Method and system for preparing linitinib and intermediates thereof without metal catalyst

Abstract

The invention belongs to the technical field of chemical synthesis, and particularly relates to a method and a system for preparing linitinib and an intermediate thereof without a metal catalyst. The preparation method of the linitinib and the intermediate of the linitinib comprises the following steps: 1) taking (2S, 5R)-1-BOC-5-amino-2-methyl-piperidine and 4-chloropyrrolopyrimidine as raw materials, and carrying out a coupling reaction to prepare a linitinib intermediate I; (2) removing Boc protection from the litexitinib intermediate I under an acidic condition to obtain a litexitinib intermediate II; and (3) carrying out amidation reaction on the linitinib intermediate II and acryloyl chloride to obtain the linitinib. According to the method, no expensive metal catalyst is used, and the litexitinib can be prepared, so that the preparation cost is greatly reduced; the obtained product has relatively high purity and yield; the route is relatively short, and the steps are simpler and more convenient.

Description

Technical Field

[0001] The present invention belongs to the technical field of chemical synthesis, and in particular relates to a method and system for preparing rituximab and its intermediates without a metal catalyst. Background Art

[0002] Lipitinib is a potent JAK3 tyrosine kinase inhibitor and TEC tyrosine kinase inhibitor. On June 23, 2023, the U.S. FDA approved Lipitinib capsules for the treatment of alopecia areata. Other indications including non-segmental vitiligo, scarring alopecia, ulcerative colitis, Crohn's disease, etc. are still in clinical trials. The structural formula of Lipitinib is shown in Formula 1.

[0003]

[0004] The preparation and crystal form patent of rituxitinib WO2020084435A1 (Chinese equivalent patent CN112888691A) discloses a preparation method of rituxitinib as shown in reaction formula 1. However, the patent uses an expensive metal catalyst and has a relatively long number of steps.

[0005] Reaction 1:

[0006]

[0007] Therefore, it is necessary to develop a new preparation method with short steps and low cost to achieve the efficient synthesis of rituximab and its key intermediates. Summary of the invention

[0008] In view of this, one of the objects of the present invention is to provide a method for preparing intermediate I of rituxitinib. The present invention uses (2S, 5R)-1-BOC-5-amino-2-methyl-piperidine and 4-chloropyrrolopyrimidine as raw materials to prepare intermediate I of rituxitinib. The method is simple, and the obtained intermediate I has a high yield and purity. The present invention provides technical support for the subsequent preparation of rituxitinib.

[0009] To achieve the above object, the present invention adopts the following technical solutions:

[0010] A method for preparing a rituxitinib intermediate I, wherein the structural formula of the rituxitinib intermediate I is shown in Formula 3; the method comprises: using (2S, 5R)-1-BOC-5-amino-2-methyl-piperidine and 4-chloropyrrolopyrimidine as raw materials, and preparing the rituxitinib intermediate I by a coupling reaction under alkaline conditions;

[0011]

[0012] Further, the synthetic reaction formula of intermediate I of rituximab is as follows:

[0013]

[0014] Among them, the compound shown in the structural formula of Formula 4 is (2S, 5R)-1-BOC-5-amino-2-methyl-piperidine; the compound shown in the structural formula of Formula 5 is 4-chloropyrrolopyrimidine.

[0015] Furthermore, in the coupling reaction, the base is any one or more of DIPEA, triethylamine, potassium carbonate, sodium carbonate, cesium carbonate, LHMDS, sodium bicarbonate, and potassium bicarbonate; and the solvent is any one or more of toluene, methanol, ethanol, n-propanol, isopropanol, butanol, acetone, butanone, methyl isobutyl ketone, and water.

[0016] Preferably, the base is DIPEA; and the solvent is isopropanol.

[0017] Furthermore, in the reaction of synthesizing the intermediate I of rituximab from (2S,5R)-1-BOC-5-amino-2-methyl-piperidine, the amount of 4-chloropyrrolopyrimidine used is 1.0eq~1.5eq, preferably 1.0eq; the amount of base used is 1.0eq~3.0eq, preferably 2.5eq; and the amount of solvent used is 3V~20V, preferably 4V.

[0018] Preferably, the temperature is controlled below 30° C. and the base is added dropwise.

[0019] Furthermore, the reaction temperature of the coupling reaction is 50-100°C.

[0020] Preferably, the reaction temperature of the coupling reaction is 80°C.

[0021] Furthermore, the coupling reaction is carried out under nitrogen protection.

[0022] Furthermore, after the coupling reaction is completed, the reaction temperature is lowered to 20°C to 30°C, crystallized, filtered, and washed to obtain the rituximab intermediate I.

