A synthetic method for rimonabant N-methyl analogue

Abstract

The invention discloses a method for synthesizing a rimonabant N-methyl analogue, using rimonabant carboxylic acid as a raw material, first performing an acyl chloride reaction, then reacting with N-methylhydroxylamine hydrochloride to generate rimonabant N-methylhydroxylamine, then reacting with p-toluenesulfonyl chloride to generate a rimonabant N-methyl-N-OTs compound, and finally reacting with piperidine to generate a rimonabant N-methyl analogue. After four-step reaction, the yield of rimonabant N-methyl analogue is 45%. The present invention adopts a novel N-N coupling strategy to achieve efficient synthesis of rimonabant N-methyl analogues, mild reaction conditions, no metal catalyst, simple process operation, and easy to achieve large-scale production.

Description

Technical Field

[0001] The invention relates to a method for synthesizing a rimonabant N-methyl analogue, and belongs to the technical field of chemical pharmacy. Background Art

[0002] Obesity is a nutritional metabolic disorder caused by the combined effects of genetic and environmental factors, and is the main cause of chronic diseases. Rimonabant is the first cannabinoid type 1 receptor (CB1) antagonist developed by Sanofi-Aventis in France for the treatment of obesity. It can significantly reduce body weight, reduce risk factors such as cardiovascular disease, and improve blood lipids, insulin resistance, and metabolic syndrome. [1][2] , rimonabant has a significant effect in treating obesity. However, subsequent studies have found that rimonabant can cause serious adverse reactions, including nausea, vomiting, diarrhea, dizziness, and mental confusion. [1][3] Christensen et al. conducted further research on rimonabant, and comprehensive analysis showed that rimonabant can cause serious adverse mental reactions, namely depression and anxiety. [4] Ultimately, Sanofi-Aventis withdrew its new drug application for rimonabant in the United States.

[0003] In addition, the existing method for constructing the rimonabant hydrazide structure is: rimonabant acyl chloride reacts with N-aminopiperidine to construct the hydrazide structure [5] However, this method can only construct hydrazide structures with hydrogen atoms on N, and due to the instability of the hydrazide structure, this method is not well tolerant to various functional groups, which increases the difficulty of modifying rimonabant and limits the structural diversity of this type of compound.

[0004] The rimonabant N-methyl analogue involved in the present invention uses rimonabant carboxylic acid, piperidine and the like as raw materials and applies the NN coupling strategy to synthesize a novel rimonabant N-methyl analogue. The present invention uses a new synthesis route to construct the hydrazide structure in rimonabant and further modify the hydrazide structure of rimonabant.

[0005] References

[0006] [1]Rissanen AM,Scheen AJ,Ziegler O, S.Effects of thecannabinoid-1receptor blocker rimonabant on weight reduction andcardiovascular risk factors in overweight patients:1-year experience from theRIO-Europe study[J].Lancet,2005,365(9468):1389-1397.

[0007] [2]Poirier B,Bidouard JP,Cadrouvele C,Marniquet X,Staels B,O’ConnorSE,Janiak P,HerbertJM.The anti-obesity effect of rimonabant is associatedwith an improved serum lipid profile[J].Diabetes,Obesity and Metabolism,2005,7(1):65-72.

[0008] [3]Després JP,Golay A, L,for the Rimonabant in Obesity–LipidsStudy Group.Effects of Rimonabant on Metabolic Risk Factors in OverweightPatients with Dyslipidemia[J].N Engl JMed,2005,353:2121-2134.

[0009] [4]Christensen R,Kristensen PK,Bartels EM,Bliddal H,Astrup A.Efficacyand safety of the weight-loss drug rimonabant:a meta-analysis ofrandomisedtrials[J].Lancet,2007,370(9600):1706-1713.

[0010] [5]Eduardo HV,Rodrigo AO,Samuel ES,Francisco HL.Synthesis,hypoglycemic activity and molecular modeling studies of pyrazole-3-carbohydrazides designed by a CoMFAmodel[J].European Journal ofMedicinalChemistry,2013,69:10-21 Summary of the invention

[0011] The purpose of the present invention is to overcome the deficiencies of the prior art, provide a method for synthesizing rimonabant N-methyl analogs, achieve further modification of the rimonabant hydrazide structure, and increase the structural diversity of such compounds. The present invention is improved on the basis of the above method, using rimonabant carboxylic acid as a raw material, first performing an acyl chloride reaction, then reacting with N-methylhydroxylamine hydrochloride to generate rimonabant N-methylhydroxylamine, then reacting with p-toluenesulfonyl chloride to generate rimonabant N-methyl-N-OTs compound, and finally reacting with piperidine to generate rimonabant N-methyl analogs ( Figure 1 The present invention uses the NN coupling strategy, has no metal catalyst, uses readily available raw materials, mild reaction conditions, and simple operation steps to synthesize the target product. The reaction is easy to scale up and realize large-scale production.

