Preparation method and application of vibron key intermediate

Abstract

The invention discloses a preparation method of a vibron key intermediate with a structural formula II and application of the vibron key intermediate in preparation of vibron. The preparation method comprises the following steps: A, taking a compound shown as a structural formula III as a starting raw material, and carrying out acylation reaction on the compound and a sulfonyl chloride compound in the presence of alkali to obtain a compound shown as a structural formula IV; b, in the presence of alkali, reacting the compound as shown in the structural formula IV with the compound as shown in the structural formula V to obtain a compound as shown in a structural formula VI; c, decarboxylating the compound shown in the structural formula VI in the presence of alkali, removing a protecting group in the presence of acid, and cyclizing to obtain a compound shown in a structural formula VII; and D, reducing the compound as shown in the structural formula VII into the vibron key intermediate as shown in the structural formula II under the action of a metal catalyst and hydrogen. In the imgabs0 #, R1 is selected from a methylsulfonyl group or a phenylsulfonyl group; and R2 is selected from C1-C2 alkyl or benzyl.

Description

Technical Field

[0001] The invention belongs to the field of organic chemistry, and specifically relates to a preparation method of a key intermediate of Viberon and application of the key intermediate in the preparation of Viberon. Background Art

[0002] Vibegron (CAS: 1190389-15-1), also known as Vibegron, trade name Chemical name: (S)-N-(4-(((2S,5R)-5-((R)-hydroxy(phenyl)methyl)pyrrolidine)methyl)phenyl)-4-carbonyl-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide, with the structural formula shown in I.

[0003]

[0004] Vibegron is a β3-adrenergic receptor (β3-AR) agonist developed by Merck for the treatment of overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency and frequency in adults. A large number of studies have shown that this product has few adverse reactions, high efficacy and good tolerability, and can provide a new treatment option for OAB patients.

[0005] PCT patent application with publication number WO2013062881A1 (publication date May 2, 2013) discloses a method for preparing Vibelong (I) by coupling compound i-11 and compound i-12.

[0006]

[0007] The key intermediate of the above structural formula i-11 is prepared by the following route:

[0008] Compound i-5 is protected by a protective group to obtain compound i-6, which is then oxidized by TEMPO and bleached by NaClO to obtain compound i-7. Compound i-7 is then subjected to a HWE coupling reaction with compound a-4 to obtain unsaturated ketone i-8. Compound i-8 is then reduced to compound i-9 by palladium carbon and hydrogen. Under acidic conditions, compound i-9 is cyclized to an imine and the protective group is removed to generate compound i-10. Compound i-10 is converted into the key intermediate i-11 of Vibelon under reduction with platinum aluminum oxide and hydrogen.

[0009]

[0010] The problems with the above route are: first, compound i-6 is oxidized to compound i-7 by TEMPO, which requires bleaching with sodium hypochlorite (NaClO) solution that is difficult to handle; at the same time, the sodium hypochlorite solution must be slowly added below 0°C, and if the conditions are not well controlled, it is easy to over-oxidize and generate carboxylic acid. Secondly, the HWE coupling reaction of this route uses a compound of structural formula a-4, which will produce phosphine-containing waste, which is very unfavorable for production and environmental protection; and the synthesis process of this compound is complicated. Thirdly, this route has many steps and involves many protecting groups. Not only are the protection and deprotection reactions cumbersome, but also with the removal of the protecting groups, the atom economy of the entire route is poor and the atom utilization rate is low, which is not conducive to reducing costs and does not meet the purpose of green chemistry.

[0011] In summary, it is urgent to develop a new method for preparing key intermediates of Vibelone that is short in route, low in cost, environmentally friendly, and does not involve phosphine intermediates. Summary of the invention

[0012] In view of the deficiencies of the prior art, the present invention provides a new preparation method of a key intermediate of Viberon, and provides the application of the preparation method in the preparation of Viberon. The new method for preparing a Viberon intermediate provided by the present invention has fewer steps, avoids the use of high-cost and difficult-to-handle phosphine-containing raw materials, can reduce production costs, and makes the preparation of Viberon more environmentally friendly and efficient.

[0013] To this end, the present invention adopts the following technical solution:

[0014] A method for preparing a key intermediate of Vibelong of structural formula II,

[0015]

[0016] The steps include:

[0017] A. Using the compound of formula III as the starting material, in the presence of a base, acylation reaction is carried out with a sulfonyl chloride compound to obtain a compound of formula IV,

[0018]

[0019] Among them, R 1 is selected from methylsulfonyl or phenylsulfonyl;

[0020] B. In the presence of a base, the compound of formula IV reacts with the compound of formula V to obtain a compound of formula VI,

[0021]

[0022] Among them, R 2 Selected from C 1 -C 2Alkyl or benzyl;

[0023] C. The compound of formula VI is first decarboxylated in the presence of a base, and then the protecting group is removed and cyclized simultaneously in the presence of an acid to obtain a compound of formula VII.

