a solution of the compound of formula (NI) in acetonitrile is added to the refluxing solution. After 5-10 minutes water is then added, the temperature adjusted to between 60°C and 70°C and the mixture stirred for 90 minutes before cooling to 30°C The solvent is removed under reduced pressure and water added. Distillation is continued until most of the solvent has been removed. Water and iso-pτopyl alcohol are added followed by the complementary acid of the desired salt and the temperature allowed to rise from 42°C to 62°C Zyo-propyl alcohol is added and the mixture stirred under reflux for about three and a half hours. The mixture is allowed to cool to 65°C over about one hour and seeded with crystals of the relevant salt of the compound of formula (III). The mixture is cooled to 25°C over eight hours and then to 5°C over one hour and stirred at 4°C for one hour. The product may be isolated as described in Example C2.

All C\. alkyl or C- _4 alkyl or alkyl containing groups in formula (I) are preferably selected from methyl, ethyl, n - and iso -propyl, n -, iso -, sec - and tert-butyl. Suitable C3..8 cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

Suitable halo substituents include fluoro, chloro and bromo. Aryl whenever mentioned herein includes but is not limited to phenyl and naphthyl. Heteroaryl whenever mentioned herein includes a 5- or 6- membered monocyclic or 9- or 10- membered bicyclic of which 5- or 6- membered monocyclic heteroaryl is preferred. In addition, 5- or 6-membered monocyclic or 9- or 10-membered bicyclic heteroaryl preferably contains one, two or three heteroatoms which are selected from the class of oxygen, nitrogen and sulfur and which, in the case of there being more than one heteroatom, are the same or different. Examples of 5- or 6-membered monocyclic heteroaryl containing one, two or three heteroatoms which are selected from the class of oxygen, nitrogen and sulfur include furyl, thienyl, pyrryl, oxazolyl, thiazolyl, imidazolyl and thiadiazolyl, and pyridyl, pyridazyl, pyrimidyl, pyrazolyl and triazolyl. Preferred examples of such groups include furanyl, thienyl, pyrryl and pyridyl, in particular 2- and 3-furyl, 2- and 3-pyrryl, 2- and 3-thienyl, and 2-, 3- and 4-pyridyl. Examples of 9- or 10-membered bicyclic heteroaryl containing one, two or three heteroatoms which are selected from the class of oxygen, nitrogen and sulfur include benzofuranyl, benzothienyl, indolyl and indazolyl, quinolyl and isoquinolyl, and quinazolyl. Preferred examples of such groups include 2- and 3-benzofuryl, 2- and 3-benzothienyl, and 2- and 3-indolyl, and 2- and 3-quinolyl.

Suitable examples of groups or atoms for optional substitution especially of aryl and heteroaryl include one, two or three substituents independently selected from Cι_4 alkyl, Cj_4 alkoxy, halo (such as fluoro, chloro, bromo), hydroxy, nitro, amino optionally substituted once or twice by C 1.4 alkyl, cyano and SO_nH, where n=0 to 2.

Preferably R\ is cyano, acetyl, nitro and ethyl. Most preferably R\ is acetyl or ethyl. Preferably R2 is hydrogen.

Preferably R3 and R4 are both methyl.

Preferably R5 is hydroxy and Rg and R9 are hydrogen.

It should be appreciated that when R7 is phenyl optionally independently substituted; this includes substitution by 1, 2, 3, 4, or 5 groups or atoms attached to the phenyl ring. Preferably there are 1 or 2 groups or atoms attached to the phenyl ring. The groups or atoms may be in any position around the phenyl ring. Likewise, it should be appreciated that when R7 is heteroaryl optionally independently substituted; this includes substituents at any vacant positions around the heteroaryl moiety. Preferably there are 1 or 2 groups or atoms around the heteroaryl moiety, most preferably there is one group or atom around the heteroaryl moiety.

