HK1100664B - An improved process for preparing n-hydroxy-4-{5-[4-(5-isopropyl-2-methyl-1,3-thiazol-4-yl)-phenoxy]-pentoxy}-benzamidine - Google Patents
An improved process for preparing n-hydroxy-4-{5-[4-(5-isopropyl-2-methyl-1,3-thiazol-4-yl)-phenoxy]-pentoxy}-benzamidine Download PDFInfo
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Description
Technical Field
The present invention relates to an improved process for the preparation of N-hydroxy-4- {5- [4- (5-isopropyl-2-methyl-1, 3-thiazol-4-yl) -phenoxy ] -pentoxy } -benzamidine.
Background
It is known a method for preparing N-hydroxy-4- {5- [4- (5-isopropyl-2-methyl-1, 3-thiazol-4-yl) -phenoxy ] -N-hydroxy]-pentoxy } -benzamidine, known as leukotriene B4Receptor antagonists (Lee, Sun-eun, Synthesis and Biological Activity of Natural Products and designed New Hybrid Compounds for the Treatment of LTB4 RelatedDisease，Ph.D thesis，Graduate School of Busan Univ.，Aug.1999)。
The preparation method of N-hydroxy-4- {5- [4- (5-isopropyl-2-methyl-1, 3-thiazol-4-yl) -phenoxy ] -pentoxy } -benzamidine disclosed in the above-mentioned document comprises the steps of preparing compound (6) (reaction 1 below), preparing compound (9) (reaction 2 below), and then reacting compound (6) with compound (9) to give the objective compound (reaction 3 below).
Reaction 1
In reaction 1, anisole (2) was reacted with isovaleryl chloride to obtain compound (3), and then compound (3) was reacted with tetra-n-butyltriammonium bromide (tetra-n-butyllammoniumtribromide) to prepare 2-bromo-1- (4-methoxy-phenyl) -3-methyl-butan-1-one (4) (yield: 77%). Compound (5) is produced by reacting the above compound (4) with thioacetamide. Compound (5) is reacted with aluminum chloride using ethanethiol and dichloromethane (1: 1) as a solvent, to give intermediate compound (6) (yield: 79%).
However, tetra-n-butyl ammonium tribromide (4) used in the above reaction is disadvantageous because it drastically reduces the preparation yield, and is expensive and difficult to handle, and thus is not suitable for use in mass production. In addition, ethanethiol used as a solvent for preparing the intermediate compound (6) generates an unpleasant odor and has disadvantages that make it unsuitable for use in a mass production process.
Reaction 2
In reaction 2, 4-hydroxy-benzonitrile (7) is reacted with 1-bromo-5-chloropentane to give compound (8), and then compound (8) is reacted with sodium iodide to give intermediate compound (9) having an iodine group substituted for a chlorine group (yield: 89%).
However, the above method is disadvantageous in that the preparation of the intermediate compound (9) requires two steps. Therefore, there is a need to improve the economics of the above-described process for mass production.
Reaction 3
In reaction 3, compound (6) produced by reaction 1 and compound (9) produced by reaction 2 are reacted with sodium hydride to produce compound (10) (yield: 94%). Subsequently, the compound (10) was reacted with hydroxylamine hydrochloride and sodium hydroxide to prepare the final compound (1) (yield: 83%).
Therefore, sodium hydride, which is an acid reactant for the above reaction, is difficult to handle and is not suitable for mass production. Further, purification by column chromatography is difficult to apply to mass production, and the yield is also reduced (total yield: about 24%).
Accordingly, the present inventors have studied an economical preparation method having a simple reaction process and a significantly increased preparation yield, and being suitable for mass production, thus leading to the present invention.
Disclosure of Invention
The present invention provides an improved process for the preparation of N-hydroxy-4- {5- [4- (5-isopropyl-2-methyl-1, 3-thiazol-4-yl) -phenoxy ] -pentoxy } -benzamidine.
Best mode for carrying out the invention
The present invention provides an improved process for the preparation of N-hydroxy-4- {5- [4- (5-isopropyl-2-methyl-1, 3-thiazol-4-yl) -phenoxy ] -pentoxy } -benzamidine, which is represented by the following formula 1.