[0012] The synthetic method of rimonabant N-methyl analogue of the present invention comprises the following steps:

[0013] Step 1: Compound a was dissolved in DCM under nitrogen protection, DMF was added under stirring, and oxalyl chloride was added dropwise. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain rimonabant chloride compound b. The product was directly subjected to the next step of reaction without further purification;

[0014]

[0015] Step 2: N-methylhydroxylamine hydrochloride and NaHCO 3 The mixture was stirred in tetrahydrofuran under nitrogen protection, and a tetrahydrofuran solution of rimonabant chloride compound b was added dropwise. After the reaction was completed, the filtrate was filtered, evaporated to dryness, dissolved in ethyl acetate, washed with water and saturated brine, and anhydrous Na 2 SO 4 Drying, filtering, concentrating the filtrate under reduced pressure, and separating by column chromatography to obtain rimonabant N-methylhydroxylamine compound c;

[0016]

[0017] Step 3: Dissolve rimonabant N-methylhydroxylamine compound c and p-toluenesulfonyl chloride in DCM under nitrogen protection, add triethylamine, stir and react at 0°C, and naturally raise the temperature to room temperature. After the reaction is completed, filter, evaporate the filtrate to dryness under reduced pressure, add ethyl acetate to dissolve, wash with water and saturated brine, and anhydrous Na 2 SO 4 The mixture was dried and filtered, and the filtrate was concentrated under reduced pressure, and separated by column chromatography to obtain rimonabant N-methyl-N-OTs compound d;

[0018]

[0019] Step 4: Place rimonabant N-methyl-N-OTs compound d and KOAc in a container under nitrogen protection, add 1,4-dioxane, add piperidine under stirring, heat to react, filter after the reaction is completed, evaporate the filtrate under reduced pressure, add ethyl acetate to dissolve, wash with water and saturated brine, anhydrous Na 2 SO 4 The product was dried and filtered, and the filtrate was concentrated under reduced pressure. Rimonabant N-methyl analogue e was obtained by column chromatography.

[0020]

[0021] Furthermore, in step 1, the molar ratio of compound a to oxalyl chloride is 1:(2-5), and the amount of catalyst DMF used is 5-10 mol% of compound a; the reaction in step 1 needs to be carried out under nitrogen protection, the reaction time is 12-20 hours, and the reaction temperature is room temperature.

[0022] Further, in step 2, compound b is reacted with N-methylhydroxylamine hydrochloric acid and NaHCO 3 The molar ratio of N-methylhydroxylamine hydrochloric acid and NaHCO in step 2 is 1:1.5:4; 3 First, mix and stir to react for 1-2 hours, then slowly dropwise add the tetrahydrofuran solution of rimonabant acyl chloride compound b. The reaction time after dropwise addition is 12-17 hours, the reaction temperature is room temperature, and the reaction needs to be carried out under nitrogen protection.

[0023] Furthermore, in step 2, the eluent used for column chromatography separation is petroleum ether:ethyl acetate (V:V)=1:1.

[0024] Furthermore, in step 3, the molar ratio of compound c, p-toluenesulfonyl chloride and triethylamine is 1:1.5:1.5; in step 3, the reaction is first carried out at 0°C for 30 minutes, and then at room temperature for 12 hours, and the reaction needs to be carried out under nitrogen protection.

[0025] Furthermore, in step 3, the eluent used for column chromatography separation is petroleum ether:ethyl acetate (V:V)=10:1.

[0026] Furthermore, in step 4, the molar ratio of compound d, KOAc and piperidine is 1:2:2; the reaction temperature in step 4 is 70-90° C., the reaction time is 12 h, and the reaction needs to be carried out under nitrogen protection.

[0027] Furthermore, in step 4, the eluent used for column chromatography separation is petroleum ether:ethyl acetate (V:V)=3:1.

[0028] The outstanding substantive features and remarkable progress of the technical solution of the present invention are mainly reflected in:

[0029] ① This method uses a new synthetic route to first construct the N-methyl-N-OTs amide structure, and then uses piperidine as a nucleophile to construct the N-methyl hydrazide structure.

[0030] ② The N-methyl analogue of rimonabant synthesized by this method no longer has a hydrogen atom on its N, but can have a methyl group or other structure.

