KR102253950B1 - Novel method for the preparation of Medetomidine - Google Patents

Abstract

The present invention relates to a method for preparing medetomidine from 1 H -imidazole-4-carbaaldehyde and 1-bromo-2,3-dimethylbenzene.

Description

Novel method for preparing medetomidine {Novel method for the preparation of Medetomidine}

The present invention relates to a novel method for preparing medetomidine represented by the formula (I).

Medetomidine is an alpha2 adrenergic receptor agonist. It acts on the alpha2 adrenergic receptors of the central and spinal nervous systems, thereby exhibiting sympathetic, sedative, and analgesic effects. Said compound of Medo Tommy Dean 5- [1- (2,3-dimethylphenyl) ethyl] -1 H - imidazole and (5- [1- (2,3-dimethylphenyl ) ethyl] -1 H -imidazole), It is mainly used in veterinary medicine as a sedative and pain reliever. Dexmedetomidine, the S-stereoisomer of medetomidine, was approved by the U.S. FDA in 1999, and is being used with approval from the Korean Ministry of Food and Drug Safety in June 2010. Dexmedetomidine has few side effects of respiratory depression and is known to maintain hemodynamic stability during surgery. In addition, in WO 2000042851 A1, KR 10-1831536 B1, KR 10-1820432 B1, KR 10-2017-0125110 A, and KR 10-2016-0034311 A, inhibition of marine biofouling of surface on a solid surface is provided. The use of medetomidine for this is disclosed.

CN 107857731 A, the 4-bromo-1-trimethylsilyl -1 H-imidazole Grignard reagent (Grignard Reagent) is prepared (4-Bromo-1-trimethylsilyl -1 H imidazole) and from magnesium and 2,3-dimethyl-benzamide A method for preparing medetomidine by reaction with aldehyde (2,3-Dimethyl benzaldehyde) is disclosed.

EP 1918282 A1 is 4-iodo-1-trityl -1 H - imidazole (4-Iodo-1-trityl -1 H -imidazole) 2 and a Grignard reagent prepared from isopropyl bromide (Isopropylmagnesium bromide) A method for preparing medetomidine by reaction with ,3-dimethyl benzaldehyde is disclosed.

Synthetic Communications, 26(8), 1585-1593 (1996) describes Grignard reagent and 1-trityl prepared from 3-bromo-1,2-dimethylbenzene and magnesium. A method for preparing medetomidine by reaction with -1 H -imidazole-4-carboxaldehyde (1-Trityl-1 H -imidazole-4-carboxaldehyde) is disclosed.

The known method for preparing medetomidine as described above mainly uses a triphenylmethyl group (trityl group) as a protecting group, but this is expensive and requires a protection/deprotection step, which takes a long time during synthesis. In addition, it is difficult to obtain a starting material, and there is a problem in that the yield is low, and thus a novel method for preparing medetomidine is required.

It is an object of the present invention to provide a novel method for preparing medetomidine represented by the formula (I).

In order to achieve the above object, the present invention provides a novel method for preparing medetomidine represented by the following formula (I).

[Formula I]

The present invention, 1) 1 H - imidazole-4-carbazole aldehyde (1 H -Imidazole-4-carbaldehyde ) a di - tert - butyl dicarbonate (Di- tert -butyl dicarbonate) represented by the formula (2) was reacted with tert - butyl 4-formyl -1 H - imidazole-1-carboxylate (tert -butyl 4-formyl-1 H -imidazole-1-carboxylate) to obtain a compound;

2) preparing a compound represented by the following Formula 4 by adding and reacting the compound represented by Formula 2 using 3-Bromo-o-xylene;

3) preparing the compound represented by Formula 4 into a compound represented by Formula 5 below;

4) preparing medetomidine represented by the formula (I) by removing the tert -butyl group of the compound represented by Chemical Formula (5).