Formula 1
In the present invention, an improved process for the preparation of N-hydroxy-4- {5- [4- (5-isopropyl-2-methyl-1, 3-thiazol-4-yl) phenoxy ] pentoxy } benzamidine (1) comprises: n-hydroxy-4- {5- [4- (5-isopropyl-2-methyl-1, 3-thiazol-4-yl) phenoxy ] pentoxy } benzamidine (1) was prepared by coupling 4- (5-chloro-pentoxy) -benzonitrile (8) or 4- (5-iodo-pentoxy) -benzonitrile (9) with 4- (5-chloro-pentoxy) -phenol (6), which was produced using anisole as a starting material, and reacting the resulting compound with hydroxylamine hydrochloride.
In the above production method of the present invention, the production of 4- (5-isopropyl-2-methyl-1, 3-thiazol-4-yl) -phenol (6) comprises the steps of:
1) reacting anisole (2) with isovaleryl chloride to produce 1- (4-methoxy-phenyl) -3-methyl-butan-1-one (3),
2) reacting the compound (3) prepared in step 1) with bromine, sulfuryl chloride, N-bromosuccinimide or copper bromide to prepare 2-halo-1- (4-methoxy-phenyl) -3-methyl-butan-1-one (4),
3) reacting the compound (4) prepared in step 2) with thioacetamide to prepare 5-isopropyl-4- (4-methoxy-phenyl) -2-methyl-thiazole (5), and
4) reacting the compound (5) prepared in step 3) with bromic acid and acetic acid, sodium cyanide and dimethyl sulfoxide, or tetrabutylammonium iodide and boron trifluoride-diethyl ether to prepare 4- (5-isopropyl-2-methyl-1, 3-thiazol-4-yl) -phenol (6).
In the above preparation process of the present invention, 4- (5-chloro-pentoxy) -benzonitrile (8) is prepared by reacting 4-hydroxy-benzonitrile with 1-bromo-5-chloropentane.
In the above preparation method of the present invention, the preparation of 4- (5-iodo-pentoxy) -benzonitrile (9) comprises the steps of:
1) reacting 4-hydroxy-benzonitrile (7) with 1-bromo-5-chloropentane to prepare 4- (5-chloro-pentoxy) -benzonitrile (8), and
2) reacting the compound (8) prepared in step 1) with iodide to prepare 4- (5-iodo-pentoxy) -benzonitrile (9).
Specifically, according to one aspect of the present invention, the preparation method comprises the steps of:
1) reacting anisole (2) with isovaleryl chloride to produce 1- (4-methoxy-phenyl) -3-methyl-butan-1-one (3),
2) reacting the compound (3) prepared in step 1) with bromine, sulfuryl chloride, N-bromosuccinimide or copper bromide to prepare 2-halo-1- (4-methoxy-phenyl) -3-methyl-butan-1-one (4),
3) reacting the compound (4) prepared in step 2) with thioacetamide to prepare 5-isopropyl-4- (4-methoxy-phenyl) -2-methyl-thiazole (5),
4) reacting the compound (5) prepared in step 3) with bromic acid and acetic acid, sodium cyanide and dimethyl sulfoxide, or tetrabutylammonium iodide and boron trifluoride-diethyl ether to prepare 4- (5-isopropyl-2-methyl-1, 3-thiazol-4-yl) -phenol (6),
5) reacting 4-hydroxy-benzonitrile (7) with 1-bromo-5-chloropentane to prepare 4- (5-chloro-pentoxy) -benzonitrile (8),
6) reacting the compound (6) obtained in step 4) with the compound (8) obtained in step 5) in the presence of sodium hydroxide to prepare 4- {5- [4- (5-isopropyl-2-methyl-1, 3-thiazol-4-yl) -phenoxy ] -pentoxy } -benzonitrile (10), and
7) reacting the compound (10) prepared in step 6) with hydroxylamine hydrochloride and a base to prepare N-hydroxy-4- {5- [4- (5-isopropyl-2-methyl-1, 3-thiazol-4-yl) phenoxy ] pentoxy } benzamidine (1), all the steps of which are shown in reaction 4 as follows:
reaction 4
Each step of the improved process of the present invention for the preparation of N-hydroxy-4- {5- [4- (5-isopropyl-2-methyl-1, 3-thiazol-4-yl) -phenoxy ] -pentoxy } -benzamidine is described separately below.
