Preparation method of baricitinib

Abstract

The invention belongs to the technical field of medicine manufacturing, and particularly relates to a preparation method of baricitinib, which comprises the following steps: carrying out nucleophilic substitution reaction on a compound azetidine-3-one hydrochloride and a compound ethyl sulfonyl chloride to obtain an intermediate III, mixing bromoacetonitrile and Rieke Zn, stirring, reacting with the intermediate III to obtain an intermediate V, and carrying out recrystallization to obtain the baricitinib. The preparation method comprises the following steps: carrying out a mitsunobu Mitsunobu reaction on an intermediate V and 4-pyrazol boronic acid pinacol ester under the action of triphenylphosphine and diethyl azodicarboxylate (DEAD) to obtain an intermediate VII, and carrying out a coupling reaction on the intermediate VII and 4-chloro-7H-pyrrolo [2, 3-d] pyrimidine under the action of cesium fluoride and Pd (acac) 2 to generate baricitinib. According to the method, baricitinib is synthesized only through four-step chemical reaction, the use of dangerous and expensive reagent hazardous chemical substances NaH and diethyl cyanomethylphosphonate is avoided, the key intermediate can be obtained only through short-time stirring reaction under the room temperature condition, the yield of each step reaches up to 96%-98%, the synthesis route is short, the reaction time is short, and the method is suitable for industrial production. The method is very suitable for industrial production.

Description

Technical Field

[0001] The present invention belongs to the technical field of drug manufacturing, and in particular relates to a method for preparing baricitinib. Background Art

[0002] Baricitinib ) is an oral JAK1 and JAK2 inhibitor developed by Eli Lilly and Incyte Pharmaceuticals (INCYTE). Baricitinib's mechanism of action is to reduce inflammation by inhibiting two enzymes, JAK1 and JAK2, which play a key role in regulating the activity of immune cells. By reducing inflammation, baricitinib can reduce pain and swelling in arthritis patients and improve joint function. Baricitinib CAS registration number is 1187594-09-7, molecular formula: C 16 H 17 The molecular weight of N7O2S is 371.4169 and the structural formula is shown below.

[0003]

[0004] The currently known synthesis routes of baricitinib are as follows:

[0005] 1. The synthesis route of baricitinib disclosed in US20070135461 is as follows. The steps for preparing the key intermediate 2-[1-(ethylsulfonyl)-3-azetidinylidene]acetonitrile A4 are relatively long, and the price of diethyl cyanomethylphosphonate used is relatively high, resulting in excessive cost of this fragment. Sodium hydride is required when 2-(trimethylsilyl)ethoxymethyl is used for protection in the subsequent reaction. NaH is a hazardous chemical and its operation is very dangerous.

[0006]

[0007] 2. The preparation route of baricitinib disclosed in CN105541891 uses tert-butyl 3-oxoazetidine-1-carboxylate B1 as the starting material, obtains olefin intermediate B2 through Wittig-Horner reaction under alkaline conditions, and then obtains intermediate B4 through de-Boc and sulfonamidation, but the reaction still uses expensive reagents such as diethyl cyanomethyl phosphate and hazardous chemicals such as NaH. Then, the borate intermediate B6 is obtained through nucleophilic addition reaction, and finally the target product is obtained through Suzuki coupling reaction, as shown below:

[0008]

[0009] 3. The preparation route of baricitinib disclosed in CN106496195 uses cyanoacetic acid to obtain intermediate C3, which reduces the cost of the route and avoids the use of NaH. However, it needs to reflux in toluene for 24 hours, which is too time-consuming and not suitable for large-scale industrial production. In addition, the reaction temperature of this step is 60-140°C and cannot be carried out at room temperature. The reaction temperature conditions are relatively strict. Then, intermediate C5 is obtained by nucleophilic addition reaction, and borate intermediate C6 is obtained by palladium catalyst catalysis. Finally, the target product is obtained by Suzuki coupling reaction.

[0010]

[0011] Fourth, the preparation route of baricitinib disclosed in "CN106946917" uses 1-amino-3-chloropropyl-2-ol hydrochloride D1 as the starting compound, and obtains alcohol intermediate D3 through amidation and intramolecular nucleophilic substitution. Then, the ketone intermediate D4 is obtained by oxidation with TEMPO, NaBr, and sodium hypochlorite system. Then, the key intermediate D6 is obtained by Wittig reaction with triphenylphosphine acetonitrile. According to the method, when preparing intermediate D6 from intermediate D4, the reaction can be carried out at room temperature, but the disadvantage is that it is not only time-consuming but also has a low yield. The reaction process of this step alone takes 3 to 4 hours, and after a series of operations such as extraction, washing, concentration, and recrystallization, the yield is only 67%, which seriously affects the subsequent production.