[0024]

[0025] D. The compound of structural formula VII is reduced to the key intermediate of Vibelon of structural formula II under the action of a metal catalyst and hydrogen.

[0026]

[0027] Preferably, the R 1 It is methylsulfonyl.

[0028] Preferably, the R 2 It is methyl or ethyl.

[0029] Preferably, in the step A, the molar ratio of the compound of formula III to the sulfonyl chloride compound is 1:1 to 1:6, more preferably 1:1 to 1:2.

[0030] Preferably, in step A, the base is selected from triethylamine, diisopropylethylamine, diisopropylamine or sodium carbonate, more preferably triethylamine.

[0031] Preferably, in step A, the reaction solvent is selected from tetrahydrofuran, acetonitrile, ethyl acetate, dichloromethane, N,N-dimethylformamide, DMSO or toluene, more preferably dichloromethane.

[0032] Preferably, in step A, the reaction temperature is 25 to 80°C, more preferably 25 to 40°C.

[0033] Preferably, in step B, the molar ratio of the compound of formula IV to the compound of formula V is 1:1 to 1:5, more preferably 1:1 to 1:2.

[0034] Preferably, in step B, the base is selected from magnesium ethoxide, sodium ethoxide, sodium methoxide, potassium tert-butoxide, cesium carbonate or sodium carbonate, more preferably magnesium ethoxide.

[0035] Preferably, in step B, the reaction solvent is selected from tetrahydrofuran, acetonitrile, ethyl acetate, dichloromethane, N,N-dimethylformamide, DMSO or toluene, more preferably toluene.

[0036] Preferably, in step B, the reaction temperature is -20 to 25°C, more preferably 0°C.

[0037] Preferably, in step C, the base is selected from saturated sodium carbonate solution, saturated sodium bicarbonate solution, 30% w / w sodium hydroxide solution, more preferably 30% w / w sodium hydroxide solution.

[0038] Preferably, in step C, the acid is selected from 15% w / w hydrochloric acid isopropanol solution, 15% w / w hydrochloric acid ethanol solution or 15% w / w hydrochloric acid aqueous solution, and most preferably is 15% w / w hydrochloric acid isopropanol solution.

[0039] Preferably, in step C, the molar ratio of compound VI to acid is 1:1 to 1:20, more preferably 1:10 to 1:12.

[0040] Preferably, the reaction temperature of step C is 25-80°C, more preferably 25-40°C.

[0041] Preferably, in step D, the metal catalyst is selected from 5% Pd / C, 5% Pt / C, 5% Pt / Al 2 O 3 or 5% Raney Nickel, more preferably 5% Pt / Al 2 O 3 .

[0042] Preferably, in step D, the reaction solvent is selected from tetrahydrofuran, methanol, ethanol, acetonitrile, dichloromethane or toluene, more preferably tetrahydrofuran.

[0043] Preferably, the reaction temperature of step D is 25-80°C, more preferably 25-40°C.

[0044] In the above step B, the compound of structural formula V can be prepared from p-nitrobenzeneacetyl chloride and a malonic acid monoester (such as methyl malonate, ethyl malonate or benzyl malonate) according to conventional methods in the art.

[0045] Using the compound of structural formula III as the starting material, the synthesis route of the key intermediate of Vibelone of structural formula II of the present invention is as follows:

[0046]

[0047] Another object of the present invention is to provide the use of the method for preparing the key intermediate of Viberon of the above structural formula II in the preparation of Viberon; that is, the key intermediate of Viberon of the structural formula II is prepared by the above method, and then reacted with the compound of the structural formula VIII to obtain Viberon of the structural formula I;

[0048]

[0049] The reaction of the compound of the above structural formula II and the compound of the structural formula VIII can be carried out according to the process conditions disclosed in the prior art, such as the reaction conditions disclosed in the PCT patent application with publication number WO2013062881A1 (publication date May 2, 2013).

[0050] The preparation method of the key intermediate of Vibelone of structural formula II provided by the present invention has a short route, uses cheap and readily available raw materials, does not use phosphine-containing raw materials, and is environmentally friendly. In addition, the preparation method of the present invention has mild process conditions and is suitable for industrial production. DETAILED DESCRIPTION

[0051] The present invention is described below with reference to specific examples. It will be appreciated by those skilled in the art that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention in any way.

