EP0719244A1 - Process of preparing 2,3,5-trihalobenzaldehyde - Google Patents

Process of preparing 2,3,5-trihalobenzaldehyde

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Publication number
EP0719244A1
EP0719244A1 EP94926334A EP94926334A EP0719244A1 EP 0719244 A1 EP0719244 A1 EP 0719244A1 EP 94926334 A EP94926334 A EP 94926334A EP 94926334 A EP94926334 A EP 94926334A EP 0719244 A1 EP0719244 A1 EP 0719244A1
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EP
European Patent Office
Prior art keywords
process according
trihalobenzaldehyde
water
added
solution
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP94926334A
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German (de)
French (fr)
Inventor
Terence William Temple Hill PACKHAM
Andrew Lawrence Temple Hill GERMAIN
Rajnikant Temple Hill PATEL
James Robert Temple Hill BARRAS
David John Temple Hill MILNE
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Wellcome Foundation Ltd
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Wellcome Foundation Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C17/00—Preparation of halogenated hydrocarbons
    • C07C17/093—Preparation of halogenated hydrocarbons by replacement by halogens
    • C07C17/16—Preparation of halogenated hydrocarbons by replacement by halogens of hydroxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/51—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition
    • C07C45/516—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition involving transformation of nitrogen-containing compounds to >C = O groups

Definitions

  • the present invention relates to a novel process of preparing 2,3,5-trihalobenzaldehyde which is a useful starting material in the preparation of a number of pharmaceutical products.
  • EP-A-0372934 and EP-A- 0459819 describe classes of 5-phenylpyrimidines that are potent inhibitors of glutamate release. Preferred examples are those wherein the phenyl ring is substituted in the 2,3,5- positions by halogen, especially chloro. Particular examples include 4-amino-2-(4-methylpiperazin-l-yl)-5-(2,3,5-trichlorophenyl) pyrimidine and 4-ammo-2-(4-n-propylpipera2-in-l-yl)-5-(2,3,5- trichlorophenyl) pyrimidine. Such 5-phenylpyrimidines are of utility in the treatment of cerebral ischaemic damage including particularly that resulting from stroke and head injury.
  • the chemical synthesis of the preferred examples of 5-phenylpyrimidines i.e. those wherein the phenyl ring is substituted in the 2,3,5- positions by halogen, generally requires the use of the correspondingly substituted benzaldehyde as the starting material.
  • This benzaldehyde may generally be prepared in turn from sodium 3-amino-2,5- dihalobenzoate.
  • 2, 3, 5 trihalobenzaldehyde can be prepared from 1, 2, 4 trihalobenzene via a complex intermediate.
  • the advantages of this process are that 1, 2, 4 trihalobenzene is readily available and the reaction is relatively simple and straightforward.
  • the present invention provides a process of preparing 2, 3, 5- trihalobenzaldehyde, which comprises the steps of
  • Hal is halogen, with a di-C ⁇ .4 alkyformamide
  • halogen examples include chloro.
  • a preferred example of a di-C ⁇ - alkylformamide is dimethylformamide (DMF).
  • the reaction between a compound of formula (I) and a di-C ⁇ _4 alkylformamide is carried out at a reduced temperature to avoid tarring.
  • this may be at a temperature from -20°C to -80°C, such as -60°C.
  • Hal is halogen
  • 2, 3, 5- trihalobenzaldehyde is produced.
  • the latter may optionally be reduced by, for example, sodium borohydride to form the corresponding 2, 3, 5-trihalobenzyl alcohol for further processing should such be required.
  • the compound of formula (I) may in turn be obtained by reacting a 1, 2, 4- trihalobenzene with a C ⁇ . alkyllithium in a cyclic or open-chain ether solvent at a reduced temperature preferably below -20°C, and most preferably below -60°C.
  • the preferred C ] _6 alkyllithium has a straight carbon chain with methyllithium or n- butyllithium being the most preferred.
  • the cyclic or open chained ether solvent is diethyl ether or THF.
  • the molar ratio of C ⁇ . alkyllithium : di C1-.4 alkyl formamide is 1 : 2.55, the overall yield of 2, 3, 5 trihalobenzaldehyde is approximately 35% at approximately 95% purity.
  • a ratio of 1 : 5.45 of C1--.4 alkyllithium : di C1--.4 alkylformamide gave the very much increased yield of 70%, at 95% purity.
  • Dry THF 250ml was stirred under nitrogen while cooling in an SVM dry ice bath.
  • a 2.5 molar solution of n-butyllithium in hexane 44ml,0.11 mole was added dropwise keeping the temperature below -60°C.
  • a solution of 1, 2, 4-trichlorobenzene (18.14g,0.10 mole) in dry THF (50ml) was then added dropwise keeping the temperature below -60°C.
  • the resulting mixture was stirred for 30 min at -65°C to -60° C.
  • a solution of dry dimethylformamide (20.23g, 0.28 mole) in dry THF (50ml) was then added dropwise keeping the reaction temperature below -60°C.
  • N-propylpiperazine dihydrobromide (Lancaster 5g) in water (15ml) was passed onto an ion exchange column (IR410 OH form) (BDH) and eluted with water. The eluate that was positive for secondary amine was concentrated, dissolved in diethylether, dried (MgSO4) and evaporated to dryness to give n-propylpiperazine as a colourless oil (0-6g).
  • the piperazine was dissolved in water (10ml) and methylthiouronium iodide added. The solution was stirred, with nitrogen bubbled through, at room temperated for 96 hours. The solution was concentrated in vacuo. The residue was slurried with acetone, filtered and dried in vacuo to give N-propylpiperazinoformamidine hydroiodide, 0.5 lg, mp. 174- 176°C.