Preferably R7 is 2-,3-,or 4-fluorophenyl, phenyl, 2 or 3-chlorophenyl, 2,3- dichlorophenyl, 2-trifluoromethylphenyl, 2-nitrophenyl, 2-aminophenyl, 2-chloro- thiophen-3-yl, 3-chlorothiophen-2-yl or 3-chloro-4-fluorophenyl. Preferably R7 is fluorophenyl. More preferably R7 is mono-fluorophenyl and even more preferably R7 is 2-, 3 or 4-fluorophenyl. Most preferably R7 is 3- chloro-4-fluoropheny 1.

Preferably X is oxygen. The following Examples illustrate the invention, but do not limit it in any way:

Examples

Preparations of (3S,4S)-6-acetyl-4-amino-2,2-dimethyl-3-hydroxy-2H-l~ benzopyran.

A.

1. Preparation of (3S)-6-acetyl-3,4-dihydroxy-2,2-dimethyl-2H-l-benzopyran. A solution of (3 S, 4S)-6-acetyl-3 ,4-dihydro-2,2-dimethyl-3 ,4-eρoxy-2H- 1 - benzopyran (4.36g, 20mmol) in dichloromethane (30ml) was added to 1M aqueous sulfuric acid (20ml) and the mixture stirred for 15 minutes at ambient temperature. The aqueous layer was separated and extracted with dichloromethane (2x). The combined dichloromethane extracts were evaporated to dryness to yield the diol as a mixture of cis/trans diastereoisomers, which was used directly without purification.

(3S-c/5)-6-acetyl-3,4-dihydro-2,2-dimethyIbenzo[2H-l]pyran-3,4-dioI δ(DMSO-d₆): 1.23 (s, 3Η, CH₃), 1.38 (s, 3H, CH₃), 2.54 (s, 3H, COCH₃), 3.63 (dd, IH, J_3j = 4.2Hz, H-3), 4.74 (dd, IH, H-4), 4.95 (d, IH, 3-OH), 5.33 (dd, IH, 4-OH), 6.76 (d, IH, H-8), 7.73 (dd, IH, H-7), 8.06 (d, IH, H-5).

(3S-trαn_s)-6-acetyl-3,4-dihydro-2,2-dimethylbenzo[2H-l]pyran-3,4-diol δ(DMSO-d₆): 1.17 (s, 3H, CH3), 1.41 (s, 3H, CH3), 2.52 (s, 3H, COCH3), 3.42 (dd, IH, J_3j4 = 8.2Hz, H-3), 4.41 (dd, IH, H-4), 5.58 (d, IH, 3-OH), 5.71 (dd, IH, 4-OH), 6.82 (d, IH, H-8), 7.77 (dd, IH, H-7), 8.08 (d, IH, H-5).

2. Preparation of (3S, 4R)-6-acetyl-2,2-dimethyl-3-hydroxy-4-methoxy-2H-l- benzopyran. 4-Toluenesulfonic acid (19mg) was added to a solution of (3S, 4S)-6-acetyl-3,4- dihydro-2,2-dimethyl-3,4-epoxy-2H-l -benzopyran (4.36g, 20mmol) in methanol (50ml) and stirred for 30-60 minutes. The solvent was then removed under vacuum to yield the product as almost exclusively the trans diastereoisomer, which was used directly without purification.

(3S-t «5)-6-acetyl-3,4-dihydro-2,2-dimethyI-4-methoxybenzo[2H-l]pyran-3- ol δ(DMSO-d₆): 1.21 (s, 3Η, CH₃), 1.36 (s, 3H, CH₃), 2.50 (s, 3H, COCH₃), 3.56 (s, 3H, OCH3), 3.68 (d, IH, J_3> = 6.5Hz, H-3), 4.25 (d, IH, H-4), 6.82 (d, IH, H- 8), 7.79 (dd, IH, H-7), 7.92 (d, IH, H-5).