In the first and second steps, after anisole (2) is reacted with isovaleryl chloride to give 1- (4-methoxy-phenyl) -3-methyl-butan-1-one (3), compound (3) is reacted with bromine, sulfuryl chloride, N-bromosuccinimide or copper bromide to produce 2-bromo-1- (4-methoxy-phenyl) -3-methyl-butan-1-one (4). At this time, the reaction temperature is preferably maintained in the range of-10 ℃ to 40 ℃, and the reaction solvent is selected from polar solvents including dichloromethane; acetonitrile; ethyl acetate; lower alcohols such as methanol, ethanol or isopropanol; ethers, such as tetrahydrofuran or 1, 4-dioxane; dimethylformamide or dimethylsulfoxide; and mixtures thereof. Among the substances reacted with the compound (3) in the second step, bromine is preferably used because it is inexpensive and increases the yield (yield: 96% or more).
In a third step, compound (4) prepared in the second step is reacted with thioacetamide to give 5-isopropyl-4- (4-methoxy-phenyl) -2-methyl-thiazole (5). Therefore, the reaction temperature is preferably maintained in the range of 20 ℃ to 100 ℃ and the reaction solvent is selected from polar solvents, including dichloromethane; acetonitrile; ethyl acetate; lower alcohols such as methanol, ethanol or isopropanol; ethers, such as tetrahydrofuran or 1, 4-dioxane; dimethylformamide or dimethylsulfoxide; and mixtures thereof.
In the fourth step, compound (5) prepared in the third step is reacted with bromic acid and acetic acid, sodium cyanide and dimethyl sulfoxide, or tetrabutylammonium iodide and boron trifluoride-diethyl ether to give 4- (5-isopropyl-2-methyl-1, 3-thiazol-4-yl) -phenol (6). Conventionally, ethanethiol is used, whereby an unpleasant odor occurs, and it is difficult to handle the reagent to such an extent that it is not suitable for mass production. However, in the present invention, the use of compound (5) and the above-mentioned substances which react therewith, specifically, i.e., bromic acid and acetic acid, results in reduction of unpleasant odor, low price, simple reagent handling, and significantly increased production yield (yield: 84%).
In the fifth step, 4-hydroxy-benzonitrile (7) is reacted with 1-bromo-5-chloropentane, thereby obtaining 4- (5-chloro-pentoxy) -benzonitrile (8) (yield: 90%). Thus, the reaction temperature is preferably maintained in the range of 20 ℃ to 82 ℃ and the reaction solvent is selected from polar solvents, including dichloromethane; acetonitrile; ethyl acetate; lower alcohols such as methanol, ethanol or isopropanol; ethers, such as tetrahydrofuran or 1, 4-dioxane; dimethylformamide or dimethylsulfoxide; and mixtures thereof. To ensure that the above reaction takes place under basic conditions, inorganic bases may be used, including potassium carbonate, sodium hydroxide, potassium hydroxide, sodium amide, sodium hydride, sodium methoxide or ethoxide, and others.
In the above reaction, the number of unnecessary steps is reduced and the process is simplified as compared with the conventional method, thereby increasing the production yield (90%). In addition, under appropriate reaction control, the compound (8) can be crystallized without additional isolation and purification, which is particularly useful in mass production processes.
In the sixth and seventh steps, compound (6) prepared in the fourth step and compound (8) prepared in the fifth step are reacted in the presence of sodium hydroxide, thereby preparing 4- {5- [4- (5-isopropyl-2-methyl-1, 3-thiazol-4-yl) -phenoxy ] -pentoxy } -benzonitrile (10) (yield: 90%). Further, compound (10) was reacted with hydroxylamine hydrochloride and a base to prepare N-hydroxy-4- {5- [4- (5-isopropyl-2-methyl-1, 3-thiazol-4-yl) phenoxy ] pentoxy } benzamidine (1) (yield: 95%). Thus, the reaction solution is directly added with water to be recrystallized, and thus can be easily prepared on a large scale.