[0031] ③ This method no longer uses N-aminopiperidine as the raw material in the old method. Instead, more stable compounds such as piperidine and other amines can be used as nucleophiles to construct N-methylhydrazide structures, which improves the tolerance of the substrate, reduces the difficulty of modifying rimonabant, and increases the structural diversity of this type of compound.

[0032] The technical solution of the present invention is further described below in conjunction with the accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1 It is the synthesis route diagram of the present invention. DETAILED DESCRIPTION

[0034] The invention provides a method for synthesizing a rimonabant N-methyl analogue. Rimonabant carboxylic acid (a) is used as a raw material, and an acyl chlorination reaction is first performed, and then the reaction is performed with N-methylhydroxylamine hydrochloride to generate rimonabant N-methylhydroxylamine (c), and then the reaction is performed with p-toluenesulfonyl chloride to generate a rimonabant N-methyl-N-OTs compound (d), and finally the reaction is performed with piperidine to generate a rimonabant N-methyl analogue (e).

[0035] Example 1: Preparation of Compound B

[0036]

[0037] 1.91 g of rimonabant carboxylic acid (a) was added to a round-bottom flask, 15 mL of dichloromethane was added under nitrogen protection, stirring was started, 5 drops of DMF and 2.13 mL of oxalyl chloride were added dropwise, and the reaction was carried out at room temperature for 20 h. After the reaction was completed, the solvent and unreacted oxalyl chloride were removed by rotary evaporation to obtain a crude product b, which was directly subjected to the next step of reaction without further treatment.

[0038] Example 2: Preparation of Compound C

[0039]

[0040] 0.626 g N-methylhydroxylamine hydrochloride and 1.68 g NaHCO 3 Add to a round-bottom flask, add 15 mL of tetrahydrofuran under nitrogen protection, stir for 1 h, then slowly drop the tetrahydrofuran solution of compound b, react at room temperature for 17 h, filter after the reaction is completed, evaporate the filtrate to dryness, dissolve in ethyl acetate, wash with water and saturated brine, and wash with anhydrous Na 2 SO 4 The mixture was dried and filtered, and the filtrate was concentrated under reduced pressure. The mixture was separated by column chromatography using petroleum ether:ethyl acetate = 1:1 to obtain 1.59 g of product c with a yield of 78%.

[0041] Example 3: Preparation of Compound d

[0042]

[0043] 1.59g of compound c and 1.12g of p-toluenesulfonyl chloride were added to a round-bottom flask, 20mL of dichloromethane was added under nitrogen protection, stirring was started, triethylamine was added, and the reaction was carried out at 0°C for 30min and at room temperature for 12h. After the reaction was completed, the filtrate was filtered, evaporated to dryness, dissolved in ethyl acetate, washed with water and saturated brine, and anhydrous Na 2 SO 4 The mixture was dried and filtered, and the filtrate was concentrated under reduced pressure. The mixture was separated by column chromatography using petroleum ether:ethyl acetate = 10:1 to obtain 1.81 g of product d with a yield of 82%. 1 H NMR (400 MHz, CDCl 3 )δ7.83(d,J=7.7Hz,2H),7.40(s,1H),7.28–7.21(m,5H),7.16(d,J=8.4Hz,1H),6.97(d,J=7.7Hz,2H),3.62(s,3H),2.34(s,3H),2.00(s,3H); 13 C NMR (101 MHz, CDCl 3 )δ164.8,146.0,143.5,142.2,136.1,135.8,135.2,132.9,131.3,130.8,130. 6,130.5,129.8,129.5,129.1,128.1,127.0,119.0,41.4,21.9,9.3;IR(neat)ν max 1696,1585,1373,1192,1177,816,762cm -1; HRMS (ESI / [M+H] + )m / zcalcd.for:C 25 H 21 C l3 N 3 O 4 S + :564.0313,found[M+H] + :564.0314.

[0044] Example 4: Preparation of Compound e

[0045]

[0046] 1.81 g of product d and 0.628 g of KOAc were added to a round-bottom flask. Under nitrogen protection, 30 mL of 1,4-dioxane and 0.632 mL of piperidine were added, and the mixture was stirred at 80 °C for 12 h. After the reaction was completed, the mixture was filtered, the filtrate was evaporated to dryness, dissolved in ethyl acetate, washed with water and saturated brine, and anhydrous Na 2 SO 4 The mixture was dried and filtered, and the filtrate was concentrated under reduced pressure. The mixture was separated by column chromatography using petroleum ether:ethyl acetate = 3:1 to obtain 1.07 g of product e with a yield of 70%. 1 H NMR (400 MHz, CDCl 3 )δ7.31(s,1H),7.25–7.15(m,4H),7.00(d,J=8.0Hz,2H),3.04(s,3H),2.84(d,J=9.7Hz,2H),2. 60(t,J=11.2Hz,2H),2.04(s,3H),1.53(t,J=12.0Hz,3H),1.40–1.26(m,2H),1.01–0.91(m,1H); 13 C NMR (101 MHz, CDCl 3 )δ167.4,149.5,140.6,136.5,135.3,134.4,133.0,130.9,130.6,130.0,128.8,128.0,127.8,113.7,52.8,25.8,24.1,23.3,8.9; IR(neat)ν max 1650,1485,1444,1398,1361,1094,966,824,753cm -1 ; HRMS (ESI / [M+H] + )m / zcalcd.for C 23 H 24 35 Cl 3 N4 O + :477.1010,found[M+H] + :477.1011。