3. Preparation of (3R)-6-acetyl-4-chloro-2,2-dimethyl-3-hydroxy-2fT-l- benzopyran.

Concentrated HC1 (20ml) was added to a solution of (3S, 4S)-6-acety 1-3,4- dihydro-2,2-dimethyl-3,4-epoxy-2H-l -benzopyran (4.36g, 20mmol) in dichloromethane (50ml), and the mixture stirred for 1 hour at ambient temperature. The organic layer was separated and water (20ml) was added to the acid layer. The aqueous layer was extracted with dichloromethane and the combined organic solution washed with water. The solvent was removed to afford the chlorohydrin as a mixture of cis/trans diastereoisomers, which was used directly without purification.

(3R- )-6-acetyl-4-chloro-2,2-dimethyI-3,4-dihydrobenzo[2H^r-l]pyran-3-ol δ(CDCl₃): 1.27 (s, 3Η, CH₃), 1.50 (s, 3H, CH₃), 2.49 (s, 3H, COCH3), 3.82 (dd, IH, J_3j4 = 5.0Hz, H-3), 5.38 (d, IH, H-4), 6.81 (d, IH, H-8), 7.78 (dd, IH, H-7), 8.07 (d, IH, H-5).

(3R-tr ns)-6-acetyI-4-chloro-2,2-dimethyl-3,4-dihydrobenzo[2H-l]pyran-3-oI δ(DMSO-d₆): 1.16 (s, 3H, CH₃), 1.44 (s, 3H, CH₃), 2.52 (s, 3H, COCH₃), 3.71 (dd, IH, J3_}4 = 8.4Hz, H-3), 5.16 (d, IH, H-4), 6.20 (d, IH, OH), 6.89 (d, IH, H- 8), 7.83 (dd, IH, H-7), 8.05 (d, IH, H-5).

A solution of the compound of formula (NIII) produced from Procedures 1, 2, or 3 above (20mmol) was dissolved in acetonitrile (30ml) and added to a solution of A1C1₃ (5.34g, 40mmol) in acetonitrile (35ml). The reaction was heated to reflux for 30 minutes, then cooled to approximately 30°C. Water (20ml) was added carefully and then stirred for 30 minutes. The aqueous layer was separated and then extracted with ethyl acetate. The ethyl acetate extract was combined with the acetonitrile solution and then evaporated to dryness. 2Ν HC1 (40ml) and toluene (30ml) were added and then heated under reflux for 3 hours. The aqueous layer was separated and washed with toluene (30ml) while hot. Zso-propyl alcohol (13ml) was added to the aqueous solution, and then 40% NaOH added to pHIO at 55-60°C The mixture was cooled to 0-5°C and left overnight. The product was filtefed, washed with water and wo-propyl alcohol, then dried under high vacuum at 50°C to give (3S, 4S)-6-acetyl-4-amino-2,2-dimethyl-3-hydroxy-2H-l- benzopyran.

B.

Aluminium chloride (0.68g) was added in portions to acetonitrile (20ml) at 0°C with stirring under an atmosphere of argon. (3S,4S)-6-Acetyl-3,4-dihydro-2,2- dimethyl-3,4-epoxy-2Η-l -benzopyran (1.09g) in acetonitrile (10ml) was then added dropwise over about twenty minutes. The reaction mixture was stirred for an additional two hours. Water (20ml) was carefully added and the mixture stirred at room temperature overnight. The solution was basified with sodium bicarbonate and extracted with ethyl acetate. The organic extract was dried with anhydrous magnesium sulfate, filtered, and evaporated to yield a gum (1.4g). Chromatography on silica gel with elution by ethyl acetate gave 500mg of (3S,4S)-N-acetyl-6-acetyl-4-amino-2,2-dimethyl-3-hydroxy-2H-l-benzopyran. (3S,4S)-N-Acetyl-6-acetyl-4-amino-2,2-dimethyl-3-hydroxy-2H-l-benzopyran (300mg) was heated under reflux in ethanol (7ml) and 40% aqueous sodium hydroxide solution (2ml) for twenty-four hours under an atmosphere of argon. The solution was partially evaporated, salified, and extracted with ethyl acetate. The crude extract was chromatographed on silica gel with elution by a mixture of ethyl acetate and 20% methanol/ethyl acetate to give (3S,4S)-6-acetyl-4-amino- 2,2-dimethyl-3 -hydroxy-2H- 1 -benzopyran ( 140mg). Melting point: 190-194°C [α]_D ²⁵ -88.5° (c=1.0, methanol)