Abstract

A process of preparing 2,3,5-trihalobenzaldehyde, which comprises the steps of (i) reacting a compound of formula (I), wherein Hal is halogen, with a di-C1-4 alkylformamide; (ii) allowing the resulting complex to rearrange; and (iii) quenching the rearranged complex with water.

Description

PROCESS OF PREPARING 2,3,5 - TRIHALOBENZALDEHYDE
The present invention relates to a novel process of preparing 2,3,5-trihalobenzaldehyde which is a useful starting material in the preparation of a number of pharmaceutical products.
EP-A-0372934 and EP-A- 0459819 describe classes of 5-phenylpyrimidines that are potent inhibitors of glutamate release. Preferred examples are those wherein the phenyl ring is substituted in the 2,3,5- positions by halogen, especially chloro. Particular examples include 4-amino-2-(4-methylpiperazin-l-yl)-5-(2,3,5-trichlorophenyl) pyrimidine and 4-ammo-2-(4-n-propylpipera2-in-l-yl)-5-(2,3,5- trichlorophenyl) pyrimidine. Such 5-phenylpyrimidines are of utility in the treatment of cerebral ischaemic damage including particularly that resulting from stroke and head injury.
The chemical synthesis of the preferred examples of 5-phenylpyrimidines, i.e. those wherein the phenyl ring is substituted in the 2,3,5- positions by halogen, generally requires the use of the correspondingly substituted benzaldehyde as the starting material. This benzaldehyde may generally be prepared in turn from sodium 3-amino-2,5- dihalobenzoate. For example, it is known to prepare the 2,3,5 trichlorobenzaldehyde from sodium-3-amino-2, 5-dichlorobenzoate via a Sandmeyer reaction and a DibalH reduction step as shown below:
(i) NaNO2, conc H2SO4,ArOH (ϋ) CuCl,conc HCl (iϋ) MeOH, cone H2SO4 catalyst (iv) DIBALH -70°C
(see standard organic chemistry textbooks, for example: J.March, Advanced Organic Chemistry Reactions, Mechanism and Structure, 4th Ed. (1992), pp 723 and Muraki and Mukaiyama, Chem. Lett.. 1974, 1447; 1975, 212). The disadvantages of this process are that the starting material itself is only available in limited quantities and in relatively impure form and that the DibalH reduction step is often low yielding.
It has now been found that 2, 3, 5 trihalobenzaldehyde can be prepared from 1, 2, 4 trihalobenzene via a complex intermediate. The advantages of this process are that 1, 2, 4 trihalobenzene is readily available and the reaction is relatively simple and straightforward.
Accordingly, the present invention provides a process of preparing 2, 3, 5- trihalobenzaldehyde, which comprises the steps of
(i) reacting a compound of formula (I) :
wherein Hal is halogen, with a di-Cι.4 alkyformamide;
(ϋ) allowing the resulting complex to rearrange; and
(iii) quenching the rearranged complex with water
Examples of halogen include chloro.
A preferred example of a di-Cι- alkylformamide is dimethylformamide (DMF).
Preferably, the reaction between a compound of formula (I) and a di-Cι_4 alkylformamide is carried out at a reduced temperature to avoid tarring. Conveniently, this may be at a temperature from -20°C to -80°C, such as -60°C.
Although not wishing to be bound in any way, it is believed that the complex resulting from the reaction between a compound of formula (I) and a di-C]_4 alkylformamide is of formula (II): wherein Hal is halogen.
If the complex of formula (II) is quenched immediately with water, it will result in 2, 3,
6-trihalobenzaldehyde exclusively. If however, the complex is left for more than, say, 2 or 3 hours (say 2 to 24 hours) at or about room temperature (for example from 15°C t0 35°C), it rearranges into a further complex that is believed to be of formula (in):