In the above reaction step, the reaction temperature is preferably controlled from room temperature to solvent returnThe temperature of the stream. The reaction solvent is selected from polar solvents including dichloromethane; acetonitrile; ethyl acetate; lower alcohols such as methanol, ethanol or isopropanol; ethers, such as tetrahydrofuran or 1, 4-dioxane; dimethylformamide or dimethylsulfoxide; and mixtures thereof. The base used in the reaction is selected from organic bases including triethylamine, 1, 8-diazabicyclo [5.4.0 ]]Undec-7-ene, DBU, diethylmethylamine (Et)2NMe), N-methylmorpholine, N-methylpiperidine, pyridine, 2, 6-lutidine, or from inorganic bases including potassium carbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, sodium amide, sodium hydride, sodium methoxide or ethoxide and other basic compounds. In the present invention, triethylamine is preferable, and is used in an equivalent of 1 to 4.
Therefore, the total reaction yield (33%) of the present production method shown in reaction 4 was found to be significantly higher than the total yield (24%) of the method disclosed in the above-mentioned document.
Specifically, according to another aspect of the present invention, the preparation method comprises the steps of:
1) reacting anisole (2) with isovaleryl chloride to produce 1- (4-methoxy-phenyl) -3-methyl-butan-1-one (3),
2) reacting the compound (3) prepared in step 1) with bromine, sulfuryl chloride, N-bromosuccinimide or copper bromide to prepare 2-halo-1- (4-methoxy-phenyl) -3-methyl-butan-1-one (4),
3) reacting the compound (4) prepared in step 2) with thioacetamide to prepare 5-isopropyl-4- (4-methoxy-phenyl) -2-methyl-thiazole (5),
4) reacting the compound (5) prepared in step 3) with bromic acid and acetic acid, sodium cyanide and dimethyl sulfoxide, or tetrabutylammonium iodide and boron trifluoride-diethyl ether to prepare 4- (5-isopropyl-2-methyl-1, 3-thiazol-4-yl) -phenol (6),
5) reacting 4-hydroxy-benzonitrile (7) with 1-bromo-5-chloropentane to give 4- (5-chloro-pentoxy) -benzonitrile (8), and then reacting compound (8) with iodide to give 4- (5-iodo-pentoxy) -benzonitrile (9),
6) reacting the compound (6) obtained in the step 4) with the compound (9) obtained in the step 5) in the presence of sodium hydroxide to prepare 4- {5- [4- (5-isopropyl-2-methyl-1, 3-thiazol-4-yl) -phenoxy ] -pentoxy } -benzonitrile (10), and
7) reacting the compound (10) prepared in step 6) with hydroxylamine hydrochloride and a base to prepare N-hydroxy-4- {5- [4- (5-isopropyl-2-methyl-1, 3-thiazol-4-yl) phenoxy ] pentoxy } benzamidine (1), all the steps of which are shown in reaction 5 as follows:
reaction 5
Each step of the improved process of the present invention for the preparation of N-hydroxy-4- {5- [4- (5-isopropyl-2-methyl-1, 3-thiazol-4-yl) -phenoxy ] -pentoxy } -benzamidine is described separately below.
The first to fourth steps are as described above.
In the fifth step, 4-hydroxy-benzonitrile (7) is reacted with 1-bromo-5-chloropentane to give 4- (5-chloro-pentoxy) -benzonitrile (8) (yield: 90%). At this time, the reaction temperature is preferably maintained in the range of 20 ℃ to 82 ℃, and the reaction solvent is selected from polar solvents including dichloromethane; acetonitrile; ethyl acetate; lower alcohols such as methanol, ethanol or isopropanol; ethers, such as tetrahydrofuran or 1, 4-dioxane; dimethylformamide or dimethylsulfoxide; and mixtures thereof. To ensure that the above reaction takes place under basic conditions, inorganic bases may be used, including potassium carbonate, sodium hydroxide, potassium hydroxide, sodium amide, sodium hydride, sodium methoxide or ethoxide, and others. Subsequently, 4- (5-chloro-pentoxy) -benzonitrile (8) is reacted with iodide, thereby preparing 4- (5-iodo-pentoxy) -benzonitrile (9) (yield: 99%). As iodide, sodium iodide may be used.