[0052] The experimental methods in the following examples are conventional methods unless otherwise specified. The raw materials, reagents, etc. used in the following examples are commercially available products unless otherwise specified.

[0053] Example 1 Preparation of the compound of formula IV-1

[0054]

[0055] 1.1 Add 10.75g (35mmol) of the compound of formula III and 5ml of triethylamine to the reaction flask, slowly drop 4.79g (42mmol) of methylsulfonyl chloride, and then add 30ml of dichloromethane as solvent. React overnight at room temperature. After TLC detection, remove the excess triethylamine with a rotary evaporator, add 20ml × 3 of water to fully extract, combine the organic phases, and distill off the solvent to obtain the compound of formula IV-1 (12.13g, yield 90%).

[0056] 1.2 Add 9.21g (30mmol) of the compound of formula III and 4.5ml of diisopropylethylamine to the reaction flask, slowly drop 4.10g (36mmol) of methylsulfonyl chloride, and then add 30ml of tetrahydrofuran as solvent. React overnight at room temperature. After TLC detection shows that the reaction is complete, remove the excess diisopropylethylamine with a rotary evaporator, add 20ml×3 of ethyl acetate and 20ml×3 of water to fully extract, combine the organic phases, and distill off the solvent to obtain a compound of formula IV-1 (9.81g, yield 85%).

[0057] 1 H-NMR (400M, DMSO-d 6): 7.43-7.11(5H,m), 5.04(1H,d), 4.44-4.42(1H,m), 4.15-3.96(2H,d), 3.03(3H,s), 1.47(9H,s), 1.45(6H,s).

[0058] Example 2 Preparation of the compound of formula IV-2

[0059]

[0060] 2.1 Add 9.21g (30mmol) of the compound of formula III and 5ml of triethylamine to the reaction flask, slowly drop 5.29g (30mmol) of benzenesulfonyl chloride, and then add 30ml of dichloromethane as solvent. React overnight at room temperature. After TLC detection, remove the excess triethylamine with a rotary evaporator, add 20ml × 3 of water to fully extract, combine the organic phases, and distill off the solvent to obtain a compound of formula IV-2 (11.93g, yield 89%).

[0061] 1 H-NMR (400M, DMSO-d 6 ):7.92(2H,d),7.73-7.65(3H,m),7.45-7.30(3H,m)7.11(2H,d),5.11( 1H,m),4.47(1H,m),3.90(1H,m),3.70(1H,m),1.47(9H,s),1.42(6H,s).

[0062] Example 3 Preparation of the compound of formula VI-1

[0063]

[0064] 3.1 Add 13.48g (35mmol) of the compound of formula IV-1 prepared according to the method described in Example 1 and 12.44g (52.5mmol) of the compound of formula V-1 to the reaction flask in sequence, then add 20ml of toluene as solvent, and slowly drop the pre-prepared toluene solution of magnesium ethoxide (35ml, 1M). React overnight under ice bath, after TLC detection, add 30ml×3 of water for full extraction, combine the organic phases, and distill to remove the solvent to obtain the compound of formula VI-1 (16.94g, yield 92%).

[0065] 3.2 Add 14.63g (38.0mmol) of the compound of formula IV-1 prepared according to the method described in Example 1 and 14.41g (60.8mmol) of the compound of formula V-1 to the reaction flask in sequence, add 15ml of tetrahydrofuran as solvent, and then add a pre-prepared tetrahydrofuran solution of sodium methoxide (38ml, 1M). React overnight under ice bath. After TLC detection, add 30ml×3 of water for full extraction, combine the organic phases, and distill to remove the solvent to obtain the compound of formula VI-1 (17.59g, yield 88%).

[0066] 1 H-NMR (400M, DMSO-d 6 ): 7.72-7.33(5H,m), 7.15-6.90(4H,m), 4.97(1H,d), 4.42(1H,q), 4.31-4.25(2H,m), 3.80-3.78(1H,m), 3 .76(1H,t), 3.44-3.42(1H,m), 2.67-2.64(1H,m), 2.31-2.29(1H,m), 1.50(6H,s),1.47(9H,s), 1.23(3H,s)

[0067] Example 4 Preparation of the compound of formula VI-2

[0068]

[0069] 4.1 Add 14.30g (32mmol) of the compound of formula IV-2 prepared according to the method described in Example 2 and 11.38g (48mmol) of the compound of formula V-2 to the reaction flask in sequence, then add 20ml of toluene as solvent, and slowly drop the pre-prepared toluene solution of magnesium ethoxide (35ml, 1M). React overnight under ice bath, after TLC detection, add 30ml×3 of water for full extraction, combine the organic phases, and distill to remove the solvent to obtain the compound of formula VI-1 (15.15g, yield 90%).

