A preparation method of Omarigliptin

Abstract

The present invention relates to omarigliptin, and more specifically, to a novel method for preparing istradefylline. The method comprises the following steps: a coupling reaction of compound Ia with TMS acetylene to obtain intermediate Ib; a bromination reaction of intermediate Ic under the action of NBS to obtain intermediate Id; a substitution reaction of intermediate Id with tert-butyl carbamate under the action of potassium tert-butoxide to obtain intermediate Ie; a reaction of intermediate Ie with paraformaldehyde to obtain intermediate If; a cycloaddition reaction of intermediate If with intermediate Ib to obtain key intermediate Ig; an asymmetric catalytic hydrogenation reduction of intermediate Ig to obtain intermediate Ih; and deprotection of intermediate Ih in a hydrochloric acid and ethyl acetate system to obtain the final product. The method has a short route, simple operation, mild conditions, high reaction yield, avoids the use of dangerous and highly toxic substances and regulated hazardous chemicals, is environmentally friendly, and is easy to industrialize.

Description

Technical Field

[0001] The present invention relates to a method for synthesizing Omarigliptin, and in particular to a new method for preparing Omarigliptin. Background Art

[0002] Omarigliptin is a novel, long-acting dipeptidyl peptidase-4 (DPP-4) inhibitor developed by Merck. It is primarily used to treat type 2 diabetes and requires only a once-weekly dose, significantly improving patient compliance and therapeutic efficacy. By inhibiting DPP-4, omarigliptin increases levels of the gut hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), thereby promoting insulin secretion and lowering blood sugar levels. On September 28, 2015, Japan approved Merck's omarigliptin for the treatment of type 2 diabetes under the trade name Arizev, available in 25mg and 125mg tablets. Omarigliptin, CAS number: 1226781-44-7; Chemical name: (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-(methylsulfonyl)pyrrolo[3,4-c]pyrazol-5(2H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine; Molecular formula: C 17 H 20 F2N4O3S; molecular weight: 398.427, structural formula is shown below.

[0003]

[0004] By searching the patent literature, we know that patent WO2010056708 reports the synthesis route of Omarigliptin. It is shown below:

[0005]

[0006] The starting materials for this route are difficult to obtain and are expensive to purchase. The synthesis route involves hazardous chemicals such as Grignard reagent, iodine, and regulated substances such as sulfuric acid. At the same time, the synthesis process involves multiple chiral control reactions, and the steps are cumbersome, resulting in low product yields and poor quality, which is not conducive to environmentally friendly industrial production requirements. Summary of the Invention

[0007] The technical problem to be solved by the present invention is to provide a novel method for preparing omarigliptin, which overcomes the drawbacks of existing omarigliptin preparation methods, such as limited raw material availability, high cost, low yield, and cumbersome chirality control steps. The preparation method of the present invention features readily available raw materials, high yield, a novel route, and is suitable for industrial production. The present invention provides a novel method for synthesizing omarigliptin, employing the following technical route:

[0008]

[0009] The steps are as follows:

[0010] S1: Synthesis of compound Ib

[0011] Dissolve compound Ia in toluene solution, add copper acetate, sodium carbonate, TMS acetylene, heat and stir to react, and obtain compound Ib;

[0012] S2: Synthesis of Compound Id

[0013] Compound Ic was dissolved in acetonitrile solution, NBS was added, and the mixture was heated and stirred to obtain compound Id;

[0014] S3: Synthesis of Compound Ie

[0015] Compound Id was dissolved in 2-methyltetrahydrofuran solution, potassium tert-butoxide and tert-butyl carbamate were added, and the mixture was heated and stirred to react to obtain compound Ie;

[0016] S4: Synthesis of Compound If

[0017] Dissolve compound Ie in methanol solution, add paraformaldehyde, and stir at room temperature to react to obtain compound If;

[0018] S5: Synthesis of Compound Ig

[0019] Dissolve compound If in TFE (2,2,2-trifluoroethanol) solution, add sodium carbonate and compound Ib, and heat and stir to react to obtain compound Ig;

[0020] S6: Synthesis of Compound Ih

[0021] Compound Ig was dissolved in isopropanol solution, sodium carbonate and (S)-Ru(OAc)2(BINAP) were added, and hydrogen was introduced to obtain compound Ih;

[0022] S7: Synthesis of Omarigliptin

[0023] Compound Ih was dissolved in ethyl acetate and hydrochloric acid solution, stirred for reaction, and then subjected to a pulping process to obtain Omarigliptin.

[0024] Wherein, in step S5, the molar ratio of compound If to compound Ib is 1:(1.0-1.2), and the reaction temperature is 60-70°C.