[0012]

[0013] The above-mentioned reported technical routes have many defects, such as the use of hazardous chemicals, long reaction time, expensive starting materials, strict reaction temperature conditions, low product yield, and poor atom economy. At the same time, they cause serious environmental pollution and generate a lot of waste liquid, which does not meet the requirements of green chemistry. Summary of the invention

[0014] In order to overcome the defects of the above technical route that is not conducive to environmental protection and industrial production, the present invention provides a method for preparing baricitinib that is prepared almost entirely at room temperature, has a high yield, a short reaction synthesis route, and a short reaction time. The specific reaction route used is:

[0015]

[0016] The specific steps are:

[0017] Step 1: Synthesis of Intermediate III

[0018] Compound I azetidine-3-one hydrochloride and compound II ethylsulfonyl chloride are dissolved in a dichloromethane solution, triethylamine is added, and the mixture is stirred at room temperature. After the disappearance of compound I is detected, the solvent is removed under reduced pressure, and then a solvent and water are added to separate the liquids for extraction to obtain intermediate III;

[0019] Step 2: Synthesis of Intermediate V

[0020] Dissolve bromoacetonitrile in anhydrous tetrahydrofuran, add Rieke Zn under inert gas protection, stir at room temperature, then add intermediate III, add saturated ammonium chloride to quench the reaction after the reaction is detected to be complete, extract with ethyl acetate, and spin-dry the organic layer to obtain intermediate V;

[0021] Step 3: Synthesis of intermediate VII

[0022] Dissolve intermediate V, compound VI and triphenylphosphine in anhydrous tetrahydrofuran, slowly add DEAD dropwise, stir at room temperature, remove the solvent under reduced pressure after detecting that intermediate V disappears, then add solvent and water, separate and extract, spin-dry the organic layer to obtain intermediate VII;

[0023] Step 4: Synthesis of Baricitinib

[0024] Intermediate VII, compound VIII, cesium fluoride and Pd(acac)2 are dissolved in 1,4-dioxane, and heated under the protection of an inert gas to obtain baricitinib.

[0025] Moreover, in step 1, the molar ratio of compound I:compound II:triethylamine is 1:1:1.5.

[0026] Furthermore, the molar ratio of bromoacetonitrile:Rieke Zn (10% in THF, 2.0 M):Intermediate III in step 2 is 1:1:1.

[0027] Moreover, in step 3, the molar ratio of intermediate V: compound VI: triphenylphosphine: DEAD is 1:1:1.2:1.2.

[0028] Moreover, in step 4, the molar ratio of intermediate VII: compound VIII: cesium fluoride: Pd(acac)2 is 1:1:1.2:0.02, and the reaction temperature is 80°C.

[0029] Moreover, in step 1, the room temperature is 20-30° C. and the stirring is performed for 1-2 hours, in step 2, the room temperature is 20-30° C. and the stirring is performed for 1-2 hours, and in step 3, the room temperature is 20-30° C. and the stirring is performed for 10-12 hours.

[0030] The principle of the reaction route of the preparation method is: 1) Compound I (chemical name: azetidine-3-one hydrochloride) undergoes a nucleophilic substitution reaction with compound II (ethylsulfonyl chloride) to obtain intermediate III; 2) Bromoacetonitrile and Rieke Zn are mixed and stirred, and then reacted with intermediate III to obtain intermediate V; 3) Intermediate V, under the action of triphenylphosphine and diethyl azodicarboxylate (DEAD), undergoes a mitsunobu reaction with 4-pyrazoleboronic acid pinacol ester (compound VI) to obtain intermediate VII; 4) Intermediate VII undergoes a coupling reaction with 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (compound VIII) under the action of cesium fluoride and Pd(acac)2 to generate baricitinib.