NMR δ (CDCI3/CD3OD): 1.28 (3Η, s), 1.51 (3H, s), 2.58 (3H, s), 3.31 (3H, br s), 3.61 (IH, d, J=4Hz), 4.08 (IH, d, J=4Hz), 6.87 (IH, d, J=8Hz), 7.70 (IH, dd, J=8Hz, 2Hz), 8.12 (IH, d, J=2Hz).

Cl.

Acetonitrile (398 L) was charged to a nitrogen purged vessel. Trifluoromethanesulfonic acid (24.2 kg, 160.9 moles) was added to the vessel and flushed through with acetonitrile (4 L). The trifluoromethanesulfonic acid solution was then heated to 79°C A solution of (3S,4S)-6-Acetyl-3,4-dihydro- 2,2-dimethyl-3,4-epoxy-2H-l -benzopyran (33.2 kg, 152.3 moles) in acetonitrile (96 L) was added to the hot trifluoromethanesulfonic acid over 40 minutes maintaining a steady reflux. A further 5 L of acetonitrile was added and the mixture allowed to stir under reflux for a further 7 minutes then cooled to 78°C Water (38 L) was added and the mixture stirred for 1 hour at 49-60°C The mixture was distilled in vacuo and 485 L of distillate were collected. Water (149 L) was added, the distillation continued and approximately 140 L of distillate were collected. Water (195 L) was added followed by 36% hydrochloric acid (53 L) and toluene (229 L). The mixture was then heated under reflux (83°C) for 35 hours and allowed to separate. The lower aqueous phase was separated and the upper organic phase was cooled and run off to waste. Toluene (229 L) was added to the aqueous phase and the mixture heated to 70°C The hot mixture was stirred vigorously for 10 minutes and the phases were allowed to separate. The lower aqueous phase was separated and retained and the organic phase was cooled and run to waste. Isopropanol (103 L) was added to the aqueous acidic solution and the pH of the mixture was adjusted from pH 0.21 to pH 9.0 with 32% wt/wt sodium hydroxide solution (87 L). The mixture was cooled to 1°C and then stirred at 1°C for 13.5 hours. The solid was filtered off, washed twice with process water and then twice with isopropanol using a total of 152 L of water and 76 L of isopropanol. The product was unloaded on to trays and dried at 58°C for 40 hours to give (3S,4S)-6-acetyl-4-amino-2,2-dimethyl-3-hydroxy-2H-l- benzopyran (20.04 kg).

(3S- '_s)-6-acetyl-4-amino-3,4-dihydro-2,2-dimethylbenzo[2H-l]pyran-3-ol δ(DMSO-d₆): 1.20 (s, 3Η, CH₃), 1.38 (s, 3H, CH₃), 2.49 (s, 3H, COCH₃), 3.49 (d, IH, J₃ 4 = 3.6Hz, H-3), 3.94 (d, IH, H-4), 6.73 (d, IH, H-8), 7.69 (dd, IH, H- 7), 8.24 (d, IH, H-5).