[0025] In step S6, the asymmetric reduction catalyst is (S)-Ru(OAc)2(BINAP), and the molar ratio of compound Ig to (S)-Ru(OAc)2(BINAP) is 1:(0.1-0.2).

[0026] Beneficial effects

[0027] 1. The innovation of the present invention lies in: the present invention adopts completely different starting materials and a new synthetic route from the prior art. The key point of the present invention is: the open-ring compound If is subjected to a Diels-Alder reaction with compound Ib to obtain the closed-ring compound Ig, and further an asymmetric reaction is carried out using a (S)-Ru(OAc)2(BINAP) chiral catalyst to cleverly obtain the S-type compound Ih. The target product is directly obtained without chiral resolution. Compared with the prior art route, this method has a shorter reaction route and a higher yield.

[0028] 2. The present invention provides a novel method for preparing Omarigliptin, which avoids the supervision of highly toxic hazardous chemicals, harsh reaction conditions, and the drawbacks of expensive starting materials, greatly simplifies the chiral control steps, and reduces harm to humans and the environment as well as production costs.

[0029] 2. The raw materials of the method of the present invention are cheap and easily available, the reaction conditions are mild, and the atom economy is good. DETAILED DESCRIPTION

[0030] In order to make the purpose, technical solutions and advantages of the present invention more clearly understood, the following specific examples further illustrate the present invention in detail. The experimental methods in the present invention are all conventional methods unless otherwise specified. It should be understood that the specific examples described herein are only used to illustrate the present invention and are not intended to limit the present invention.

[0031] The progress of the reaction of the present invention can be monitored by conventional monitoring methods in the art (such as TLC, HPLC or NMR), and the disappearance of the starting material is generally regarded as the reaction endpoint.

[0032] The chemical reagents and raw materials of the present invention were purchased from San Chemical Technology (Shanghai) Co., Ltd.

[0033] Example 1:

[0034] Example 1 of the present invention provides a method for preparing intermediate Ib, and its synthetic route is as follows:

[0035]

[0036] Specifically prepared by the following method:

[0037] Compound Ia (10 g, 53.41 mmol) was dissolved in toluene (100 mL), and TMS acetylene (5.77 g, 58.76 mmol), sodium carbonate (11.32 g, 106.83 mmol), and copper acetate (970.18 mg, 5.34 mmol) were added. The mixture was stirred at 60°C for 8 h and detected by TLC until compound Ia disappeared. The solvent was removed under reduced pressure, and ethyl acetate (100 mL*3) and water (200 mL) were added. The mixture was separated and extracted to give 11 g of compound Ib in a yield of 97.49%. ESI-MS (m / z): 212.1.

[0038] Example 2:

[0039] Example 2 of the present invention provides a method for preparing intermediate Id, and its synthetic route is as follows:

[0040]

[0041] Specifically prepared by the following method:

[0042] Compound Ic (15 g, 96.07 mmol) was dissolved in acetonitrile (100 mL), and NBS (18.81 g, 105.68 mmol) was added portionwise. The mixture was reacted at 60°C for 8 h. The reaction temperature was lowered to room temperature and the mixture was detected by TLC until compound Ic disappeared. The solvent was removed under reduced pressure, and ethyl acetate (100 mL*3) and saturated aqueous ammonium chloride solution (200 mL) were added. The mixture was separated and extracted to obtain 21 g of compound Id in a yield of 93.00%. ESI-MS (m / z): 235.0.

[0043] Example 3:

[0044] Example 3 of the present invention provides a method for preparing intermediate Ie, and its synthetic route is as follows:

[0045]

[0046] Specifically prepared by the following method:

[0047] Compound Id (21 g, 89.35 mmol) was dissolved in 2-methyltetrahydrofuran (100 mL), and potassium tert-butoxide (20.05 g, 178.70 mmol) and tert-butyl carbamate (11.51 g, 98.29 mmol) were added. The mixture was reacted at 70°C for 12 h. The reaction mixture was cooled to room temperature, dried, and slurried with ethyl acetate to obtain 23 g of compound Ie with a yield of 94.89%. ESI-MS (m / z): 272.1.

[0048] Example 4:

[0049] Example 4 of the present invention provides a method for preparing an intermediate If, ​​and its synthetic route is as follows:

[0050]

[0051] Specifically prepared by the following method:

[0052] Compound Ie (23 g, 84.79 mmol) was dissolved in acetonitrile (100 mL), and paraformaldehyde (5.09 g, 169.58 mmol) was added. The mixture was reacted at 60°C for 8 h, cooled to room temperature, and dried to obtain 22.8 g of compound If with a yield of 94.93%. ESI-MS (m / z): 284.1.