wherein Hal is halogen.
If the complex of formula (III) is then quenched with water, 2, 3, 5- trihalobenzaldehyde is produced. The latter may optionally be reduced by, for example, sodium borohydride to form the corresponding 2, 3, 5-trihalobenzyl alcohol for further processing should such be required.
The rearrangement of the complex of formula (II), is quite unexpected from the prior art, especially Synthesis Communication, October 1988 (p803). T.H. Kress and M.R. Leanna. This prior art provides no indication at all that, if the complex is left, it will rearrange in this way.
The compound of formula (I) may in turn be obtained by reacting a 1, 2, 4- trihalobenzene with a C\. alkyllithium in a cyclic or open-chain ether solvent at a reduced temperature preferably below -20°C, and most preferably below -60°C. The preferred C]_6 alkyllithium has a straight carbon chain with methyllithium or n- butyllithium being the most preferred.
Preferably, the cyclic or open chained ether solvent is diethyl ether or THF. When the molar ratio of C\. alkyllithium : di C1-.4 alkyl formamide is 1 : 2.55, the overall yield of 2, 3, 5 trihalobenzaldehyde is approximately 35% at approximately 95% purity. Surprisingly, it was found that a ratio of 1 : 5.45 of C1--.4 alkyllithium : di C1--.4 alkylformamide gave the very much increased yield of 70%, at 95% purity.
The following examples are provided by way of illustration of the present invention and should not be construed in any way as constituting a limitation thereof.
Example 1
(a) Preparation of 2. 3. 5-trichlorobenzaldehyde
H20
Reagents
1, 2, 4-Trichlorobenzene 18.14g 0.10 mole
THF (dry) (tetrahydrofuran) 250ml;50ml;50ml n-butyllithium 2.5M in hexane 44ml 0.11 mole
DMF (dry) 20.23g. 0.28 mole
Water 5ml
Saturated aqueous sodium chloride solution 400ml
Ethylacetate 2 x 200 ml
Dry THF (250ml) was stirred under nitrogen while cooling in an SVM dry ice bath. A 2.5 molar solution of n-butyllithium in hexane (44ml,0.11 mole) was added dropwise keeping the temperature below -60°C. A solution of 1, 2, 4-trichlorobenzene (18.14g,0.10 mole) in dry THF (50ml) was then added dropwise keeping the temperature below -60°C. The resulting mixture was stirred for 30 min at -65°C to -60° C. To the latter, a solution of dry dimethylformamide (20.23g, 0.28 mole) in dry THF (50ml) was then added dropwise keeping the reaction temperature below -60°C. The reaction mixture was allowed to warm to room temperature and left to stand overnight. Water (5ml) was added and the mixture was stirred for 15 min. The mixture was then poured into sat. sodium chloride solution (400ml). After stirring the latter for 10 mins, the two phases were separated and the aqueous phase extracted with ethyl acetate (2 x 200ml). The combined organic extracts were dried over anhydrous magnesium sulphate, and concentrated under reduced pressure to a golden oil (26.6g).
(b) Preparation of 2.3.5-Trichlorobenaldehyde
Reagents
1 ,2,4-Trichlorobenzene 362.9g 2.0 mole
THF (dry) 3270ml
Butyllithium
(2.5M in hexane) 923ml 2.3 mole
DMF (dry) 804. lg 11.0 mole
A solution of 1,2,4-trichlorobenzene (362.9g, 2.0 mole) in dry THF (3270ml) was stirred whilst cooling in an acetone/dry ice bath. A 2.5 molar solution of butyllithium in hexane (923ml, 2.3 mole) was added dropwise keeping the temperature below -60°C. After stirring for 10 minutes, dry dimethylformadide (804. lg, 11.0 mole) was added dropwise below -60°C. The reaction mixture was stirred for 18 hours whilst warming to ambient temperature. Water (3000ml) was added and the mixture was stirred for 15min. The mixture was then poured into sat. sodium chloride solution (400ml). After stirring the latter for 10 mins, the two phases were separated and the aqueous phase extracted with ethyl acetate (2 x 3000ml). The combined organic extracts were dried over anhydrous magnesium sulphate, and concentrated under reduced pressure to a golden oil (292g).