The step 3) includes a step 3-1) of reacting with methanesulfonyl chloride in the presence of thionyl chloride or diisopropylethylamine, and the step 3-1) It characterized in that it comprises a; 3-2) step of reacting with methylmagnesium chloride (Methylmagnesium chloride) after.

In step 3-2), methylmagnesium chloride is added at 0°C to -15°C, and the reaction is performed at room temperature for 2 to 3 hours.

In step 2), 3-Bromo-o-xylene is stirred with zinc (Zn) and cobalt (II) bromide to formula 3-1 below. It is prepared and used as the indicated compound, and the stirring is performed at room temperature for 4 hours.

Steps 1) and 2) use acetonitrile as a solvent, and step 3-2) uses tetrahydrofuran as a solvent.

In step 2), the molar ratio of zinc (Zn): 3-Bromo-o-xylene is 1.5:1 to 3:1.

The method for preparing medetomidine according to the present invention is economical, and by using a novel intermediate for medetomidine, there is an effect of manufacturing safety and stability of the manufacturing process and the final material with high purity.

Hereinafter, a novel method for preparing medetomidine of the present invention will be described in detail.

The present invention provides a method for preparing medetomidine represented by the following formula (I).

[Formula I]

Medetomidine represented by Chemical Formula 1 of the present invention may be prepared by a method according to Scheme 1 below.

[Scheme 1]

Specifically, the production process according to the present invention is 1) 1 H - imidazole-4-kava aldehyde (1 H -Imidazole-4-carbaldehyde ) di - tert - butyl dicarbonate (Di- tert -butyl dicarbonate) and Reacted and represented by the formula (2) tert - butyl 4-formyl -1 H - imidazole-1-carboxylate (tert -butyl 4-formyl-1 H -imidazole-1-carboxylate) to obtain a compound;

2) preparing a compound represented by the following Formula 4 by adding and reacting the compound represented by Formula 2 using 3-Bromo-o-xylene;

3) preparing the compound represented by Formula 4 into a compound represented by Formula 5 below;

4) removing the tert -butyl group of the compound represented by Chemical Formula 5 to prepare medetomidine represented by Chemical Formula I.

The step 3) includes a step 3-1) of reacting with methanesulfonyl chloride in the presence of thionyl chloride or diisopropylethylamine, and the step 3-1) It is preferable to include; 3-2) step of reacting with methylmagnesium chloride afterwards.

In step 3-2), methylmagnesium chloride is preferably added at 0°C or -15°C and reacted at room temperature for 2 hours or 3 hours.

In step 2), 3-Bromo-o-xylene is stirred with zinc (Zn) and cobalt (II) bromide to formula 3-1 below. It is prepared and used as the indicated compound, and the stirring is preferably carried out at room temperature for 4 hours.

Steps 1) and 2) preferably use acetonitrile as a solvent, and step 3-2) preferably uses tetrahydrofuran as a solvent.

In step 2), the molar ratio of zinc (Zn): 3-Bromo-o-xylene is preferably 1.5:1 to 3:1.

Hereinafter, the present invention will be described in detail through examples of the present invention. However, the following examples are merely illustrative of the present invention, and the contents of the present invention are not limited by the following examples.

[ Manufacturing example One] tert -Butyl 4- Formyl -One H -Imidazole-1- Carboxylate ( tert -Butyl 4-formyl-1 H Preparation of -imidazole-1-carboxylate (Chemical Formula 2))

After dissolving Formula 1 (30 g, 312 mmol) in acetonitrile (400 mL), triethylamine (4.3 mL, 31 mmol) and a catalyst amount of 4-dimethylaminopyridine were added. Di - tert - butyl dicarbonate (Di- tert -butyl dicarbonate) (97 g, 446 mmol) the mixture was stirred for 7 hours at room temperature after which was added dropwise within 30 minutes at 0 ℃ to the mixture was dissolved in acetonitrile (250 mL) And then concentrated under reduced pressure. Formula 2 was obtained by recrystallization using tetrahydrofuran (200 mL) (white solid, 55 g, yield 90%).

