JPH09502712A - Process for producing 2,3,5-trihalobenzaldehyde - Google Patents

Abstract

(57) [Summary] (i) Compound of formula (I): (Wherein Hal is halogen in the above formula) is reacted with diC _1-4 alkylformamide to rearrange the resulting complex (ii) and (iii) quench the rearranged complex with water. Process for producing 3,5-trihalobenzaldehyde.

Description

Detailed Description of the Invention               Process for producing 2,3,5-trihalobenzaldehyde   The present invention is a useful starting material for the manufacture of some pharmaceuticals, 2,3,5-triha. The present invention relates to a new method for producing lobenzaldehyde.   EP-A-0372934 and EP-A-045998 are glutamic acids. Describes a class of 5-phenylpyrimidines that are strong release inhibitors You. A preferred example is where the phenyl ring is at the 2,3,5-position by halogen, especially chloro. It has been replaced. A specific example is 4-amino-2- (4-methylpiperazyl N-1-yl) -5- (2,3,5-trichlorophenyl) pyrimidine and 4 -Amino-2- (4-n-propylpiperazin-1-yl) -5- (2,3,5 -Trichlorophenyl) pyrimidine. Such 5-phenylpyrimidine For the treatment of cerebral ischemic disorders, including those caused by stroke and head injury. It is for.   Preferred examples of 5-phenylpyrimidines, ie, the phenyl ring is replaced by a halogen It is usually used as a starting material in the chemical synthesis of compounds with substitutions at the 3,3,5-position. Requires the use of benzaldehyde that has been substituted. This benzaldehyde is It is usually prepared sequentially from sodium 3-amino-2,5-dihalobenzoate. For example , 3-amino-2,5-diene in the Sandmeyer reaction and the DibalH reduction step as described below. Production of 2,3,5-trichlorobenzaldehyde from sodium chlorobenzoate Known to do: (I) NaNO₂, Concentrated H₂SO_Four, ArOH (Ii) CuCl, concentrated HCl (Iii) MeOH, concentrated H₂SO_Fourcatalyst (Iv) DIBALH-70 ° C (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 disadvantage of this method is that the starting material itself is available in limited quantities and in relatively impure form. In addition, the DibalH reduction step is often low yielding.   2,3,5-trihalobenzaldehyde from 1,2,4-trihalobenzene It has now been found that it can be produced via a complex intermediate. The advantages of this method are 1, 2, Because 4-trihalobenzene is readily available, the reaction is relatively simple and direct is there.   Therefore, the present invention   (I) Compound of formula (I): (Wherein Hal is halogen)_1-4Reacted with alkylformamide Let   (Ii) rearrange the obtained complex,   (Iii) Quench the rearrangement complex with water Provided is a method for producing 2,3,5-trihalobenzaldehyde, comprising the steps of: .   An example of halogen is chloro.   Di C_1-4A preferred example of alkylformamide is dimethylformamide (DMF ).   Preferably, the compound of formula (I) and di-C_1-4The reaction with alkylformamide is It is carried out at low temperature to avoid tarring. Preferably, this is between -20 and -80 ° C. The temperature is, for example, -60 ° C.   Without being bound by the following description, the compound of formula (I) and di-C_1-4Archi The complex resulting from the reaction with ruformamide is believed to be of formula (II): (In the above formula, Hal is halogen)   If the complex of formula (II) is immediately quenched with water, it is exclusively 2,3,6-toluene. This produces rehalobenzaldehyde. However, if the complex is at or near room temperature ( For example, if it is stored at 15 to 35 ° C for about 2 or 3 hours or more (about 2 to 24 hours) For example, it rearranges to the next complex, which is believed to be of formula (III): (In the above formula, Hal is halogen)   If the complex of formula (III) is quenched with water, 2,3,5-trihalobenz A Ludehide is produced. The latter is a response 2,3 that requires such processing. To form the 5,5-trihalobenzyl alcohol, optionally by hydrogenation, for example. It may be reduced with sodium boron.   Rearrangement of the complex of formula (II) is known in the prior art, for example Synthesis Communication, October. Not expected from 1988 (p.803), T.H.Kress and M.R.Leanna. This prior art Does not show any such rearrangement upon leaving the complex.   The compounds of formula (I) are low temperature, preferably below -20 ° C, most preferably -60 ° C. In the following, 1,2,4-trihalobenzene was converted to C in a cyclic or open chain solvent._1-6 Obtained by reacting with alkyllithium. Preferred C_1-6Alkyrie Tium has a straight-chain carbon, with methyllithium or n-butyllithium being the most preferred. New   Preferably, the cyclic or open chained solvent is diethyl ether or Is THF.   