Example 2
Preparation of N-methylpiperazinoformamidine hydriodide
Thiourea (10.8g) was dissolved in acetone (250ml) at 50°C. Iodomethane (10ml) was added and the reaction was stirred at 50°C for 4 hours. After cooling, the solution was diluted with ether (1 litre) and the methiodide salt was filtered, washed with ether and dried in vacuo. 29.2g, mp. 113-115°C. The methiodide salt (5g) was dissolved in water (30ml) and N-methylpiperazine was added. The solution was stirred, with nitrogen bubbled through, at room temperature for 24 hours. The solution was concentrated in vacuo. The residue was sluπied with ethanol, filtered and dried in vacuo. 4.98g, mp. 230-242°C.
Example 3
(i) Preparation of 2.3.4-trichlorobenzylalcohol
To a solution of 2,3,5-trichlorobenzaldehyde (Aldrich, 50gms) in ethanol (1.0 1) at room temperature was added aBH4 (7.00gms) and the resulting mixture stirred for 3.5 hours. The reaction was quenched with water and the solvent evaporated in vacuo before partitioning the residue between CHCI3 and saturated NaHCO3 solution. The organic phase was washed with brine, dried over MgSO4, filtered and the solvent evaporated in vacuo to leave a white solid, 43.00gms, mp. 90-93°C.
(ϋ) Preparation of 2.3.5-trichlorobenzyl bromide
To a solution of the alcohol in benzene (400 ml) under N2 was added PBr3 (126.48gms) and the mixture stirred at 55-60°C for 3.5 hours. After cooling, the mixture was poured onto crushed ice (2 1) and the benzene layer separated. The aqueous phase was washed with benzene (x3) and the combined benzene extracts washed with saturated NaHCO3 solution and water, dried over MgSO4, filtered and the solvent evaporated to leave a brownish liquid which solidified on standing, 37.53gms, mp. 40-42°C.
(iii) Preparation of 2.3.5 -trichlorophenylacetonitrile
The bromide was suspended in dimethylformamide (DMF) (130ml)/water (86.67ml) at 0°C and KCN (12.99gms) added in portions. After stirring at 30-35°C for 3 hours, the suspension was diluted with water and extracted with diethyl ether (Et2θ). The combined ether extracts were washed with water, dried over MgSO4, filtered and the solvent evaporated in vacuo. Chromatography on silica gel eluting with hexane to 20% ether-hexane gave the desired product as a white solid, 18.52gms, mp. 60-62°C.
(iv) Preparation of 2-f2.3.5-tricMorophenyl)-3-oxo-propionitrile sodium salt To a solution of sodium ethoxide (NaOEt) (from 0.803g of sodium) in ethanol (55ml) cooled in ice, under nitrogen, was added 2,3,5-trichlorophenyl acetonitrile. Ethyl formate (5.1ml) was added and the mixture was stirred at room temperature overnight. After stirring for a further 2.5 hours at 50°C, the mixture was cooled and filtered. The filtrate was evaporated, and the residue was titurated with diethyl ether, filtered and dried (6.82g).
(v) Preparation of 2-f 2.3.5-trichlorophenylV3 -methoxy-acrylonitrile
The above solid was dissolved in DMF (36ml) and methyliodide (2ml) was added. The reaction vessel was sealed before stirring the contents at 40°C for 3 hours. The solvent was then evaporated. The residue was partitioned between water and ethyl acetate. The organic phase was washed with water, dried (MgSO4) and the solvent evaporated to give the crude product as a red-brown oil that solidified on standing (5.04g).