[0023] The second object of the present invention is to provide a method for preparing intermediate II of rituximab.

[0024] To achieve the above object, the present invention adopts the following technical solutions:

[0025] A method for preparing a rituximab intermediate II, wherein the structural formula of the rituximab intermediate II is shown in Formula 2; the method comprises the following steps:

[0026] (1) preparing rituximab intermediate I by the aforementioned method;

[0027] (2) Deprotect the Boc group of the rituximab intermediate I prepared in step (1) under acidic conditions to obtain the rituximab intermediate II;

[0028]

[0029] Furthermore, the synthetic reaction formula from the rituximab intermediate I to the rituximab intermediate II is as follows:

[0030]

[0031] Furthermore, in step (2), the acid is any one or more of hydrochloric acid, hydrogen chloride in ethanol, hydrogen bromide in ethanol, hydrogen bromide in acetic acid, and hydrogen chloride in methanol; the solvent is any one or more of water, methanol, ethanol, n-propanol, isopropanol, butanol, acetone, butanone, methyl isobutyl ketone, tetrahydrofuran, and 2-methyltetrahydrofuran.

[0032] Furthermore, in step (2), in the reaction of the rituximab intermediate I to synthesize the rituximab intermediate II, the amount of the acid used is 1.0 eq to 10.0 eq; the amount of the solvent used is 5V to 20V.

[0033] Preferably, in step (2), the acid is hydrochloric acid, and the amount of the hydrochloric acid used is 6.0 eq;

[0034] Preferably, in step (2), the solvent is tetrahydrofuran and water, and the amount used is 8V; the volume ratio of tetrahydrofuran to water is 1:1.

[0035] Preferably, the temperature is controlled below 30 °C, and the hydrochloric acid is added dropwise.

[0036] Furthermore, in step (2), the reaction temperature is 0 to 60 °C.

[0037] Preferably, in step (2), the reaction temperature is 40 to 50 °C.

[0038] Furthermore, step (2) is carried out under nitrogen protection.

[0039] Furthermore, after the reaction in step (2) is completed, the reaction is cooled to 20 °C to 30 °C for extraction, crystallization, filtration, and washing with water to obtain the rituximab intermediate II.

[0040] Preferably, the extraction solvent is water and ethyl acetate; the number of extraction times is 2 times.

[0041] More preferably, in the extraction solvent, the volume ratio of water to ethyl acetate is 1:1.

[0042] Preferably, the pH value of the aqueous phase obtained by extraction is adjusted to 8 with ammonia water and then crystallization is carried out.

[0043] A third object of the present invention is to provide a method for preparing ritlecitinib without a metal catalyst, which method has short steps and can obtain ritlecitinib with high purity and high yield without using a metal catalyst.

[0044] To achieve the above object, the present invention adopts the following technical solutions:

[0045] A method for preparing ritlecitinib without a metal catalyst, the structural formula of the ritlecitinib is shown in Formula 1; the method comprises the following steps:

[0046] (1) Prepare ritlecitinib intermediate II by the foregoing method;

[0047] (2) Add acryloyl chloride to the ritlecitinib intermediate II prepared in step (1) to carry out an amidation reaction to obtain the ritlecitinib;

[0048]

[0049] Furthermore, the synthesis reaction formula from ritlecitinib intermediate II to ritlecitinib is as follows:

[0050]

[0051] Furthermore, in step (2), the base is any one or more of DIPEA, triethylamine, potassium carbonate, sodium carbonate, cesium carbonate, LHMDS, sodium bicarbonate, potassium bicarbonate; the solvent is any one or more of toluene, methanol, ethanol, n-propanol, isopropanol, butanol, acetone, butanone, methyl isobutyl ketone, water, tetrahydrofuran, 2-methyltetrahydrofuran.

[0052] Furthermore, in the reaction of synthesizing ritlecitinib from ritlecitinib intermediate II, the amount of the base used is 2.0eq - 10.0eq; the amount of acryloyl chloride used is 1.0eq - 2.0eq; the amount of the solvent used is 5V - 20V.

[0053] Preferably, in step (2), the base is sodium bicarbonate, and the amount used is 4.0eq; the solvent is tetrahydrofuran, and the amount used is 10V.

[0054] Furthermore, in step (2), the reaction temperature of the amidation reaction is -10 to 30°C.

[0055] Preferably, in step (2), the reaction temperature of the amidation reaction is 0 to 10°C.

[0056] Furthermore, after the reaction in step (2) is completed, the reaction is heated to 20°C - 30°C, and after extraction, distillation, crystallization, filtration, and drying, the ritlecitinib is obtained.

