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Preparation method of belogliptin tocetate and its intermediate

A technology of intermediates and forms, which is applied in the field of preparation of belgliptin toxinate and intermediates thereof, can solve the problems of unfavorable safety and environmental protection, complicated operation, low total yield and the like, and is beneficial to industrial scale-up and preparation. The process is simple and the effect of improving the reaction yield

Active Publication Date: 2019-02-12
JIANGSU HANSOH PHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] (3) The main chain yield is low;
[0008] (4) isocyanation reaction productive rate is very low, and uses the trimethylsilyl cyanide of five times molar quantity and the silver perchlorate of three times molar quantity, and cost is high; Silver perchlorate is a heavy metal compound, explosive, not Conducive to safety and environmental protection;
[0010] Tetrahedron1993,49,5047, Tetrahedron Letters2002,43,5763 and Tetrahedron2008,64,67 have reported the Pauson-Khand cyclization reaction of formula (II) compound, but or use the expensive octacarbonyl dicobalt of equimolar equivalent, or use Molecular sieves are activated, and all require post-processing of column chromatography purification, which cannot be used to scale up production at all
[0011] Tetrahedron1993,49,5047 reported the synthetic method of formula (V) compound, but it needs complex operation such as column chromatography, and yield is lower
[0012] Patent WO2009094866 reports the conversion of compound VI to compound VII, but using five times the molar amount of trimethylsilyl cyanide and three times the molar amount of silver perchlorate, the cost is too high; and silver perchlorate is a heavy metal compound, explosive, Not conducive to safety and environmental protection; the above method also needs two post-processing of column chromatography purification
[0013] CN101318922A discloses a method for synthesizing side chain (2S, 4S)-1-(2-chloroacetyl)-4-fluoro-2-cyanopyrrolidine with Cbz protecting group, but the overall yield is lower (14.7% ); 20% Pd / C is used to remove Cbz, the yield is only 53%, and the cost is too large; 3 column chromatography purification processes are required
The method of above-mentioned document all is to first remove Boc with p-toluenesulfonic acid in acetonitrile, then adds triethylamine in dichloromethane to make acid-binding agent and completes the two-step reaction of chloroacetylation and completes, and record in above-mentioned document The raw material cost of the method is high, the operation is complicated, and column chromatography purification is required for post-treatment, which is not suitable for large-scale industrial production

Method used

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  • Preparation method of belogliptin tocetate and its intermediate
  • Preparation method of belogliptin tocetate and its intermediate
  • Preparation method of belogliptin tocetate and its intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0051] Example 1: Synthetic route of (3aS,6aR)-5-amino-N,N,5-trimethyl-hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide (compound VII) one:

[0052] Step 1: Preparation of tert-butyl 2-propenyl-2-propynylcarbamate

[0053]

[0054] Under nitrogen protection, cool to -5°C-0°C, add sodium hydride (118.4 g, 2.96 mol) into N,N-dimethylformamide (1550 mL). A solution of tert-butoxypropylene N-carbamate (310.0 g, 1.97 mol, Tetrahedron 2007, 63, 4472) in toluene (200 mL) was then added slowly. After adding room temperature and reacting for 3 hours, TLC detected the completion of the reaction, poured ice water (1.55L) to quench the reaction, and slowly added dilute hydrochloric acid (1M, 1.55L) dropwise to adjust to pH=7. Extracted with methyl tert-butyl ether (3100mL), washed the organic layer with water (750mL), dried the organic layer with anhydrous sodium sulfate, filtered, concentrated to remove the solvent, and distilled under reduced pressure to obtain 2-propenyl-2-propynyl...

Embodiment 2

[0077] Example 2: Synthetic route of (3aS,6aR)-5-amino-N,N,5-trimethyl-hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide (compound VII) two

[0078] Step 1: Preparation of allyl propargylamine

[0079]

[0080] Dissolve allylamine (287g, 5.03mol) in dichloromethane (900mL), cool to 5°C, slowly add propyne bromide (200g, 1.68mol) in dichloromethane (100mL) solution, after addition, warm to room temperature 25 ℃. After stirring for 3 hours, TLC monitored the completion of the reaction, slowly added sodium hydroxide solution (4N, 500mL), layered and separated, the upper layer was the organic layer, washed three times with water (500mL×3), the organic layer was in the lower layer, After separating the organic layer, add anhydrous sodium sulfate to dry, filter, remove dichloromethane under reduced pressure, and distill under reduced pressure to obtain allyl propargylamine (pale yellow oil, 64.5g).

[0081] 1 H-NMR (CDCl 3,400MHz)δ1.31(br,1H),2.23(s,1H),3.34(d,J=6Hz,2H),3.43(s...

Embodiment 3

[0100] Example 3: Synthesis of fluorine-containing side chain (2S,4S)-1-(2-chloroacetyl)-4-fluoro-2-cyanopyrrolidine (compound XIII)

[0101] Step 1: Preparation of (4S)-1-tert-butoxycarbonyl-4-fluoro-L-proline

[0102]

[0103] (4R)-1-tert-butoxycarbonyl-4-hydroxy-L-proline methyl ester (240g, 0.978mol), dichloromethane (1920mL) and triethylamine (408mL, 2.93mol) were added to the reaction In the bottle, adjust the temperature to 0-5°C, and add trifluoromethanesulfonic anhydride (414g, 1.47mol) dropwise. After the addition, triethylamine trihydrogen fluoride (356 mL, 1.99 mol) was added again, and the reaction was maintained at room temperature for 12 hours. Add water (2L) to quench the reaction, add dilute hydrochloric acid aqueous solution (1M, about 100mL) dropwise to adjust the pH to 5-6, stir for 5 minutes and then separate the liquids, and wash the organic phase with aqueous hydrochloric acid solution (1M, 500mL×1). Then, petroleum ether (2 L) and 10% potassium car...

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Abstract

The invention relates to a preparation method of besigliptin and its intermediate, and concretely relates to a preparation method of an azadicyclic compound besigliptin and its key intermediate. The preparation method comprises the following steps: carrying out step a, step b and step c to prepare the key intermediate compound of formula VII, carryin gout isomer resolution and protective group removal on the compound of formula VII to obtain a compound of formula XV, coupling the compound of formula XV with the compound of formula XIII, and salifying to form a target compound I. The preparation method has the advantages of substantial reduction of the production cost, simple production flow, yield increase, and suitableness for industrial production.

Description

technical field [0001] The present invention relates to the preparation method of belogliptin tocetate and its intermediate. Background technique [0002] Beragliptin (I) is an innovative compound DPP-IV inhibitor independently designed and developed by Hansoh Company. It has high activity, low toxicity, good stability and relatively long half-life, and has entered late-stage clinical trials . [0003] [0004] Patent WO2009094866 reported for the first time the synthesis of tociac acid belogliptin samples, but this route is only suitable for the synthesis of a small amount of medicine, and cannot achieve industrial scale-up at all. This route has the following disadvantages: [0005] (1) The source of raw materials for the main chain does not report the synthesis method, and the purchase price is expensive; [0006] (2) The main chain requires at least 3 column chromatography purification processes; [0007] (3) The main chain yield is low; [0008] (4) isocyanation...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D209/52C07D403/12C07D207/16
CPCY02P20/55
Inventor 王听中苏熠东王宝珠冯卫东匡远卓邹国勇陈玉龙杜祖银
Owner JIANGSU HANSOH PHARMA CO LTD