(vi) Preparation of 4-amino-2-(4-methylpiperazine-l-yl)-5-f2.3.5- trichlorophenyDpyrimidine
To a solution of NaOEt (from 0.2g of sodium) in ethanol (20ml) was added N- methylpiperazinoformamidine hydriodide (2.06g) (Example 2). After stirring for a further 10 minutes, the 2-(2,3,5-trichlorophenyl)-3-methoxy-acrylonitrile was added and the mixture was stirred at reflux for 4 hours. The mixture was left standing at room temperature overnight and then filtered. The filtrate was concentrated and the residue was purified by chromatography on Siθ2, eluting with CHCI3 to 4% MeOH CHCl3 to give the title compound as the free base, 0.89g, mp. 162-164°C.
The free base (0.805g) was then dissolved in ethanol (35ml) and cooled in an ice bath. Methanesulphonic acid (0.21g) was added and the reaction was stirred at room temperature for 2 hours. The solvent was then evaporated and the residue was triturated with diethyl ether, filtered, dissolved in cold water and freeze dried to give the title salt as a pale green solid, 0.98g, mp. 143-146°C.
1H MR data (δ), dimethylsulphoxide (DMSO)-d6 : 7.8(d,lH), 7.65(s,lH), 7.36(d,lH), 6.33-6.23(brs,2H), 3.68(t,4H), 2.32(t,4H), 2.2(s,3H). In the foregoing, the signals have been abbreviated as follows: s = singlet; d = doublet; t = triplet; brs = broad singlet.
Example 4
(i) Preparation of methylthiouronium iodide
Thiourea (10.89g) was dissolved in acetone (250ml) at 50°C. Iodomethane (10ml) was added and the reaction was stirred at 50°C for 4 hours. After cooling, the solution was diluted with ether (1 litre) and the methiodide salt was filtered, washed with ether and dried in vacuo. 29.2g, mp. 113-115°C.
(ii) Preparation of 4- Amino-2-(4-n-propylpiperazine-l-ylV5- 2.3.5- trichlorophenyDpyrimidine dimesylate
N-propylpiperazine dihydrobromide (Lancaster 5g) in water (15ml) was passed onto an ion exchange column (IR410 OH form) (BDH) and eluted with water. The eluate that was positive for secondary amine was concentrated, dissolved in diethylether, dried (MgSO4) and evaporated to dryness to give n-propylpiperazine as a colourless oil (0-6g).
The piperazine was dissolved in water (10ml) and methylthiouronium iodide added. The solution was stirred, with nitrogen bubbled through, at room temperated for 96 hours. The solution was concentrated in vacuo. The residue was slurried with acetone, filtered and dried in vacuo to give N-propylpiperazinoformamidine hydroiodide, 0.5 lg, mp. 174- 176°C.
To a solution of NaOEt (from 0.52g of sodium) in ethanol (5ml) was added N- propylpiperazmofo-rmamidine hydroiodide 0.506g). After stirring for a further 10 minutes, the 2-(2,3,5-trichlorophenyl)-3-methoxy-acrylonitrile of Reference Example 3(v) (0.226g) was added and the mixture was stirred at reflux for 5 hours. The mixture was concentrated, dissolved in chloroform and filtered. The filtrate was reconcentrated and the residue was purified by chromatography on SiO2, eluting with 5% MeOH/CHCl3 to give the title compound as the free base. 0.26g.
The free base (0.26g) was dissolved in Et2O and cooled in an ice bath. Methanesulphonic acid (0.062g) was added and the reaction was stirred in the ice bath for 1 hour. The solid was filtered and dried in vacuo to give the title salt as a yellow amorphous solid, 0.21g, dec. 83°C.
NMR Assignment (δ)
Solvent - DMSO
δ 0.95(t,3H), δ 1.75(m,2H), δ 2.35(s,6H), δ 3.10(d,br,2H), δ 3.40(t,br,4H), δ 3.60(d,br, 2H), δ 4.60(d,2H), δ 7.45(d,lH), δ 7.90(s,lH), δ 7.95(d,lH).