In the sixth and seventh steps, compound (6) prepared in the fourth step and compound (9) prepared in the fifth step are reacted in the presence of sodium hydroxide, thereby preparing 4- {5- [4- (5-isopropyl-2-methyl-1, 3-thiazol-4-yl) -phenoxy ] -pentoxy } -benzonitrile (10) (yield: 94%). The compound (10) was reacted with hydroxylamine hydrochloride and a base to finally obtain N-hydroxy-4- {5- [4- (5-isopropyl-2-methyl-1, 3-thiazol-4-yl) phenoxy ] pentoxy } benzamidine (1) (yield: 91%). Thus, the reaction solution is directly added with water to be recrystallized, and thus can be easily prepared on a large scale.
In the above reaction step, the reaction temperature is preferably controlled in the range of room temperature to the reflux temperature of the solvent. The reaction solvent is selected from polar solvents including dichloromethane; acetonitrile; ethyl acetate; lower alcohols such as methanol, ethanol or isopropanol; ethers, such as tetrahydrofuran or 1, 4-dioxane; dimethylformamide or dimethylsulfoxide; and mixtures thereof. The base used in the reaction is selected from organic bases including triethylamine, 1, 8-diazabicyclo [5.4.0 ]]Undec-7-ene, DBU, diethylmethylamine (Et)2NMe), N-methylmorpholine, N-methylpiperidine, pyridine, 2, 6-lutidine, or from an inorganic base including potassium carbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, sodium amide, sodium hydride, sodium methoxide or ethoxide and others. In the present invention, triethylamine is preferable, and is used in an equivalent of 1 to 4.
Therefore, the total reaction yield (34%) of the present production method shown in reaction 5 was found to be significantly higher than the total yield (24%) of the method disclosed in the above-mentioned document.
As described above, the preparation process of the present invention is economical and simple, and has a high preparation yield, and thus is suitable for mass production of N-hydroxy-4- {5- [4- (5-isopropyl-2-methyl-1, 3-thiazol-4-yl) -phenoxy ] -pentoxy } -benzamidine (1).
A better understanding of the present invention may be obtained through the following examples which are set forth to illustrate, but are not to be construed as the limit of the present invention.
Example 1: preparation of 1- (4-methoxy-phenyl) -3-methyl-butan-1-one (Compound 3)
While 40g of isovaleryl chloride and 44g of aluminum chloride were added to 140ml of methylene chloride and stirred, 32.6ml of anisole was slowly added dropwise at-10 ℃ or lower, and stirring was continued at room temperature for 40 min. Subsequently, 36.6ml of isovaleryl chloride was slowly added dropwise and stirring was continued for an additional 18hr at room temperature. After the reaction was completed, 200ml of dichloromethane was added to the resultant reaction mixture, which was then washed with a saturated aqueous solution of sodium hydrogencarbonate and water in this order, and after that, the dichloromethane layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain 56.9g of the title compound (yield: 98.6%) as a pale yellow liquid.
m/z 193[M++1]；
1H NMR(CDCl3)δ(ppm)0.96(d，6H)，2.26(m，1H)，2.75(d，2H)，3.84(s，3H)，6.90(d，2H)，7.92(d，2H)。
Example 2: preparation of 2-bromo-1- (4-methoxy-phenyl) -3-methyl-butan-1-one (Compound 4)
While 56.9g of 1- (4-methoxy-phenyl) -3-methyl-butan-1-one (3) prepared in example 1 was added to 200ml of ethyl acetate and stirred, 18.2ml of bromine was added at room temperature and stirring was continued at the same temperature for 1 hr. After the reaction was completed, the resultant reaction mixture was washed with brine and water in this order, and then, the ethyl acetate layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure, thereby obtaining 77.0g of the title compound (yield: 96.0%) as a pale yellow liquid.