C2. Preparation of (3S,4S)-6-acetyl-4-amino-2,2-dimethyl-3-hydroxy-2H-l- benzopyran hydrogen sulfate (3 S,4S)-6-Acetyl-3,4-dihydro-2,2-dimethyl-3,4-epoxy-2H-l -benzopyran (104.7kg, 479.8 moles) was mixed with acetonitrile (177.0kg). Trifluoromethanesulfonic acid (65.7kg) was mixed with acetonitrile (1052.7kg) and the mixture heated to reflux. The (3S,4S)-6-acetyl-3,4-dihydro-2,2-dimethyl- 3, 4-epoxy-2H-l -benzopyran solution was added over 19 minutes to the refluxing solution. The reactor and transfer line were washed with acetonitrile (12.0kg), the wash was added to the mixture and the mixture stirred for 5 minutes. Demineralized water (123.0L) was added, the temperature adjusted to between 60 and 70°C and the mixture stirred at this temperature for 90 minutes. The in- process check showed that the reaction was complete and the mixture was cooled to 30°C. Solvent (1690.0L) was removed by distillation under vacuum to leave 175.0L and demineralized water (246.0L) was added. Vacuum distillation was continued to leave 175.0L, (184.0L removed). Demineralized water (350.0L) and z^'so-propyl alcohol (245.8kg) were added. Sulfuric acid (143.1kg) was added allowing the temperature to rise from 43°C to 62°C Zyo-propyl alcohol (30.0kg) was added, the mixture heated to reflux (86°C) and stirred at reflux for 3 hours and 25 minutes. The mixture was allowed to cool to 65°C over 52 minutes. Seed crystals [(3S,4S)-6-acetyl-4-amino-2,2-dimethyl-3-hydroxy-2H-l-benzopyran hydrogen sulfate, 1.02kg] were added and the mixture was cooled to 25°C over 8 hours, then to 5°C over 57 minutes and stirred at 4°C for one hour.

The product was isolated in a centrifuge, washed with z^'so-propyl alcohol (2 x 96.4kg, 1 x 48.2kg) and dried under vacuum at ambient temperature to give a yield of 95.9kg, 56.9%.

(3S-c _s)-6-acetyl-4-amino-3,4-dihydro-2,2-dimethylbenzo[2H-l]pyran-3-ol hydrogen sulfate δ(DMSO-d₆): 1.23 (s, 3Η, CH₃), 1.43 (s, 3H, CH₃), 2.53 (s, 3H, COCH₃), 3.90 (d, IH, J_3j = 3.8Hz, H-3), 4.68 (d, IH, H-4), 6.91 (d, IH, H-8), 7.85 (dd, IH, H- 7), 8.21 (d, 1H. H-5).

Description

Preparation of (3S,4S)-6-acetyI-4-(3-chIoro-4-fluorobenzamido)-3,4-dihydro- 2,2-dimethyl-3-hydroxy-2H-l-benzopyran

(3S,4S)-6-Acetyl-4-amino-2,2-dimethyl-3-hydroxy-2H-l-benzopyran hydrogen sulfate (90.0kg, 256.0 moles) was mixed with toluene (780.3kg) and demineralized water (423.0L). Sodium hydroxide solution (sodium hydroxide, 35.9kg, in demineralized water, 90.0L) was added maintaining the temperature between 20 and 25°C A solution of 3-chloro-4-fluorobenzoyl chloride (49.4kg, 256.0 moles) in toluene (109.2kg) was added to the mixture over 17 minutes, maintaining the temperature between 20 and 25°C. Toluene (15.6kg) was added and the mixture stirred at 20 and 25°C for 75 minutes. An hvprocess check showed that the reaction was complete. The mixture was heated to 70 to 80°C and the lower, aqueous, phase was separated and filtered. The aqueous phase was washed, at 70 to 80°, with toluene (445.0kg) and the phases separated. The combined toluene solutions were washed, at 60 to 70°C, with a solution of concentrated hydrochloric acid (5.2kg) in demineralised water (465.0 L), then with demineralised water (515.0 L) at between 70°C and 80°C. A slurry of charcoal (15.0kg) in toluene (31.0kg) was added to the toluene solution, the mixture was heated to between 80°C and 85°C and filtered. The filters and transfer lines were washed with toluene (156.0kg) and the wash added to the bulk. Solvent (774.0L) was removed by distillation under vacuum to leave a residual volume of 1105.0 L. The mixture was heated to between 80°C and 90°C to give complete solution and cooled to 78°C. Seed crystals of (3S,4S)-6-acetyl-4-(3- chloro-4-fluorobenzamido)-3,4-dihydro-2,2-dimethyl-3-hydroxy-2H-l- benzopyran (1.0kg) were added and the mixture was cooled to 25°C over 10 hours and 30 minutes, then to 10°C over one hour and 15 minutes and stirred at 8°C for one hour. The product was isolated in the centrifuge and washed with filtered toluene (173.0kg). The product was dried in a vacuum pan drier at 50°C to give a yield of 85.9kg, 85.6%. [(3S-cκ)-N-6-acetyI-3,4-dihydro-2,2-dimethyl-3-hydroxybenzo [2H-1] pyran-4- yl]-3-chloro-4-fluorobenzamide δ(DMSO-d₆): 1.32 (s, 3Η, CH₃), 1.44 (s, 3H, CH₃), 2.47 (s, 3H, COCH₃), 3.75 (dd, IH, J_3j4 = 3.5Hz, H-3), 5.50 (dd, IH, H-4), 5.66 (d, IH, OH), 6.86 (d, IH, H- 8), 7.55 (dd, IH, H-5'), 7.75-7.82 (m, 2H, H-5,7), 8.06 (m, IH, H-6*), 8.29 (dd, IH, H-2'), 8.74 (d, 1H, ΝH).