[0031] Compared with the prior art, the beneficial effects of this technical solution are:

[0032] 1. The reaction route of the present invention avoids the use of dangerous and expensive reagents such as hazardous chemicals such as NaH and diethyl cyanomethyl phosphate, and synthesizes baricitinib through only four chemical reactions, thereby improving atom economy and significantly reducing production costs. Except for the last step of the reaction which requires heating, the entire process is prepared at room temperature. The preparation of key intermediates III, intermediates V, and intermediates VII can be obtained by only a short-time stirring reaction at room temperature, which is very suitable for industrial production.

[0033] 2. The present invention provides a new method for preparing baricitinib, which avoids the defects of supervising highly toxic hazardous chemicals, harsh reaction conditions, and expensive starting materials. It is significantly better than the prior art "US20070135461" and "CN105541891", and greatly reduces the harm to human body and environment.

[0034] 3. The intermediate V is efficiently prepared by adopting the Reformatsky reaction. The reaction conditions of this step are mild: it can be carried out at room temperature, the reaction time is short: the reaction stirring time only takes 1 to 2 hours, and the yield is high: reaching 97.75%, which is a significant improvement compared with the prior art "CN106496195" and "CN106946917".

[0035] 4. Efficiently prepare intermediate VII by using Mitsunobu reaction. In this step, compound VII can be obtained by stirring the reaction at room temperature using Mitsunobu reaction. The reaction conditions are mild, green and environmentally friendly, and avoid the use of heavy metals and high-temperature heating conditions. The prior art "CN106496195" and "CN106946917" both use palladium catalytic coupling, and high-temperature heating is required to obtain the intermediate.

[0036] 5. The raw materials of the method of the present invention are cheap and readily available and the reaction conditions are mild. The yield of each step is as high as 96% to 98%, and the atom economy is good. DETAILED DESCRIPTION

[0037] The present invention is described in detail below with reference to examples, but the present invention is not limited to the following examples.

[0038] 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.

[0039] The chemical reagents and raw materials of the present invention were purchased from Sane Chemical Technology (Shanghai) Co., Ltd.

[0040] Embodiment 1:

[0041] The preparation of intermediate III, its synthetic route is as follows:

[0042]

[0043] The specific preparation method is as follows:

[0044] Compound I (50 g, 464.96 mmol) was dissolved in dichloromethane (0.4 L), and ethylsulfonyl chloride (59.78 g, 464.96 mmol) and triethylamine (70.58 g, 697.43 mmol) were added. The mixture was stirred at room temperature (20-30 ° C) for 2 h. TLC was performed until compound I disappeared. The solvent was removed under reduced pressure, ethyl acetate (0.1 L*3) and water (0.5 L) were added, and the mixture was separated and extracted. The solvent was removed under reduced pressure to obtain 74 g of intermediate III with a yield of 97.53%. ESI-MS (m / z): 164.1.

[0045] Embodiment 2:

[0046] The preparation of intermediate V, its synthetic route is as follows:

[0047]

[0048] The specific preparation method is as follows:

[0049] Bromoacetonitrile (60.00 g, 500.21 mmol) was dissolved in anhydrous tetrahydrofuran (0.1 L), and Rieke Zn (10% in THF, 2.0 M) (250.11 mL) was added under nitrogen protection. The reaction was allowed to proceed at room temperature (20-30° C.) for 2 h, and then intermediate III (81.63 g, 500.21 mmol) was added. The reaction was completed after LCMS monitoring. Saturated ammonium chloride was added to quench the reaction, and the mixture was separated and extracted with ethyl acetate. The organic layer was spin-dried to obtain 100 g of intermediate V with a yield of 97.881%. ESI-MS (m / z): 205.2. 1 H NMR (DMSO-d6, 400 MHz)δ H 4.31(d,J=8.7Hz 2H),4.12(m,2H),3.91(m,2H),3.16(s,2H),1.25(t,J=8.7Hz,3H).

[0050] Embodiment 3:

[0051] The preparation of intermediate VII, its synthetic route is as follows:

[0052]

[0053] Intermediate V (100 g, 489.61 mmol), compound VI (95 g, 489.61 mmol), and triphenylphosphine (154.10 g, 587.53 mmol) were dissolved in anhydrous THF (1 L), and then DEAD (102.32 g, 587.53 mmol) was added. The reaction was stirred at room temperature (20-30° C.) for 12 h, and TLC was detected until intermediate V disappeared. The solvent was removed under reduced pressure, ethyl acetate (0.5 L*3) and water (4 L) were added, and the liquids were separated and extracted. The organic layer was spin-dried, and the solid was slurried with MTBE / methanol = 20 / 1 to obtain 182 g of intermediate VII with a yield of 97.75%. ESI-MS (m / z): 381.3.