Claims

1. A process of preparing 2, 3, 5 -trihalobenzaldehyde, which comprises the steps of
(i) reacting a compound of formula (I):
wherein Hal is halogen, with a di-Cι_4 alkylformamide;
(ii) allowing the resulting complex to rearrange; and
(ϋi) quenching the rearranged complex with water.
2. A process according to claim 1, wherein halogen is chloro.
3. A process according to claim 1 or 2, wherein the di-Cι_4 alkylformamide is dimethylformamide.
4. A process according to any of the preceding claims, wherein step (i) is carried out at a temperature of from -20 to -80°C
5. A process according to any of the preceding claims, wherein step (ii) is carried out over a period from 2 to 24 hours.
6. A process according to any of the preceding claims, wherein step (ii) is carried out at a temperature of from 15 to 35 °C.
7. A process according to claim 1, wherein the compound of formula (I) is prepared by reacting 2,2,4-trihalobenzene with C\_$ alkyllithium.
8. A process according to claim 7, wherein the molar ratio of Cj_4 alkyllithium to di Cι_4 alkylformamide is 1 : 5.45.
9. A process according to claim 7 or 8, wherein the C . alkyllithium is methyllithium or n-butyllithium.
10. Use of a 2, 3, 5-trihalobenzaldehyde prepared in accordance with any of the preceding claims in the chemical synthesis of 4-amino-2-(4-methylpiperazin-l-yl)- 5-(2, 3, 5-trihalophenyl) pyrimidine or 4-amino-2-(4-n-propylpiperazin-l-yl)-5- (2,3,5-trihalophenyl) pyrimidine.
11. Use of a 2,3,5 trihalobenzaldehyde according to claim 9, wherein halo is chloro.
EP94926334A 1993-09-17 1994-09-16 Process of preparing 2,3,5-trihalobenzaldehyde Withdrawn EP0719244A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GB9319341 1993-09-17
GB939319341A GB9319341D0 (en) 1993-09-17 1993-09-17 Novel process
PCT/GB1994/002017 WO1995007877A1 (en) 1993-09-17 1994-09-16 Process of preparing 2,3,5-trihalobenzaldehyde

Publications (1)

Publication Number Publication Date
EP0719244A1 true EP0719244A1 (en) 1996-07-03

Family

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Family Applications (1)

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EP94926334A Withdrawn EP0719244A1 (en) 1993-09-17 1994-09-16 Process of preparing 2,3,5-trihalobenzaldehyde

Country Status (5)

Country Link
EP (1) EP0719244A1 (en)
JP (1) JPH09502712A (en)
GB (1) GB9319341D0 (en)
IL (1) IL110981A0 (en)
WO (1) WO1995007877A1 (en)

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1080167A (en) * 1963-06-14 1967-08-23 Smith Kline French Lab Improvements in or relating to the production of halogenated benzene derivatives
PL140069B1 (en) * 1982-12-21 1987-03-31 Pfizer Method of obtaining new derivatives of dihydropiridine
GB9012316D0 (en) * 1990-06-01 1990-07-18 Wellcome Found Pharmacologically active cns compounds

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9507877A1 *

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JPH09502712A (en) 1997-03-18
GB9319341D0 (en) 1993-11-03
IL110981A0 (en) 1994-11-28
WO1995007877A1 (en) 1995-03-23

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