Claims

1. A method for synthesizing rimonabant N-methyl analogues, characterized in that: Rimonabant carboxylic acid a is used as a raw material, and chlorination reaction is first performed to obtain rimonabant acyl chloride compound b, and then N -Methylhydroxylamine hydrochloride reacts to form rimonabant N -Methylhydroxylamine c, then reacts with p-toluenesulfonyl chloride to produce rimonabant N -methyl- N -OTs compound d, and finally reacted with piperidine to generate rimonabant N -Methyl analog e; comprising the steps of: Step 1: Compound a was dissolved in DCM under nitrogen protection, DMF was added under stirring, and oxalyl chloride was added dropwise. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain rimonabant chloride compound b. The product was directly subjected to the next step of reaction without further purification; Step 2: N -Methylhydroxylamine hydrochloride and NaHCO3 were stirred in tetrahydrofuran under nitrogen protection for reaction, and then a tetrahydrofuran solution of rimonabant acyl chloride compound b was added dropwise. After the reaction was completed, the filtrate was filtered, evaporated to dryness, dissolved in ethyl acetate, washed with water and saturated brine, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure and separated by column chromatography to obtain rimonabant. N -Methylhydroxylamine compound c; Step 3: Add rimonabant N -Methylhydroxylamine compound c and p-toluenesulfonyl chloride were dissolved in DCM under nitrogen protection, triethylamine was added, and the reaction was stirred at 0°C. The temperature naturally rose to room temperature. After the reaction was completed, the filtrate was filtered, and the filtrate was evaporated to dryness under reduced pressure. Ethyl acetate was added to dissolve, washed with water and saturated brine, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. Rimonabant was separated by column chromatography. N -methyl- N -OTs compound d; Step 4: Add rimonabant N -methyl- N -OTs compound d and KOAc were placed in a container under nitrogen protection, 1,4-dioxane was added, piperidine was added under stirring, and the reaction was heated. After the reaction was completed, the filtrate was filtered, and the filtrate was evaporated to dryness under reduced pressure. Ethyl acetate was added to dissolve, washed with water and saturated brine, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain rimonabant by column chromatography. N -Methyl analogue e; The reaction route is as follows: 。 2. The synthesis method according to claim 1, characterized in that: In step 1, the molar ratio of compound a to oxalyl chloride is 1:(2-5), and the amount of catalyst DMF used is 5-10 mol% of compound a.

3. The synthesis method according to claim 1, characterized in that: The reaction in step 1 is carried out under nitrogen protection, the reaction time is 12-20 h, and the reaction temperature is room temperature.

4. The synthesis method according to claim 1, characterized in that: In step 2, compound b and N -The molar ratio of methylhydroxylamine hydrochloric acid and NaHCO3 is 1:1.5:

4.

5. The synthesis method according to claim 1, characterized in that: In step 2 N -Methylhydroxylamine hydrochloric acid and NaHCO3 are first mixed and stirred for reaction for 1-2 h, and then the tetrahydrofuran solution of rimonabant chloride compound b is slowly added dropwise. The reaction time after the addition is 12-17 h, the reaction temperature is room temperature, and the reaction needs to be carried out under nitrogen protection.

6. The synthesis method according to claim 1, characterized in that: In step 3, the molar ratio of compound c, p-toluenesulfonyl chloride and triethylamine is 1:1.5:1.

5.

7. The synthesis method according to claim 1, characterized in that: In step 3, the reaction is first carried out at 0°C for 30 minutes and then at room temperature for 12 hours. The reaction needs to be carried out under nitrogen protection.

8. The synthesis method according to claim 1, characterized in that: In step 4, the molar ratio of compound d, KOAc and piperidine is 1:2:

2.

9. The synthesis method according to claim 1, characterized in that: In step 4, the reaction temperature is 70-90° C., the reaction time is 12 h, and the reaction needs to be carried out under nitrogen protection.

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