Formula 2 : ¹ H-NMR (300 MHz, Chloroform- d ) δ 1.65(s, 9H), 8.03(d, J = 1.2 Hz, 1H), 8.14( d , J = 1.2 Hz, 1H), 9.94(s, 1H) .

[ Manufacturing example 2] tert -Butyl 4-((2,3- Dimethylphenyl )( Hydroxy ) methyl )-One H -Imidazole-1-carboxylate ( tert -Butyl 4-((2,3- dimethylphenyl )( hydroxy )methyl)-1 H Preparation of -imidazole-1-carboxylate (Chemical Formula 4))

Example 1

After dissolving zinc dust (<10 μm, ≥98%) (7.9 g, 121 mmol) and cobalt bromide (886 mg, 4.05 mmol) in acetonitrile (68 mL), Allyl chloride (0.99 mL, 12.15 mmol) and trifluoroacetic acid (0.26 mL, 3.24 mmol) were added, and argon gas was charged for 5 minutes, followed by stirring at room temperature. Formula 3 3-Bromo-o-xylene (3-Bromo-o-xylene) (15 g, 81.05 mmol) was added dropwise within 5 minutes, followed by stirring at room temperature for 4 hours, and Formula 2 (12.7 g, 64 mmol) ) Was dissolved in acetonitrile (20 mL) and added dropwise to the mixture at 4° C. within 1 hour. Then, the mixture was cooled to -15°C, and water (10 mL), ethyl acetate (EA) (100 mL), and 2N aqueous HCl (100 mL) were added to the mixture, followed by stirring for 30 minutes. After filtering using Celite, the mixture was extracted, and the acidic extract (100 mL) was extracted using EA (30 mL). EA (250 mL) was added to the combined organic extract, followed by washing with 0.5N aqueous HCl (6×50 mL). The combined organic extract was _{washed with a saturated aqueous solution of NaHCO 3} (6×50 mL) and a saturated aqueous solution of NaCl (200 mL), _{dried over MgSO 4} , and concentrated under reduced pressure. The mixture was dissolved in EA (200 mL) and then recrystallized using hexane (50 mL) to obtain Chemical Formula 4 (white solid, 9 g, yield 50%, filtrate 4 g).

Example 2

After dissolving zinc dust (<10 μm, ≥98%) (2.6 g, 40 mmol) and cobalt bromide (295 mg, 1.35 mmol) in acetonitrile (27 mL), Bromobenzene (0.14 mL, 1.35 mmol) and trifluoromethanesulfonic acid (0.09 mL, 1.08 mmol) were added, and argon gas was charged for 5 minutes, followed by stirring at room temperature. Formula 3 3-Bromo-o-xylene (5.0 g, 27 mmol) was added dropwise within 5 minutes, followed by stirring at room temperature for 4 hours. The mixture was analyzed by LC/MS.

Example 3

After dissolving zinc dust (<10 μm, ≥98%) (3.5 g, 54 mmol) and cobalt(II) bromide (295 mg, 1.35 mmol) in acetonitrile (27 mL), Bromobenzene (0.14 mL, 1.35 mmol) and trifluoromethanesulfonic acid (0.09 mL, 1.08 mmol) were added, and argon gas was charged for 5 minutes, followed by stirring at room temperature. Formula 3 3-Bromo-o-xylene (5.0 g, 27 mmol) was added dropwise within 5 minutes, followed by stirring at room temperature for 4 hours. The mixture was analyzed by LC/MS.