Preparation of (3S,4S)-6-acetyI-3,4-dihydro-2,2-dimethyl-3,4-epoxy-2H-l- benzopyran Sodium dihydrogen orthophosphate (2.8kg) was dissolved in demineralized water (390.0L). Sodium hypochlorite solution (69.2kg at 13.59% w/w, 57.9kg at 13.63%, 230.5kg at 14.72% and 102.2kg at 14.65%, 889.2 moles) and demineralised water (130.0L) were added. The pH of the mixture was adjusted to 11.3 by the addition of phosphoric acid (1.0kg). The solution was cooled to 7°C. Dichloromethane (700.0 kg) was added. 6-Acetyl-2,2-dimethyl-2H-l- benzopyran( 120.0kg, 593.3 moles) was added followed by dichloromethane (57.0 kg). The temperature of the mixture was adjusted to 7°C. S,S-Jacobsen catalyst (formula (X)) (0.769 kg, 1.21 moles) and isoquinoline-N-oxide (4.3kg, 29.6 moles) were added and the mixture was stirred for 75 minutes allowing the temperature to rise to 24°C The in-process check (ΗPLC) showed that the reaction was complete. Celite (5.0 kg) was added and the mixture stirred for 15 minutes. The mixture was filtered through a centrifuge and the phases separated. The organic phase was washed twice with demineralised water (2 x 480.0L) and filtered. The reactor and transfer line were washed with dichloromethane and the wash added to the bulk. Solvent (190.0L) was removed by distillation at atmospheric pressure to leave a residual volume of 310.0L. Di/so-propyl ether (207.4kg) was added and distillation continued under vacuum to leave a residual volume of 310.0L (288.0L of distillate were collected). Dπso-propyl ether (155.5kg) was added and vacuum distillation continued to leave a residual volume of 215.0L (268.0L of distillate were collected). Dώo-propyl ether (147.0kg) was added and the mixture was heated to 60°C to give a clear solution. The solution was cooled to 5°C and the resulting slurry stirred at 0 to 5°C for 2 hours and 10 minutes.The product was isolated in a filter drier, washed with dπsø-propyl ether (86.4kg) and dried under vacuum at ambient temperature to give a yield of 104.7kg, 80.9%.

(3S- s)-6-acetyl-3,4-dihydro-2,2-dimethyI-3,4-epoxybenzo[2H-l]pyran δ(CDCl₃): 1.28 (s, 3H, CH₃), 1.59 (s, 3H, CH₃), 2.55 (s, 3H, COCH3), 3.53 (d, IH, J_3>4 = 4.3Hz, H-3), 3.96 (d, IH, H-4), 6.84 (d, IH, H-8), 7.86 (dd, IH, H-7), 8.00 (d, IH, H-5).