m/z 271[M+]；
1H NMR(CDCl3)δ(ppm)0.97(d，3H)，1.17(d，3H)，2.42(m，1H)，3.82(s，3H)，4.86(d，1H)，6.88(d，2H)，7.89(d，2H)
Example 3: preparation of 5-isopropyl-4- (4-methoxy-phenyl) -2-methyl-1, 3-thiazole (Compound 5)
While 77.0g of 2-bromo-1- (4-methoxy-phenyl) -3-methyl-butan-1-one (4) prepared in example 2 was added to 200ml of ethanol and stirred, 42.7g of thioacetamide was added. Subsequently, the temperature was gradually increased, and stirring was continued under reflux for 22 hr. After the reaction was completed, 300ml of ethyl acetate was added to the resultant reaction mixture, which was then washed with a saturated aqueous solution of potassium carbonate. The ethyl acetate layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure, thereby obtaining 35.8g of the title compound as a brown liquid (yield 51.0%).
m/z 248[M++1]；
1H NMR(CDCl3)δ(ppm)1.28(d，6H)，2.67(s，3H)，3.37(m，1H)，3.84(s，3H)，6.94(d，2H)，7.46(d，2H)
Example 4: preparation of 4- (5-isopropyl-2-methyl-1, 3-thiazol-4-yl) -phenol (Compound 6)
While 35.8g of 5-isopropyl-4- (4-methoxy-phenyl) -2-methyl-1, 3-thiazole (5) prepared in example 3 was added to 86ml of acetic acid and stirred, 500ml of 48% bromic acid was added. Subsequently, the temperature was gradually increased and stirring was continued under reflux for 18 hr. The temperature was allowed to fall to room temperature, 400ml of dichloromethane were added and stirring was continued for a further 30 min. Then, the dichloromethane layer was removed. Thereafter, a saturated aqueous solution of potassium carbonate was added to the obtained reaction solution to neutralize to pH7-8, and after that, the precipitated solid was filtered and then washed with water to obtain 28.4g of the title compound (yield: 84%) as a solid.
m.p.165℃；
m/z 234[M++1]；
1H NMR(CDCl3)δ(ppm)1.29(d，6H)，2.72(s，3H)，3.38(m，1H)，7.42(d，2H)，7.28(d，2H)
Example 5: preparation of 4- (5-chloro-pentoxy) -benzonitrile (Compound 8)
While 70g of 4-hydroxybenzonitrile (7) was added to 500ml of acetonitrile and stirred, 85.3g of potassium carbonate and 77.4ml of 1-bromo-5-chloropentane were added. Subsequently, the temperature was gradually increased and stirring was continued under reflux for 8hr, and then at room temperature for another 18 hr. After the reaction was completed, 500ml of ethyl acetate was added to the resultant reaction mixture, and washed with water. Thereafter, the ethyl acetate layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The concentrated compound was dissolved in 280ml of methanol, stirred at 0 ℃ for 2hr, and then filtered, thereby obtaining 118g of the title compound (yield: 90%) as a white solid.
m.p.47℃；
m/z 224[M++1]；
1H NMR(CDCl3)δ(ppm)1.64(m，2H)，1.82(m，4H)，3.57(t，2H)，4.01(t，2H)，6.93(d，2H)，7.57(d，2H)
Example 6: preparation of 4- (5-iodo-pentoxy) -benzonitrile (Compound 9)
While 50g of 4- (5-chloro-pentoxy) -benzonitrile (8) prepared in example 5 was added to 500ml of 2-butanone and stirred, 167g of sodium iodide was added. Subsequently, the reaction temperature was gradually increased and stirring was continued at 70 ℃ to 80 ℃ for 6 hr. After the reaction was completed, the reaction temperature was lowered to room temperature, and 1L of ethyl acetate was added to the resultant reaction mixture, which was then washed with water and brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The remaining solution was crystallized from methanol, thereby obtaining 69.7g of the title compound (yield: 99%) as a white solid.