[0070] 4.2 Add 15.65g (35.0mmol) of the compound of formula IV-2 prepared according to the method described in Example 2 and 12.44g (52.5mmol) of the compound of formula V-2 to the reaction flask in sequence, add 15ml of tetrahydrofuran as solvent, and then add a pre-prepared tetrahydrofuran solution of sodium methoxide (38ml, 1M). React overnight under ice bath. After TLC detection, add 30ml×3 of water for full extraction, combine the organic phases, and distill to remove the solvent to obtain the compound of formula VI-1 (15.65g, yield 85%).

[0071] 1 H-NMR (400M, DMSO-d 6 ): 7.72(2H,d), 7.45-6.90(7H,m), 4.99(1H,d), 4.43-4.41(1H,m), 3.80-3.76(2H,m), 3.61 (3H,s), 3.44-3.42(1H,m), 2.67-2.64(1H,m), 2.31-2.29(1H,m), 1.48(6H,s), 1.46(9H,s).

[0072] Example 5 Preparation of Compound F

[0073]

[0074] 5.1 Add 15.78g (30.0mmol) of the compound of formula VI-1 prepared according to the method described in Example 3, 15ml of tetrahydrofuran and 30ml of 30% w / w sodium hydroxide solution into the reaction flask in sequence. Stir the reaction at 60°C overnight, monitor the reaction by TLC, and after the raw materials are completely consumed, add 150ml of 15% w / w hydrochloric acid isopropanol solution and react at 60°C for 24 hours. Adjust the pH of the reaction system to 8 with saturated sodium bicarbonate solution, add 30ml×3 of ethyl acetate to fully extract, combine the organic phases, dry with anhydrous sodium sulfate, filter, wash the filter cake with 10ml of ethyl acetate, combine the organic phases, and distill to remove the solvent to obtain the compound of formula VII (8.37g, yield 91%).

[0075] 5.2 Add 15.78g (30.0mmol) of the compound of formula VI-2 prepared according to the method described in Example 4, 20ml of tetrahydrofuran and 35ml of 30% w / w sodium hydroxide solution into the reaction flask in sequence. Stir the reaction at 60°C for 6 hours, monitor the reaction by TLC, and after the raw materials are completely consumed, add 170ml of 15% w / w hydrochloric acid ethanol solution, react at 65°C for 24 hours, and after the reaction is complete by TLC monitoring, slowly drop saturated sodium carbonate solution, stop dropping when no bubbles appear (pH≈8 at this time), add 30ml×3 of ethyl acetate to fully extract, combine the organic phases, dry with anhydrous sodium sulfate, filter, wash the filter cake with 10ml of ethyl acetate, combine the organic phases, and distill to remove the solvent to obtain the compound of formula VII (7.70g, yield 91%).

[0076] 1 H-NMR (400M, DMSO-d 6): 7.47-7.28(9H,m),5.07-5.05(1H,m),4.74(1H,d),4.23(1H,m),3.67-3.31(2H,m),2.89(1H,m),2.78(1H,m),1.96(1H,m),1.86(1H,m).

[0077] Example 6 Preparation of Compound of Formula II

[0078]

[0079] 6.1 Add 19.74 g (70.0 mmol) of the compound of formula VII prepared according to the method described in Example 3 and 0.98 g of 5% Pt / Al 2 O 3 Then add 50 ml of tetrahydrofuran as solvent, hydrogen pressure 0.6 MPa, react overnight at room temperature, after TLC detection, remove Pt / Al by filtration. 2 O 3 , the reaction solvent was removed by rotary evaporator to obtain a compound of formula II (18.75 g, yield 95%)

[0080] 6.2 Add 22.94 g (74.0 mmol) of the compound of formula VII prepared according to the method described in Example 3 and 1.15 g of 5% Pt / C into a hydrogenation reactor, then add 20 ml of methanol as a solvent, hydrogen pressure of 0.4 MPa, react overnight at 40°C, and after TLC detection of the completion of the reaction, filter out Pt / C, and use a rotary evaporator to remove the reaction solvent to obtain a compound of formula II (18.78 g, yield 90%).