(X)

Claims

1. A process for the preparation of the cw-isomer of a compound of formula (I)

(I) or a pharmaceutically acceptable salt or solvate thereof, comprising reacting the cz^'s-isomer of a compound of formula (III)

(III)

or a salt thereof with an acylating agent of formula (IN)

R₇COL (IN) wherein: either Y is Ν and R2 is hydrogen, or Y is C-R^ where: either one of R\ and R2 is hydrogen and the other is selected from the class of hydrogen, C3..8 cycloalkyl, C\. alkyl optionally interrupted by oxygen or substituted by hydroxy, C\. alkoxy or substituted aminocarbonyl, \.β alkylcarbonyl, Cι_6 alkoxycarbonyl, C\. alkylcarbonyloxy, C\. alkoxy, nitro, cyano, halo, trifluoromethyl, CF3S, or a group CF3-A-, where A is -CF2-, -CO-, - CH2-, CH(OH), SO2, SO, CH₂-O, or CONH, or a group CF₂H-A- where A' is oxygen, sulfur, SO, SO2, CF2 or CFH; trifluoromethoxy, C\.β alkylsulfinyl, perfluoro C2-6 alkylsulfonyl, C\. alkylsulfonyl, Cμg alkoxysulfmyl, C\. alkoxysulfonyl, aryl, heteroaryl, arylcarbonyl, heteroarylcarbonyl, phosphono, arylcarbonyloxy, heteroarylcarbonyloxy, arylsulfinyl, heteroarylsulfinyl, arylsulfonyl, heteroarylsulfonyl in which any aromatic moiety is optionally substituted, C\. alkylcarbonylamino, C\.β alkoxycarbonylamino, Cγ.β alkyl-thiocarbonyl, C\.β alkoxy-thiocarbonyl, \. alkyl-thiocarbonyloxy, 1- mercapto C2-7 alkyl, formyl, or aminosulfinyl, aminosulfonyl or aminocarbonyl, any amino moiety being optionally substituted by one or two C\.β alkyl groups, or Cι_6 alkylsulfmylamino, C\_β alkylsulfonylamino,Cι_6 alkoxysulfinylamino or C\.β alkoxysulfonylamino, or ethylenyl terminally substituted by C \.β alkylcarbonyl, nitro or cyano, or -C(Cι_6 alkyl)NOH or -C(Cι_6 alkyl)NNH2, or one of R\ and R2 is nitro, cyano or C 1.3 alkylcarbonyl and the other is methoxy or amino optionally substituted by one or two C\_β alkyl or by C2-7 alkanoyl; or R and R2 together are -(CH2)4- or -CH = CH-CH = CH-, or form an optionally substituted triazole or oxadiazole ring; one of R3 and R4 is hydrogen or C 1.4 alkyl and the other is C 1.4 alkyl, CF3 or CH2 X^a where X^a is fluoro, chloro, bromo, iodo, C1.4 alkoxy, hydroxy, Cι_4 alkylcarbonyloxy, -S-C1.4 alkyl, nitro, amino optionally substituted by one or two Cι_4 alkyl groups; cyano or C .4 alkoxycarbonyl or R3 and R4 together are C2.5 polymethylene optionally substituted by C _4 alkyl;

R5 is Cj_6 alkylcarbonyloxy, benzoyloxy, ONO2, benzyloxy, phenyloxy or C\.β alkoxy and Rβ and R9 are hydrogen or R5 is hydroxy and Rβ is hydrogen or Cι_2 alkyl and R9 is hydrogen;

R7 is heteroaryl or phenyl; both of which are optionally substituted one or more times independently with a group or atom selected from chloro, fluoro, bromo, iodo, nitro, amino optionally substituted once or twice by C 1.4 alkyl, cyano, azido, Cι_4 alkyl, C1.4 alkoxy, trifluoromethoxy and trifluoromethyl; H-N-CO-R7 group being cis to the R5 group; L is a suitable leaving group such as chloro; and X is oxygen or NRj Q where Rj 0 is hydrogen or C „β alkyl.