[0053] Example 5:

[0054] Example 5 of the present invention provides a method for preparing an intermediate Ig, and its synthetic route is as follows:

[0055]

[0056] Specifically prepared by the following method:

[0057] Compound If (10 g, 35.30 mmol) was dissolved in TFE (100 mL), and compound Ib (8.2 g, 38.83 mmol) and sodium carbonate (7.48 g, 70.60 mmol) were added. The mixture was reacted at 70° C. for 12 h, and the temperature was lowered to room temperature. The mixture was spin-dried to obtain 15.9 g of compound Ig with a yield of 91.08%. ESI-MS (m / z): 495.1.

[0058] Example 6:

[0059] Example 6 of the present invention provides a method for preparing intermediate Ih, and its synthetic route is as follows:

[0060]

[0061] Specifically prepared by the following method:

[0062] Compound Ig (1 g, 2.02 mmol) was dissolved in isopropanol (10 mL), and (S)-Ru(OAc)2(BINAP) (340.47 mg, 404.44 μmol) was added. After nitrogen replacement, hydrogen was introduced, and the mixture was reacted at 25°C for 6 h. The reaction temperature was lowered to room temperature and the mixture was dried by spin drying. Ethyl acetate (20 mL*3) and saturated aqueous ammonium chloride solution (40 mL) were then added and extracted to give 0.89 g of compound Ih in a yield of 88.28%. ESI-MS (m / z): 499.2.

[0063] Example 7:

[0064] Example 7 of the present invention provides a method for preparing Omarigliptin:

[0065]

[0066] Compound Ih (0.2 g, 401.17 μmol) was dissolved in 4 M ethyl acetate-hydrochloric acid solution (10 mL) and stirred at 25°C for 12 h. The reaction solution was then spin-dried to dryness, and the filter cake was slurried with isopropanol to obtain 0.15 g of pure omarigliptin with a yield of 93.85% and an ee value of 99.6%. The omarigliptin assay results are as follows:

[0067] ESI-MS (m / z): 399.1. 1 H NMR(CD3OD,500MHz)δ7.87(s,1H),7.30–7.26(m,1H),7.24–7.13(m,2H),4.53(d,1H,J=12Hz),4.35–4.31(m,1H),3.94–3.9 0(m,4H),3.48(t,1H,J=12Hz),3.40–3.37(m,1H),3.18–3.12(m,1H),2.84(s,3H),2.62–2.58(m,1H),1.71(q,1H,J=12Hz).

[0068] The specific embodiments of the present invention described above do not limit the scope of protection of the present invention. Any other corresponding changes and modifications made based on the technical concept of the present invention should be included in the scope of protection of the claims of the present invention.

Claims

1. A method for synthesizing Omarigliptin, characterized in that: Follow these steps to achieve this: The steps are as follows: S1: Synthesis of compound Ib Dissolve compound Ia in toluene solution, add copper acetate, sodium carbonate, TMS acetylene, heat and stir to react, and obtain compound Ib; S2: Synthesis of Compound Id Compound Ic was dissolved in acetonitrile solution, NBS was added, and the mixture was heated and stirred to obtain compound Id; S3: Synthesis of Compound Ie Compound Id was dissolved in 2-methyltetrahydrofuran solution, potassium tert-butoxide and tert-butyl carbamate were added, and the mixture was heated and stirred to react to obtain compound Ie; S4: Synthesis of Compound If Dissolve compound Ie in methanol solution, add paraformaldehyde, and stir at room temperature to react to obtain compound If; S5: Synthesis of Compound Ig Dissolve compound If in 2,2,2-trifluoroethanol solution, add sodium carbonate and compound Ib, and heat and stir to react to obtain compound Ig; S6: Synthesis of Compound Ih Compound Ig was dissolved in isopropanol solution, (S)-Ru(OAc)2(BINAP) was added, and hydrogen was introduced to obtain compound Ih; S7: Synthesis of Omarigliptin Compound Ih was dissolved in ethyl acetate and hydrochloric acid solution, stirred for reaction, and then subjected to a pulping process to obtain Omarigliptin.

2. The method for synthesizing Omarigliptin according to claim 1, wherein: In step S5, the molar ratio of compound If to compound Ib is 1:1.0-1.2, and the reaction temperature is 60-70°C.

3. The method for synthesizing Omarigliptin according to claim 1, wherein: In step S6, the asymmetric reduction catalyst is (S)-Ru(OAc)2(BINAP), and the molar ratio of compound Ig to (S)-Ru(OAc)2(BINAP) is 1:0.1-0.2.

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