C_1-6Alkyl lithium: di-C_1-4Alkylformamide molar ratio is 1: 2.5 5, the overall yield of 2,3,5-trihalobenzaldehyde is about 95% pure. Is about 35%. Surprisingly, C_1-4Alkyl lithium: di-C_1-4Alkyl form A 1: 5.45 ratio of amides gives a reasonably high yield of 70% at 95% purity. I understood.   The following examples are given for the purpose of illustrating the invention and are in no way meant to limit the invention. Should not be done.Example 1 (A)Production of 2,3,5-trichlorobenzaldehyde reagent   Dry THF (250 ml) under nitrogen while cooling with SVM / dry ice bath. Stirred. 2.5 of n-butyllithium (44 ml, 0.11 mol) in hexane The molar solution was added dropwise while keeping the temperature below -60 ° C. Then dry THF (50m A solution of 1,2,4-trichlorobenzene (18.14 g, 0.10 mol) in l) Was added dropwise while maintaining the temperature at -60 ° C or lower. The obtained mixed liquid is -65 to -60 ° C. For 30 minutes. For the latter, dry dimethylformamide in dry THF (50 ml). While keeping the solution of 20 g (20.23 g, 0.28 mol) below the reaction temperature of -60 ° C. Dropped. The reaction mixture is warmed to room temperature and left overnight. Add water (5 ml) Then, the mixture was stirred for 15 minutes. The mixture is then treated with saturated sodium chloride solution (40 0 ml). After stirring the latter for 10 minutes, the two phases are separated and the aqueous phase is vinegared. Extracted with ethyl acidate (2 x 200 ml). Combine the combined organic extracts with anhydrous magnesium sulfate. Dry with sium and concentrate under reduced pressure to give a golden oil (26.6g). (B)Production of 2,3,5-trichlorobenzaldehyde reagent   1,2,4-Trichlorobenzene (362.9 in dry THF (3270 ml) g, 2.0 mol) was stirred with cooling in an acetone / dry ice bath. Temperature of a 2.5 molar solution of butyllithium in hexane (923 ml, 2.3 moles) The solution was added dropwise while keeping it at -60 ° C or lower. After stirring for 10 minutes, dry dimethylformami (804.1 g, 11.0 mol) was added dropwise at -60 ° C or lower. Ring the reaction mixture The mixture was stirred for 18 hours while warming to room temperature. Add water (3000 ml) and mix Was stirred for 15 minutes. The mixture is then in saturated sodium chloride solution (400 ml) Poured into. After stirring the latter for 10 minutes, the two phases were separated and the aqueous phase was extracted with ethyl acetate ( 2 × 3000 ml). Combine the organic extracts with anhydrous magnesium sulfate. Dry and concentrate under reduced pressure to give a golden oil (292g).Example 2 Preparation of N-methylpiperazinoformamidine hydriodide   Thiourea (10.8g) was dissolved in acetone (250ml) at 50 ° C. Yaw Domethane (10 ml) was added and the reaction was stirred at 50 ° C. for 4 hours. Solution after cooling Was diluted with ether (1 l) and the methiodide salt was filtered, washed with ether and Dry under air. 29.2 g, mp 113-115 ° C. Methiodide salt (5g ) Was dissolved in water (30 ml) and N-methylpiperazine was added. Bring the solution to room temperature 2 The mixture was stirred for 4 hours while blowing nitrogen. The solution was concentrated under vacuum. Residue Was slurried with ethanol, filtered and dried under vacuum. 4.98g, mp 230-242 ° C.Example 3 (I)Production of 2,3,4-trichlorobenzyl alcohol   2,3,5-Trichlorobenzaldehyde (Aldric h, 50 g) at room temperature with NaBH_Four(7.00 g) was added to obtain The resulting mixture was stirred for 3.5 hours. The reaction was quenched with water and the solvent evaporated under vacuum. From the residue to CHCl_ThreeAnd saturated NaHCO_ThreePartitioned into solution. Wash the organic phase with brine Purified, MgSO_FourDried, filtered and the solvent evaporated under vacuum to give a white solid 4 Obtained 3.00 gms, mp 90-93 ° C. (Ii)Preparation of 2,3,5-trichlorobenzyl bromide   N to a solution of alcohol in benzene (400 ml)₂Below PBr_Three(126.48 g) was added and the mixture was stirred at 55-60 ° C. for 3.5 hours. Crush the mixture after cooling Poured onto ice (21) and separated the benzene layer. Wash the aqueous phase with benzene (× 3) The combined benzene extracts with saturated NaHCO 3._ThreeWash with solution and water, MgS O_FourDried at rt, filtered and evaporated the solvent to give a brownish liquid which It solidified on standing. 37.53 gms, mp40-42 (Iii)Production of 2,3,5-trichlorophenylacetonitrile   Bromide was added to dimethylformamide (DMF) (130 ml) / water (86 . 67 ml) and KCN (12.99 g) was added little by little. 30-35 After stirring at ℃ for 3 hours, the suspension was diluted with water and diluted with diethyl ether (Et.