Example 4

After dissolving zinc dust (<10 μm, ≥98%) (5.3 g, 81 mmol) and cobalt(II) bromide (590 mg, 2.69 mmol) in acetonitrile (43 mL), Bromobenzene (0.28 mL, 2.69 mmol) and trifluoromethanesulfonic acid (0.18 mL, 1.99 mmol) were added, and argon gas was charged for 5 minutes and stirred at room temperature. Formula 3 3-Bromo-o-xylene (5 g, 27 mmol) was added dropwise within 5 minutes, followed by stirring at room temperature for 4 hours, and formula 2 (4.24 g, 21 mmol) ) Was dissolved in acetonitrile (10 mL) and added dropwise within 30 minutes at 4°C. Then, it was cooled to -15°C, 2N aqueous HCl (100 mL) was added to the mixture, and the mixture was stirred for 30 minutes. The mixture was extracted, and the acidic extract (100 mL) was extracted using EA (2 x 50 mL). The combined organic extract was washed with a saturated aqueous solution of 0.5N aqueous HCl (100 mL) and NaCl (100 mL), _{dried over MgSO 4} and filtered with silica. The mixture was dissolved in EA (60 mL) and then recrystallized using hexane (15 mL) to obtain Chemical Formula 4 (white solid, 6 g, yield 63%, filtrate 795 mg).

Formula 4 : ¹ H-NMR (300 MHz, Chloroform- d ) δ 1.58 (s, 9H), 2.21 (s, 3H), 2.30 (s, 3H), 3.14 (s, 1H), 6.04 (s, 1H) , 6.95 (t, J = 1.2 Hz, 1H), 7.10-7.19 (m, 2H), 7.39-7.45 (m, 1H), 8.04 (d, J = 1.3 Hz, 1H).

Formula 4 : ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ 1.56 (s, 9H), 2.18 (s, 3H), 2.23 (s, 3H), 5.66 (d, J = 4.5 Hz, 1H), 5.81 (d, J = 4.9 Hz, 1H), 7.05 (d, J = 4.3 Hz, 2H), 7.13 (s, 1H), 7.24 (t, J = 4.7 Hz, 1H), 8.09 (s, 1H).

[ Manufacturing example 3] Of medetomidine (formula I) Produce

1) Preparation of Formula 5

Example 5

After dissolving Formula 4 (848 mg, 2.8 mmol) in methylene chloride (20 mL), thionyl chloride (0.3 mL, 4.2 mmol) was added dropwise at 0°C within 5 minutes, and then at room temperature. The mixture was stirred for 24 hours and concentrated under reduced pressure. Then, toluene (10 mL) was added to the mixture, followed by concentration under reduced pressure. Thereafter, the mixture was dissolved in tetrahydrofuran (20 mL), and then 1.3 M methylmagnesium chloride solution in THF (2.6 mL, 3.3 mmol) was added dropwise at 0° C. within 10 minutes, followed by stirring at room temperature for 2 hours. . Water (10 mL) was added to the mixture, 2N aqueous HCl (10 mL) was added dropwise, followed by stirring for 30 minutes, followed by washing. The organic extract was _{dried over Na 2} SO ₄ and concentrated under reduced pressure. The mixture was column (EA:Hx = 1:9 → 1:6) to obtain Chemical Formula 5 (yellow oil, 478 mg, yield 56%).

Formula 5 : ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 1.46 ( d , J = 7.1 Hz, 3H), 1.55 (s, 9H), 2.22 (s, 3H), 2.24 (s, 3H), 4.24-4.33 (m, 1H), 6.98 (m, 3H), 7.12 (t, J = 1.2 Hz, 1H), 8.08 (d, J = 1.3 Hz, 1H).

2) Preparation of Formula I

Example 6

After dissolving Formula 4 (1 g, 3.3 mmol) in tetrahydrofuran (20 mL), N,N-diisopropylethylamine (N,N-Diisoproylethylamine) (1.26 mL, 7.27 mmol) was added. , Methanesulfonyl chloride (0.28 mL, 3.63 mmol) was added dropwise at -10°C, followed by stirring at 0°C for 30 minutes. 3.0 M methylmagnesium chloride solution in THF (3.5 mL, 10.58 mmol) was added dropwise at -15°C within 5 minutes, followed by stirring at room temperature for 3 hours. 2N aqueous HCl (15 mL) was added to the mixture at 0°C, and MeOH (3 mL) was added, followed by stirring at room temperature for 1 hour. It was neutralized by dropwise addition of 5N aqueous NaOH, and EA (20 mL) was added, followed by extraction after a celite pad filter. The organic extract was _{dried over Na 2} SO ₄ and concentrated under reduced pressure. The mixture was column (EA = MC:MeOH = 10:1) to obtain formula I (yellow foam, 193 mg, yield 29%).

