Preparation method of Omarlliptin

Abstract

The invention relates to Omarlliptin, in particular to a novel method for preparing Istradafylline, and relates to a preparation method of Istradafylline, in particular to a preparation method of Istradafylline. The method comprises the following steps: carrying out coupling reaction on a compound Ia and TMS acetylene to obtain an intermediate Ib; carrying out bromination reaction on the intermediate Ic under the action of NBS (N-bromosuccinimide) to obtain an intermediate Id; carrying out substitution reaction on the intermediate Id and tert-butyl carbamate under the action of potassium tert-butoxide to obtain an intermediate Ie; reacting the intermediate Ie with paraformaldehyde to obtain an intermediate If; carrying out cycloaddition reaction on the intermediate If and the intermediate Ib to obtain a key intermediate Ig; carrying out asymmetric catalytic hydrogenation reduction on the intermediate Ig to obtain an intermediate Ih; and removing a protecting group from the intermediate Ih in a hydrochloric acid and ethyl acetate system to obtain a final product. The method is short in route, simple and convenient to operate, mild in condition, high in reaction yield, environment-friendly and easy for industrial production, and dangerous and highly toxic products are prevented from being used and hazardous chemicals are supervised. # imgabs0 #

Description

Technical Field

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

[0002] Omarigliptin is a new long-acting dipeptidyl peptidase-4 (DPP-4) inhibitor developed by Merck. It is mainly used to treat type 2 diabetes and only needs to be taken once a week, which greatly improves patient compliance and treatment effects. Omarigliptin increases the concentration of intestinal hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) by inhibiting DPP-4, 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, with the trade name Arizev, and specifications of 25mg (tablets) and 125mg (tablets). Omarigliptin, CAS No.: 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 of this route are not easy to obtain and are expensive to purchase. The synthetic route involves hazardous chemicals such as Grignard reagent, iodine, and regulated substances such as sulfuric acid. At the same time, the synthetic process involves chiral control reactions many times, and the steps are cumbersome, resulting in low product yield 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 overcome the defects of the existing preparation method of Omarigliptin, such as the difficulty in obtaining raw materials, high cost, low yield, and complicated chiral control conditions and steps, and provide a new preparation method of Omarigliptin. The preparation method of the present invention has easy-to-obtain raw materials, high yield, novel route, and is suitable for industrial production. The present invention provides a new method for synthesizing Omarigliptin, which adopts 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] Dissolve compound Ic in acetonitrile solution, add NBS, heat and stir, and react to obtain compound Id;

[0014] S3: Synthesis of Compound Ie

[0015] Dissolve compound Id in 2-methyltetrahydrofuran solution, add potassium tert-butoxide and tert-butyl carbamate, heat and stir 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, 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 hydrochloric acid solution, stirred for reaction, and Omarigliptin was obtained through a pulping process.

[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] 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).

[0026] Beneficial Effects

[0027] 1. The innovation of the present invention lies in that the present invention adopts completely different starting materials and a completely new synthetic route from the prior art, wherein the key point of the present invention lies in that the open-ring compound If is creatively reacted with the compound Ib to undergo a Diels-Alder reaction 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, and the target product is directly obtained without chiral separation. Compared with the prior art route, this method has a shorter reaction route and a higher yield.

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

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

[0030] In order to make the purpose, technical scheme and advantages of the present invention clearer, the following specific examples further describe the present invention in detail. The experimental methods in the present invention are conventional methods unless otherwise specified. It should be understood that the specific embodiments described herein are only used to explain 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 Sane Chemical Technology (Shanghai) Co., Ltd.

[0033] Embodiment 1:

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

[0035]

[0036] The specific preparation method is as follows:

[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, followed by stirring at 60 ° C for 8 h, and TLC detection was performed until compound Ia disappeared. The solvent was removed under reduced pressure, and ethyl acetate (100 mL*3) and water (200 mL) were added. The liquids were separated and extracted to obtain 11 g of compound Ib with a yield of 97.49%. ESI-MS (m / z): 212.1.

[0038] Embodiment 2:

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

[0040]

[0041] The specific preparation method is as follows:

[0042] Compound Ic (15 g, 96.07 mmol) was dissolved in acetonitrile (100 mL), and NBS (18.81 g, 105.68 mmol) was added in batches, followed by reaction at 60 °C for 8 h. The reaction was cooled to room temperature and 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 give 21 g of compound Id with a yield of 93.00%. ESI-MS (m / z): 235.0.

[0043] Embodiment 3:

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

[0045]

[0046] The specific preparation method is as follows:

[0047] Compound Id (21 g, 89.35 mmol) was dissolved in 2-methyltetrahydrofuran (100 mL), potassium tert-butoxide (20.05 g, 178.70 mmol) and tert-butyl carbamate (11.51 g, 98.29 mmol) were added, and the mixture was reacted at 70°C for 12 h. The reaction mixture was cooled to room temperature, dried by spin drying, 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] Embodiment 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] The specific preparation method is as follows:

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

[0053] Embodiment 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] The specific preparation method is as follows:

[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, followed by reaction at 70°C for 12 h. The reaction mixture was cooled to room temperature and spin-dried to obtain 15.9 g of compound Ig with a yield of 91.08%. ESI-MS (m / z): 495.1.

[0058] Embodiment 6:

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

[0060]

[0061] The specific preparation method is as follows:

[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 mixture was cooled to room temperature and dried by spin drying. Ethyl acetate (20 mL*3) and saturated aqueous ammonium chloride solution (40 mL) were then added and extracted to obtain 0.89 g of compound Ih with a yield of 88.28%. ESI-MS (m / z): 499.2.

[0063] Embodiment 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 4M ethyl acetate hydrochloric acid solution (10 mL), stirred at 25°C for 12 h, the reaction solution was spin-dried, 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 test 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 implementation of the present invention described above does not constitute a limitation on the protection scope 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 protection scope 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 Dissolve compound Ic in acetonitrile solution, add NBS, heat and stir, and react to obtain compound Id; S3: Synthesis of Compound Ie Dissolve compound Id in 2-methyltetrahydrofuran solution, add potassium tert-butoxide and tert-butyl carbamate, heat and stir 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, heat and stir to react, to obtain compound Ig; S6: Synthesis of Compound Ih 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; S7: Synthesis of Omarigliptin Compound Ih was dissolved in ethyl acetate hydrochloric acid solution, stirred for reaction, and Omarigliptin was obtained through a pulping process.

2. The method for synthesizing Omarigliptin according to claim 1, characterized in that: 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, characterized in that: 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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