₂O) Extracted. The combined ether extracts are washed with water and MgSO 4._FourDried, filtered and dissolved. The medium was evaporated under vacuum. Hexane to 20 by silica gel chromatography Elution with% ether-hexane gave the desired product as a white solid. 18 . 52 gms, mp 60-62 ° C (Iv)2- (2,3,5-trichlorophenyl) -3-oxopropionitrile Manufacture of sodium salt   Sodium ethoxide (NaO) in ethanol (55 ml) ice-cooled under nitrogen. Et) (from 0.803 g of sodium) in a solution of 2,3,5-trichlorophene Nylacetonitrile was added. Ethyl formate (5.1 ml) was added and the mixture was stirred at room temperature. Stir overnight. After stirring at 50 ° C for an additional 2.5 hours, cool the mixture. And filtered. The filtrate is evaporated, the residue is triturated with diethyl ether, filtered and dried. Dried (6.82 g). (V)2- (2,3,5-trichlorophenyl) -3-methoxyacrylonitri Manufacturing   The above solid was dissolved in DMF (36 ml) and methyl iodide (2 ml) was added. . The reaction vessel was sealed and the contents were stirred at 40 ° C. for 3 hours. Then vaporize the solvent I fired. The residue was partitioned between water and ethyl acetate. The organic phase is washed with water, (MgSO 4_Four) Dry and evaporate the solvent to give the crude product as a reddish brown oil (5.04 g). Was. It solidified on standing. (Vi)4-amino-2- (4-methylpiperazin-1-yl) -5- (2,3, Preparation of 5-trichlorophenyl) pyrimidine   To a solution of NaOEt (from 0.2 g sodium) in ethanol (20 ml) N-methylpiperazinoformamidine hydriodide (2.06 g) (Example 2) added. After stirring for another 10 minutes, 2- (2,3,5-trichlorophenyl)- 3-Methoxyacrylonitrile was added and the mixture was stirred under reflux for 4 hours. mixture The liquid was left at room temperature overnight and then filtered. The filtrate is concentrated and the residue is₂Chroma CHCl by topography_Three~ 4% MeOH / CHCl_ThreePurify by eluting with The title compound was obtained as the free base. 0.89g, mp 162-164 ° C   The free base (0.805g) was then dissolved in ethanol (35ml) and placed in an ice bath. Cooled. Methanesulfonic acid (0.21 g) was added, and the reaction solution was stirred at room temperature for 2 hours. did. The solvent was then evaporated, the residue triturated with diethyl ether, filtered and cold water. And lyophilized to give the title salt as a pale green solid. 0.98g, mp 143-146 ° C¹ 1 H NMR data (δ) dimethyl sulfoxide (DMSO) -d₆: 7.8 (d , 1H), 7.65 (s, 1H), 7.36 (d, 1H), 6.33-6. 23 (brs, 2H), 3.68 (t, 4H), 2.32 (t, 4H), 2.2 6 (s, 3H) In the above, the signals are abbreviated as follows: s = singlet; d = Doublet; t = triplet; brs = wide singletExample 4 (I)Manufacture of methylthiouronium iodide   Thiourea (10.89 g) was dissolved in acetone (250 ml) at 50 ° C. Yo Green methane (10 ml) was added and the reaction was stirred at 50 ° C. for 4 hours. After cooling, The liquor was diluted with ether (1 l) and the methiodide salt was filtered and washed with ether, Dried under vacuum. 29.2g, mp113-115 ° C (Ii)4-Amino-2- (4-n-propylpiperazin-1-yl) -5- (2 Of 3,3,5-Trichlorophenyl) pyrimidine dimesylate   N-Propylpiperazine dihydrobromide (Lancaster 5 g in water (15 ml)) ) Through an ion exchange column (IR410 OH form) (BDH) and eluted with water. Was. The eluate positive for the secondary amine was concentrated, dissolved in diethyl ether, and gSO_Four) Dried and evaporated to dryness to give n-propylpiperazine as a colorless oil. Was obtained (0.6 g).   Dissolve piperazine in water (10 ml) and add methylthiouronium iodide. I got it. The solution was stirred at room temperature for 96 hours with nitrogen bubbling. Concentrate the solution under vacuum Shrunk. The residue is slurried with acetone, filtered, dried under vacuum and washed with N-purple. Ropilpiperazinoformamidine hydroiodide was obtained. 0.51g, mp1 74-176 ° C   To a solution of NaOEt (from 0.52 g sodium) in ethanol (5 ml) Add N-propylpiperazinoformamidine hydroiodide (0.506g) I got it. After stirring for a further 10 minutes, the 2- (2,3,5-trichloro) of Reference Example 3 (v) (Rophenyl) -3-methoxyacrylonitrile (0.226g) was added and mixed Was stirred under reflux for 5 hours. The mixture was concentrated, dissolved in chloroform and filtered . The filtrate is re-concentrated and the residue is₂5% MeOH / C by chromatography HCl_ThreePurified by eluting with to give the title compound as the free base. 0.26g play Leaving base (0.26 g) with Et₂It was dissolved in O and cooled in an ice bath. Methanesulfonic acid (0.062g) was added and the reaction was stirred in an ice bath for 1 hour. The solid is filtered and Dry under air to give the title salt as a yellow amorphous solid. 0.21 g, decomposition 83 ℃ 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, 1H), δ 7. 90 (s, 1H), δ 7.95 (d, 1H)