m.p.61℃；
m/z 316[M++1]；
1H NMR(CDCl3)δ(ppm)1.54(m，2H)，1.87(m，4H)，3.22(t，2H)，3.98(t，2H)，6.93(d，2H)，7.57(d，2H)
Example 7: preparation of 4- {5- [4- (5-isopropyl-2-methyl-1, 3-thiazol-4-yl) -phenoxy ] -pentoxy } -benzonitrile (Compound 10)
While adding 72.6g of 4- (5-isopropyl-2-methyl-1, 3-thiazol-4-yl) -phenol (6) prepared in example 4 to 850ml of dimethylformamide and stirring, 15.0g of sodium hydroxide was added. The reaction temperature was gradually increased and stirring was continued at 50-55 ℃ for 30 min. Thereafter, 70.0g of 4- (5-chloro-pentoxy) -benzonitrile (8) prepared in example 5 or 95.3g of 4- (5-iodo-pentoxy) -benzonitrile (9) prepared in example 6 were added. The reaction temperature was gradually increased and stirring was continued at 80-90 ℃ for 3 hr. After the reaction was completed, the temperature was allowed to fall to room temperature, and 850ml of ethyl acetate was added to the resulting reaction mixture, followed by washing with water and brine. Subsequently, the ethyl acetate layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The remaining solution was crystallized from ethyl acetate and n-hexane to obtain 114g of the title compound (yield: 90%) as a pale yellow solid by reaction with the compound (8), or 119.6g of the title compound (yield: 94%) as a pale yellow solid by reaction with the compound (9).
m.p.173℃；
m/z 421[M++1]；
1H NMR(CDCl3)δ(ppm)1.28(d，6H)，1.66(m，2H)，1.87(m，4H)，2.67(s，3H)，3.35(m，1H)，4.01(m，4H)，6.93(d，4H)，7.46(d，2H)，7.56(d，2H)
Example 8: preparation of N-hydroxy-4- {5- [4- (5-isopropyl-2-methyl-1, 3-thiazol-4-yl) phenoxy ] pentoxy } benzamidine (Compound 1)
While 45g of 4-5- [4- (5-isopropyl-2-methyl-1, 3-thiazol-4-yl) -phenoxy ] -pentoxy-benzonitrile (10) prepared in example 6 was added to 300ml of ethanol and stirred, 15g of hydroxylamine hydrochloride and 30ml of triethylamine were added. The temperature was gradually increased and stirring was continued under reflux for 15 hr. After the reaction was completed, the temperature was lowered to 40 ℃, and water was slowly added to the resultant reaction mixture, thereby crystallizing. The precipitated solid was filtered and washed with water, thereby obtaining 44.2g of the title compound (yield: 95%) as a white solid.
m.p.97℃；
m/z 454[M++1]；
1H NMR(DMSO-d6)δ(ppm)1.22(d，6H)，1.57(m，2H)，1.78(m，4H)，2.59(s，3H)，3.33(m，1H)，4.00(m，4H)，5.72(s，2H)，6.90(d，2H)，6.98(d，2H)，7.42(d，2H)，7.57(d，2H)
Industrial applicability
As indicated above, the present invention provides an improved process for the preparation of N-hydroxy-4- {5- [4- (5-isopropyl-2-methyl-1, 3-thiazol-4-yl) phenoxy ] pentoxy } benzamidine. The preparation method of the present invention is advantageous in that it has a simpler reaction process than conventional methods, and also it employs a recrystallization method, which is easier and suitable for mass production than conventional purification techniques, thus greatly increasing purity and preparation yield.
Although the preferred embodiments of the present invention have been disclosed for illustrative purposes, those skilled in the art will appreciate that various modifications, additions and substitutions are possible, without departing from the scope and spirit of the invention as disclosed in the accompanying claims.