Example 7

After dissolving Formula 4 (1 g, 3.3 mmol) in tetrahydrofuran (20 mL), N,N-diisopropylethylamine (N,N-Diisoproylethylamine) (0.63 mL, 3.63 mmol) was added thereto. , Thionyl chloride (0.48 mL, 6.6 mmol) was added dropwise at -10°C, stirred at room temperature for 2 hours, and concentrated under reduced pressure. The mixture was dissolved in tetrahydrofuran (20 mL), and 3.0 M methylmagnesium chloride solution in THF (3.5 mL, 10.58 mmol) was added dropwise at -15° C. within 5 minutes, followed by stirring at room temperature for 3 hours. 2N aqueous HCl (15 mL) was added to the mixture at 0°C, and MeOH (3 mL) was added, followed by stirring at room temperature for 1 hour. It was neutralized by dropwise addition of 5N aqueous NaOH, and EA (20 mL) was added, followed by extraction after a celite pad filter. The organic extract was _{dried over Na 2} SO ₄ and concentrated under reduced pressure. The mixture was column (EA = MC:MeOH = 10:1) to obtain formula I.

Formula I : ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ 1.45(d, J = 7.1 Hz, 3H), 2.21(s, 3H), 2.23(s, 3H), 4.30(q, J = 7.1 Hz, 1H ), 6.69 (s, 1H), 6.90-6.98 (m, 3H), 7.49 (d, J = 1.1 Hz, 1H), 11.79 (s, 1H).

In the above, the present invention has been exemplarily described, and various modifications may be made without departing from the essential characteristics of the present invention to those of ordinary skill in the art to which the present invention pertains. Accordingly, the embodiments disclosed in the present specification are not intended to limit the present invention, but to explain the present invention, and the spirit and scope of the present invention are not limited by these embodiments. The scope of protection of the present invention should be interpreted by the following claims, and all technologies within the scope equivalent thereto should be construed as being included in the scope of the present invention.

Claims (10)

1) 1 H-imidazole-4-carbazole aldehyde (1 H -Imidazole-4-carbaldehyde ) a di-tert-butyl dicarbonate (Di- tert -butyl dicarbonate) and by tert represented by the formula (2) reaction -butyl 4 - formyl -1 H-imidazol-1-carboxylate (tert -butyl 4-formyl-1 H -imidazole-1-carboxylate) to prepare a compound in an acetonitrile solvent;

2) 3-Bromo-o-xylene was stirred with zinc (Zn) and cobalt (II) bromide for 4 hours at room temperature, and the following formula 3- Prepared as a compound represented by 1 and added to the compound represented by Formula 2 by using it to prepare a compound represented by Formula 4 below, in an acetonitrile solvent, the zinc (Zn): the 3-bromo-o- Preparing step characterized in that the molar ratio of xylene (3-Bromo-o-xylene) is 1.5:1 to 3:1:

3) the compound represented by Chemical Formula 4,
Reacting with methanesulfonyl chloride in the presence of thionyl chloride or diisopropylethylamine 3-1);
3-2) step of reacting in a tetrahydrofuran solvent for 2 to 3 hours at room temperature by adding methylmagnesium chloride at 0°C to -15°C; to prepare a compound represented by the following Formula 5 step;

4) preparing medetomidine represented by the following formula (I) by removing the tert -butyl group from the compound represented by Chemical Formula 5;
[Formula I]

Medetomidine manufacturing method comprising a delete delete delete delete delete delete delete delete delete