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification number Internal reference number FI C07D 295/20 9283-4C C07D 295/20 A (72) Inventor Patel, Rajnikant Dartford, Kent, UK , Temple, Hill (no street number) (72) Inventor Barras, James Robert Kent, Dartford, Temple, Hill (no street number) (72) Inventor Milne, David John Kent, Dartford, Ten, England Pull, Hill (No street number)

Claims (1)

[Claims] 1. (I) Compound of formula (I): Reacting (wherein Hal is halogen) with diC _1-4 alkylformamide, (ii) rearrange the resulting complex, and (iii) quench the rearranged complex with water. A method for producing 2,3,5-trihalobenzaldehyde. 2. The method of claim 1, wherein the halogen is chloro. 3. The method according to claim 1 or 2, wherein the di C _1-4 alkylformamide is dimethylformamide. 4. The method according to any one of claims 1 to 3, wherein step (i) is carried out at a temperature of -20 to -80 ° C. 5. The method according to any one of claims 1 to 4, wherein step (ii) is performed for 2 to 24 hours. 6. The method according to any one of claims 1 to 5, wherein step (ii) is performed at a temperature of 15 to 35 ° C. 7. The process according to claim 1, wherein the compound of formula (I) is prepared by reacting 2,2,4-trihalobenzene with C _1-6 alkyllithium. 8. C _1-4 molar ratio of alkyllithium to di C _1-4 alkyl formamide is 1: 5.45, Method according to claim 7. 9. The method according to claim 7 or 8, wherein the C _1-6 alkyllithium is methyllithium or n-butyllithium. 10. 4-Amino-2- (4-methylpiperazin-1-yl) -5- (2,3,5-trihalophenyl) pyrimidine or 4-amino-2- (4-n-propylpiperazin-1-yl)- Use of 2,3,5-trihalobenzaldehyde prepared according to the method of any one of claims 1 to 9 in the chemical synthesis of 5- (2,3,5-trihalophenyl) pyrimidine. 11. Use of 2,3,5-trihalobenzaldehyde according to claim 9, wherein halo is chloro.