2. The process according to claim 1 wherein the acylating agent of formula (IN) is an acid chloride.

3. The process as claimed in claim 1 or claim 2 wherein the cts-isomer of a compound of formula (III) or salt thereof is prepared by (i) converting a compound of formula (N)

(V) to the cis-isomer of a compound of formula (III) as defined in claim 1 or a salt thereof;-or (ii) converting the compound of formula (IX)

to the ct-S-isomer of a compound of formula (III) as defined in claim 1 or salt thereof; where R2, R3, R4, Rβ, R9, X, and Y are as defined in claim 1, and R\ \ is CJ-CJO alkyl, or C3-C8 cycloalkyl optionally substituted one or more times with a group or atom selected from fluoro, chloro, bromo, iodo, nitro, amino, hydroxy, or cyano.

4. The process as claimed in claim 3 (i) comprising treating a compound of forrήula (VIII)

(Nπi) with an acid in the presence of a cyano-compound of formula (Nil)

RnCΝ (Nil) to form a compound of formula (V) as defined in claim 3 and thereafter converting the compound of formula (V) in situ to the cz^'s-isomer of a compound of formula (III) or salt thereof as defined in claim 1; where R2, R3, R4, Rβ, R-9_> X_> ^and Y are as defined in claim 1, R \ is CJ-CJO alkyl, or C3-C8 cycloalkyl optionally substituted one or more times with a group or atom selected from fluoro, chloro, bromo, iodo, nitro, amino, hydroxy, or cyano, and R12 is hydroxy, C1-C4 alkoxy, or halogen.

5. A process according to claim 4 wherein the compound of formula (VIII) as defined in claim 4 is formed by reaction of a compound of formula (VI)

Rα o

R_R

Y

R,

R, X

(VI) where R2, R3, R4, Rβ, R9, X, and Y are as defined in claim 3 with an acid in the presence of an organic solvent.

6. The process as claimed in claim 3(ii) comprising converting a compound of formula (V) as defined in claim 3 in situ to a compound of formula (IX), such as by mild acid hydrolysis.

7. The process as claimed in claim 3(i) or claim 6 comprising treating a compound of formula (VI) as defined in claim 5 with an acid in the presence of a cyano-compound of formula (VII) as defined in claim 4 to form the compound of formula (V) as defined in claim 3.

8. A process according to any one of claims 4, 5 and 7 wherein the cyano- compound of formula (VII) is acetonitrile

9. A process according to any one of claims 4, 5, 7 and 8 wherein the acid is trifluoromethanesulfonic acid.

10. A process according to any one of claims 4, 5, 7 and 8 wherein the acid is a Lewis acid such as aluminium chloride.

11. A process according to claim 5 wherein the acid is hydrochloric acid or sulfuric acid; and/or the organic solvent is methanol.

12. A compound of formula (V) as defined in claim 3, with the proviso that when Y is C-Rj, then R\ is not cyano.

13. 8-Acetyl-2-(3-methyl)-3a,9b-dihydro-4,4-dimethyl-[2H-l] benzopyrano[4,3- djoxazole.

14. A compound of formula (IX) or (VIII).

15. A process for making a compound of formula (III), (IX), (V) or (VIII) as defined in any one of claims 3-11.

16. A process as claimed in any one of claims 3-11 or 15 or a compound as defined in claim 12 or claim 13 wherein Y is C-Ri where Rj is acetyl; R₂ is H; R₃ and R_t are both methyl; R₅ is hydroxy; e and R₉ are both hydrogen; R₇ is 3- chloro-4-fluorobenzyl and X is oxygen.

17 The process as claimed in claim 1 or claim 2 wherein the cw-isomer of a compound of formula (I) is c/s-6-acetyl-4S-(3-chloro-4-fluorobenzoylamino)-3,4- dihydro-2,2-dimethyl-2H- 1 -benzopyran-3 S-ol.