[0081] 1 H NMR (400MHz, d 6 -DMSO):7.27(4H,m),7.17(1H,m),6.81(2H,d),6.45(2H,d),5.07(1H,s),4.75(2H,s),4.1 8(1H,d),3.05(2H,m),2.47(1H,dd),2.40(1H,dd),1.53(1H,m),1.34(1H,m),1.22(2H,m).

[0082] The preparation of Vibelone from the compound of structural formula II can be carried out according to the reaction conditions already described in the prior art, such as Example 3 (EXAMPLE 3) of PCT patent application with publication number WO2013 / 062881A1.

Claims

1. A method for preparing a key intermediate of Vibelong of structural formula II, The steps include: A. Using the compound of formula III as the starting material, in the presence of a base, acylation reaction is carried out with a sulfonyl chloride compound to obtain a compound of formula IV, in, R 1 is selected from methylsulfonyl or phenylsulfonyl; B. In the presence of a base, the compound of formula IV reacts with the compound of formula V to obtain a compound of formula VI, Among them, R 2 Selected from C1-C2 alkyl or benzyl; C. The compound of formula VI is first decarboxylated in the presence of a base, and then the protecting group is removed and cyclized simultaneously in the presence of an acid to obtain a compound of formula VII. D. The compound of structural formula VII is reduced to the key intermediate of Vibelon of structural formula II under the action of a metal catalyst and hydrogen.

2. The preparation method according to claim 1, characterized in that: The R 1 is methylsulfonyl; Preferably, the R 2 It is methyl or ethyl.

3. The preparation method according to claim 1 or 2, characterized in that: In the step A, the molar ratio of the compound of formula III to the sulfonyl chloride compound is 1:1 to 1:6, more preferably 1:1 to 1:2; Preferably, in step A, the base is selected from triethylamine, diisopropylethylamine, diisopropylamine or sodium carbonate, more preferably triethylamine; Preferably, in step A, the reaction solvent is selected from tetrahydrofuran, acetonitrile, ethyl acetate, dichloromethane, N,N-dimethylformamide, DMSO or toluene, more preferably dichloromethane; Preferably, in step A, the reaction temperature is 25 to 80°C, more preferably 25 to 40°C.

4. The preparation method according to any one of claims 1 to 3, characterized in that In the step B, the molar ratio of the compound of formula IV to the compound of formula V is 1:1 to 1:5, more preferably 1:1 to 1:

2.

5. The preparation method according to any one of claims 1 to 4, characterized in that: In the step B, the base is selected from magnesium ethoxide, sodium ethoxide, sodium methoxide, potassium tert-butoxide, cesium carbonate or sodium carbonate, more preferably magnesium ethoxide; Preferably, in step B, the reaction solvent is selected from tetrahydrofuran, acetonitrile, ethyl acetate, dichloromethane, N,N-dimethylformamide, DMSO or toluene, more preferably toluene; Preferably, in step B, the reaction temperature is -20 to 25°C, more preferably 0°C.

6. The preparation method according to any one of claims 1 to 5, characterized in that In the step C, the base is selected from saturated sodium carbonate solution, saturated sodium bicarbonate solution, 30% w / w sodium hydroxide solution, more preferably 30% w / w sodium hydroxide solution; Preferably, in step C, the acid is selected from 15% w / w hydrochloric acid isopropanol solution, 15% w / w hydrochloric acid ethanol solution or 15% w / w hydrochloric acid aqueous solution, and most preferably 15% w / w hydrochloric acid isopropanol solution; Preferably, in step C, the molar ratio of compound VI to acid is 1:1 to 1:20, more preferably 1:10 to 1:

12.

7. The preparation method according to any one of claims 1 to 6, characterized in that The reaction temperature of step C is 25-80°C, more preferably 25-40°C.

8. The preparation method according to any one of claims 1 to 7, characterized in that In the step D, the metal catalyst is selected from 5% Pd / C, 5% Pt / C, 5% Pt / Al2O3 or 5% Raney nickel, more preferably 5% Pt / Al2O3.

9. The preparation method according to any one of claims 1 to 8, characterized in that: In the step D, the reaction solvent is selected from tetrahydrofuran, methanol, ethanol, acetonitrile, dichloromethane or toluene, more preferably tetrahydrofuran; Preferably, the reaction temperature of step D is 25-80°C, more preferably 25-40°C.

10. Use of the method for preparing the key intermediate of Viberon of structural formula II according to any one of claims 1 to 9 in preparing Viberon; comprising preparing the key intermediate of Viberon of structural formula II by the method of any one of claims 1 to 9, and then reacting it with a compound of structural formula VIII to obtain Viberon of structural formula I;

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