[0057] Preferably, the extraction solvent is dichloromethane and the number of extraction times is 3 times.

[0058] Preferably, the distillation includes: first subjecting the obtained organic phase to vacuum distillation until no distillate flows out, and then adding isopropyl acetate to strip the distillate until no distillate flows out.

[0059] Preferably, the crystallization solvent is isopropyl acetate and n-heptane.

[0060] The fourth object of the present invention is to provide a production system for preparing liticiclib.

[0061] To achieve the above object, the present invention adopts the following technical solutions:

[0062] A production system for preparing liticiclib, the production system includes production unit 1, production unit 2, production unit 3, purification unit 1, purification unit 2, purification unit 3, stirring unit 1, stirring unit 2, temperature control unit and vacuum distillation unit; the production unit 1, stirring unit 1, purification unit 1, production unit 2, purification unit 2, production unit 3, stirring unit 2, vacuum distillation unit and purification unit 3 are connected in sequence; the temperature control unit is respectively connected to the production unit 1, production unit 2 and production unit 3; the (2S,5R)-1-BOC-5-amino-2-methyl-piperidine and 4-chloropyrrolo[2,3-d]pyrimidine undergo a coupling reaction in production unit 1 to obtain liticiclib intermediate I; the Boc protection of liticiclib intermediate I is removed in production unit 2 to obtain liticiclib intermediate II; the liticiclib intermediate II undergoes an amidation reaction with acryloyl chloride in production unit 3 to obtain the liticiclib.

[0063] The beneficial effects of the present invention are as follows:

[0064] 1. The present invention uses (2S,5R)-1-BOC-5-amino-2-methyl-piperidine and 4-chloropyrrolo[2,3-d]pyrimidine as raw materials, removes the Boc protection after coupling, and then reacts with acryloyl chloride to obtain liticiclib. The preparation steps are shorter, and high-purity liticiclib can be obtained without using a metal catalyst, and the preparation cost is lower.

[0065] 2. For the synthesis method provided by the present invention, the total yield of the three-step reaction of synthesizing liticiclib from (2S,5R)-1-BOC-5-amino-2-methyl-piperidine can reach 60.8%. Description of the Drawings

[0066] Figure 1 It is the overall reaction formula for synthesizing liticiclib in the present invention. Detailed Embodiments

[0067] The technical solution of the present invention will be further clearly and completely described below in conjunction with specific embodiments. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all embodiments. Therefore, based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative efforts belong to the protection scope of the present invention.

[0068] Example 1. Preparation of Liticixitinib Intermediate I with the structural formula shown in Formula 3

[0069] The reaction formula is as follows:

[0070]

[0071] Under nitrogen protection, 30 g of Compound 4 and 21.4 g of Compound 5 were added to a 1000 ml three-necked flask, 300 ml of isopropanol was added, stirred, the temperature was controlled below 30 °C, and 45.2 g of DIPEA was added dropwise. After the addition was completed, the reaction system was heated to 80 °C. After the reaction was monitored to be complete, the reaction was cooled to 20 °C - 30 °C, crystallized for 2 h, filtered, and washed with isopropanol to obtain 37.1 g of Compound 3 (Liticixitinib Intermediate I), and the yield was 80%.

[0072] Example 2. Preparation of Liticixitinib Intermediate II with the structural formula shown in Formula 2

[0073] The reaction formula is as follows:

[0074]

[0075] Under nitrogen protection, Compound 3 was added to a 500 ml three-necked flask, 100 ml of tetrahydrofuran and 100 ml of water were added. The temperature was controlled below 30 °C, and 50 ml of hydrochloric acid was added dropwise. After the addition was completed, the reaction system was heated to 40 - 50 °C. After the reaction was monitored to be complete, the reaction was cooled to 20 °C - 30 °C, 100 ml of water was added, and extracted twice with 100 ml of ethyl acetate. The organic phase was discarded, the pH value of the aqueous phase was adjusted to 8 with ammonia water, crystallized for 2 h, filtered, and washed with water to obtain 24.7 g of Compound 2 (Liticixitinib Intermediate II), and the yield was 95%.