Claims (7)
1. A process for the preparation of N-hydroxy-4- {5- [4- (5-isopropyl-2-methyl-1, 3-thiazol-4-yl) phenoxy ] pentoxy } benzamidine (1) comprising the steps of:
1) reacting anisole (2) with isovaleryl chloride to produce 1- (4-methoxy-phenyl) -3-methyl-butan-1-one (3);
2) reacting the compound (3) prepared in the step 1) with bromine, N-bromosuccinimide or copper bromide to prepare 2-bromo-1- (4-methoxy-phenyl) -3-methyl-butan-1-one (4);
3) reacting the compound (4) prepared in said step 2) with thioacetamide to prepare 5-isopropyl-4- (4-methoxy-phenyl) -2-methyl-thiazole (5);
4) reacting the compound (5) prepared in the step 3) with bromic acid and acetic acid, sodium cyanide and dimethyl sulfoxide or tetrabutylammonium iodide and boron trifluoride-diethyl ether to prepare 4- (5-isopropyl-2-methyl-1, 3-thiazol-4-yl) -phenol (6);
5) reacting the compound (6) obtained in said step 4) with 4- (5-chloro-pentoxy) -benzonitrile (8) or with 4- (5-iodo-pentoxy) -benzonitrile (9) to prepare 4- {5- [4- (5-isopropyl-2-methyl-1, 3-thiazol-4-yl) -phenoxy ] -pentoxy } -benzonitrile (10); and
6) reacting the compound (10) prepared in said step 5) with hydroxylamine hydrochloride and a base to prepare N-hydroxy-4- {5- [4- (5-isopropyl-2-methyl-1, 3-thiazol-4-yl) phenoxy ] pentoxy } benzamidine (1).
2. The process according to claim 1, wherein in said step 5), 4-hydroxy-benzonitrile (7) is reacted with 1-bromo-5-chloropentane to give 4- (5-chloro-pentoxy) -benzonitrile (8), and then (8) is reacted with compound (6) obtained in said step 4) in the presence of sodium hydroxide to prepare 4- {5- [4- (5-isopropyl-2-methyl-1, 3-thiazol-4-yl) -phenoxy ] -pentoxy } -benzonitrile (10).
3. The process of claim 1 wherein in said step 5) 4- {5- [4- (5-isopropyl-2-methyl-1, 3-thiazol-4-yl) -phenoxy ] -pentoxy } -benzonitrile (10) is prepared by reacting 4-hydroxy-benzonitrile (7) with 1-bromo-5-chloropentane to provide 4- (5-chloro-pentoxy) -benzonitrile (8), then reacting (8) with iodide to provide 4- (5-iodo-pentoxy) -benzonitrile (9), then reacting (9) with compound (6) obtained in said step 4) in the presence of sodium hydroxide.
4. The process according to claim 1, wherein in the step 2), the compound (3) prepared in the step 1) is reacted with bromine to prepare 2-bromo-1- (4-methoxy-phenyl) -3-methyl-butan-1-one (4).
5. The process of claim 1, wherein in the step 4), the compound (5) prepared in the step 3) is reacted with bromic acid and acetic acid to prepare 4- (5-isopropyl-2-methyl-1, 3-thiazol-4-yl) -phenol (6).
6. The process according to claim 1, wherein the base used in step 6) is selected from triethylamine, 1, 8-diazabicyclo [5.4.0]Undec-7-ene, diethylmethylamine (Et)2NMe), N-methylmorpholine, N-methylpiperidine, pyridine, 2, 6-lutidine, potassium carbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, sodium amide, sodium hydride, sodium methoxide and sodium ethoxide.
7. The process of claim 6, wherein the base is triethylamine.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR10-2004-0052070 | 2004-07-05 | ||
| KR20040052070 | 2004-07-05 | ||
| PCT/KR2005/002137 WO2006004368A1 (en) | 2004-07-05 | 2005-07-05 | AN IMPROVED PROCESS FOR PREPARING N-HYDROXY-4-{5- [4- (5-ISOPROPYL-2-METHYL-l, 3-THIAZOL-4-YL) -PHENOXY] -PENTOXY }-BENZAMIDINE |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| HK1100664A1 HK1100664A1 (en) | 2007-09-28 |
| HK1100664B true HK1100664B (en) | 2010-10-08 |
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