[0054] Embodiment 4:

[0055] The preparation of baricitinib, its synthetic route is as follows:

[0056]

[0057] The intermediate VII (180 g, 473.35 mmol), compound VIII (72.69 g, 473.35 mmol), cesium fluoride (86.28 g, 568.02 mmol), and Pd(acac)2 (2.90 g, 9.47 mmol) were dissolved in 1,4-dioxane (1 L) under nitrogen protection. The reaction was stirred at 80 ° C for 12 h. TLC was detected until the intermediate VII disappeared. The mixture was filtered with diatomaceous earth and dried by rotation. Ethyl acetate (0.5 L * 3) and water (4 L) were added, and the mixture was separated and extracted. Thiourea resin was added to the organic phase and stirred overnight. The mixture was filtered with suction. The filtrate was dried by rotation. The solid was slurried with a mixed solvent of isopropanol: dichloromethane: MTBE = 0.1:0.1:1 to obtain 170 g of baricitinib with a yield of 96.70%. ESI-MS (m / z): 372.1. The prepared product was characterized by H-NMR and confirmed to be baricitinib. H NMR (DMSO-d6, 400 MHz) δ H 12.13(br s,1H),8.95(s,1H),8.74(s,1H),8.41(s,1H),7.71(m,1H),6.99(m,1H),4.65(d,J=8.92H z, 2H), 4.22 (d, J = 8.92Hz, 2H), 3.69 (s, 2H), 3.22 (q, J = 8.9Hz, 2H), 1.26 (t, J = 8.9Hz, 3H).

Claims

1. A method for preparing baricitinib, characterized in that: The reaction route is: The specific steps are: Step 1: Synthesis of Intermediate III Compound I azetidine-3-one hydrochloride and compound II ethylsulfonyl chloride are dissolved in a dichloromethane solution, triethylamine is added, and the mixture is stirred at room temperature. After the disappearance of compound I is detected, the solvent is removed under reduced pressure, and then a solvent and water are added to separate the liquids for extraction to obtain intermediate III; Step 2: Synthesis of Intermediate V Dissolve bromoacetonitrile in anhydrous tetrahydrofuran, add Rieke Zn under inert gas protection, stir at room temperature, then add intermediate III, add saturated ammonium chloride to quench the reaction after the reaction is detected to be complete, extract with ethyl acetate, and spin-dry the organic layer to obtain intermediate V; Step 3: Synthesis of intermediate VII Dissolve intermediate V, compound VI and triphenylphosphine in anhydrous tetrahydrofuran, slowly add DEAD dropwise, stir at room temperature, remove the solvent under reduced pressure after detecting that intermediate V disappears, then add solvent and water, separate and extract, spin-dry the organic layer to obtain intermediate VII; Step 4: Synthesis of Baricitinib Intermediate VII, compound VIII, cesium fluoride and Pd(acac)2 are dissolved in 1,4-dioxane, and heated under the protection of an inert gas to obtain baricitinib.

2. The method for preparing baricitinib according to claim 1, characterized in that: In step 1, the molar ratio of compound I: compound II: triethylamine is 1:1:1.

5.

3. The method for preparing baricitinib according to claim 1, characterized in that: In step 2, the molar ratio of bromoacetonitrile: Rieke Zn (10% in THF, 2.0 M): intermediate III is 1:1:

1.

4. The method for preparing baricitinib according to claim 1, characterized in that: In step 3, the molar ratio of intermediate V: compound VI: triphenylphosphine: DEAD is 1:1:1.2:1.

2.

5. The method for preparing baricitinib according to claim 1, characterized in that: In step 4, the molar ratio of intermediate VII: compound VIII: cesium fluoride: Pd(acac)2 is 1:1:1.2:0.02, and the reaction temperature is 80°C.

6. The method for preparing baricitinib according to claim 1, characterized in that: In step 1, the room temperature is 20-30° C. and the mixture is stirred for 1-2 hours. In step 2, the room temperature is 20-30° C. and the mixture is stirred for 1-2 hours. In step 3, the room temperature is 20-30° C. and the mixture is stirred for 10-12 hours.

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