[0076] Example 3. Preparation of Liticixitinib

[0077] The reaction formula is as follows:

[0078]

[0079] At room temperature, 24.7 g of compound 2, 250 ml of tetrahydrofuran, and 150 ml of water were added to a 1000 ml three-necked flask. 15 g of sodium bicarbonate was added, and the mixture was stirred while controlling the temperature below 10 °C. An 80 ml tetrahydrofuran solution of 8 g of acryloyl chloride was added dropwise. After the addition was complete, the reaction was kept at a temperature below 10 °C for the reaction. After the reaction was monitored to be complete, the reaction temperature was raised to 20 °C - 30 °C. The mixture was extracted 3 times with 300 ml of dichloromethane. The organic phases were combined and distilled under reduced pressure until no distillate flowed out. 100 ml of isopropyl acetate was added to carry out the distillation until no distillate flowed out. 100 ml of isopropyl acetate and 100 ml of n-heptane were added, and crystallization was carried out for 2 h. The mixture was filtered and dried to obtain 24.4 g of ritlecitinib, with a yield of 80%; the total yield of the three-step reaction for the synthesis of ritlecitinib from (2S,5R)-1-BOC-5-amino-2-methyl-piperidine was 60.8%.

Claims

1. Preparation method of ritlecitinib intermediate I, characterized in that, The structural formula of the liticixitinib intermediate I is shown in Formula 3; the method includes: using (2S,5R)-1-BOC-5-amino-2-methyl-piperidine and 4-chloropyrrolo[2,3-d]pyrimidine as raw materials, and obtaining the liticixitinib intermediate I through a coupling reaction under alkaline conditions; 2. The method according to claim 1, wherein In the coupling reaction, the base is any one or more of DIPEA, triethylamine, potassium carbonate, sodium carbonate, cesium carbonate, LHMDS, sodium bicarbonate, and potassium bicarbonate; the solvent is any one or more of toluene, methanol, ethanol, n-propanol, isopropanol, butanol, acetone, butanone, methyl isobutyl ketone, and water.

3. The method according to claim 1, wherein The reaction temperature of the coupling reaction is 50-100 °C.

4. Preparation method of ritlecitinib intermediate II, characterized in that, The structural formula of the liticixitinib intermediate II is shown in Formula 2; the method includes the following steps: (1) Prepare the liticixitinib intermediate I by the method described in any one of claims 1-3; (2) Remove the Boc protection from the liticixitinib intermediate I prepared in step (1) under acidic conditions to obtain the liticixitinib intermediate II; 5. The method according to claim 4, characterized in that In step (2), the acid is any one or more of hydrochloric acid, hydrogen chloride ethanol, hydrogen bromide ethanol, hydrogen bromide acetic acid, and hydrogen chloride methanol; the solvent is any one or more of water, methanol, ethanol, n-propanol, isopropanol, butanol, acetone, butanone, methyl isobutyl ketone, tetrahydrofuran, and 2-methyltetrahydrofuran.

6. The method according to claim 4, characterized in that In step (2), the reaction temperature is 0-60 °C.

7. A method for preparing ritlecitinib without a metal catalyst, characterized in that, The structural formula of the liticixitinib is shown in Formula 1; the method includes the following steps: (1) Prepare the liticixitinib intermediate II by the method described in any one of claims 4-6; (2) Add acryloyl chloride to the liticixitinib intermediate II prepared in step (1) to carry out an amidation reaction to obtain the liticixitinib; 8. The method according to claim 7, wherein In step (2), the base is any one or more of DIPEA, triethylamine, potassium carbonate, sodium carbonate, cesium carbonate, LHMDS, sodium bicarbonate, and potassium bicarbonate; the solvent is any one or more of toluene, methanol, ethanol, n-propanol, isopropanol, butanol, acetone, butanone, methyl isobutyl ketone, water, tetrahydrofuran, and 2-methyltetrahydrofuran.

9. The method according to claim 7, characterized in that, In step (2), the reaction temperature of the amidation reaction is -10-30 °C.

10. A production system for preparing ritlecitinib according to any one of claims 7-9, characterized in that, The production system includes production unit 1, production unit 2, production unit 3, refining unit 1, refining unit 2, refining unit 3, stirring unit 1, stirring unit 2, temperature control unit, and vacuum distillation unit; the production unit 1, stirring unit 1, refining unit 1, production unit 2, refining unit 2, production unit 3, stirring unit 2, vacuum distillation unit, and refining unit 3 are connected in sequence; the temperature control unit is respectively connected to the production unit 1, production unit 2, and production unit 3; the (2S,5R)-1-BOC-5-amino-2-methyl-piperidine and 4-chloropyrrolo[2,3-d]pyrimidine carry out a coupling reaction in the production unit 1 to obtain the liticixitinib intermediate I; the liticixitinib intermediate I removes the Boc protection in the production unit 2 to obtain the liticixitinib intermediate II; the liticixitinib intermediate II carries out an amidation reaction with acryloyl chloride in the production unit 3 to obtain the liticixitinib.

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