Process for the preparation of a key intermediate of roscovitine

Abstract

The application discloses a preparation method of a key intermediate of Ruxolitinib, and the method comprises the following steps: (a) performing Kumada coupling reaction on a compound in a formula 3 and a compound in a formula 4 to obtain a compound in a formula 5; and (b) performing deprotection on the compound in the formula 5 to selectively remove an ethoxyethyl group, so as to obtain a compound in a formula 1. The Kumada reaction is applied to preparation of the compound in the formula 5, the reaction condition is mild, coupling can be realized through a cheap catalyst, the yield is high, the cost is low, and safe production can be realized. The overall reaction route of the application is simple, environment-friendly, raw materials are simple and easy to obtain, and the application has high economic value.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of pharmaceutical chemistry, in particular to a preparation method of a key intermediate of Ruxolitinib. BACKGROUND

[0002] Ruxolitinib is a chemical name of 4-(1H-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)- methyl)-7H-pyrrolo[2,3-D]pyrimidine, and its structural formula is as follows:

[0003]

[0004] Ruxolitinib phosphate is the active pharmaceutical ingredient of the oral drug Jakafi of Incyte Company, which has been approved in three indications in the United States: (1) for the treatment of adult patients with polycythemia vera (PV) who are not adequately responsive to or intolerant of hydroxyurea; (2) for the treatment of adult patients with intermediate or high-risk myelofibrosis (MF), including primary MF, post-PV MF, and post-essential thrombocythemia MF; (3) for the treatment of steroid-refractory acute graft-versus-host disease (GVHD). Among them, the third indication was approved by FDA in May 2019, and it is the first drug approved for this indication. Jakafi is sold by Incyte in the United States, and Novartis sells it under the brand name Jakavi in markets outside the United States. The sales of Jakafi in 2018 were 1.4 billion US dollars, and it is expected that the annual sales will reach 2.5-3 billion US dollars in 2027. In 2017, ruxolitinib phosphate was approved by CFDA in China for the treatment of patients with moderate to high risk of primary myelofibrosis (PMF), myelofibrosis secondary to polycythemia vera, or myelofibrosis secondary to essential thrombocythemia.

[0005] There are related literatures reporting the synthesis of Ruxolitinib. The method reported in the Chinese patent CN102348693B applied by the original research Incyte Company is shown in route 1. 4-chloropyrrolopyrimidine is used as a starting material, and Ruxolitinib is prepared by substitution reaction, suzuki coupling reaction, Michael addition, and removal of chiral protection group. The intermediate of formula 1 is involved in the route, and the suzuki coupling reaction involved in the reaction needs to use expensive palladium metal catalyst, the cost is uncontrollable, and it cannot adapt to industrial large-scale production.

[0006] Route 1:

[0007]

[0008] The method reported in WO2010083283A2 (Scheme 2) is different from Scheme 1 in that an ethoxyethyl group is added to the pyrazole ring to avoid side reactions in the Suzuki coupling reaction. Scheme 2 also involves intermediate Formula 1 and requires the use of expensive palladium catalysts, which is not cost-effective and cannot be adapted to industrial mass production.

[0009] Scheme 2:

[0010]

[0011] Therefore, most of the routes for the development of the raw material of Luseotinib involve the key intermediate Formula 1. The methods reported in the literature are not cost-effective, and there is a need in the art for a synthesis method that is easy to obtain raw materials, simple and safe to operate, and cost-effective. SUMMARY

[0012] The purpose of the present application is to overcome the defects of the existing production of the key intermediate of Luseotinib, such as high cost and inability to adapt to industrial mass production, and to provide a preparation method of the key intermediate of Luseotinib. The preparation method of the present application is easy to obtain raw materials, simple to operate, mild in reaction conditions, high in reaction yield, low in cost and environmentally friendly.

[0013] The present application solves the above technical problems through the following technical solutions.

[0014] The present application provides a preparation method of a compound of Formula 1, which comprises the following steps:

[0015]

[0016] (a) Formula 3 compound and Formula 4 compound are subjected to Kumada coupling reaction to obtain Formula 5 compound; X is Cl or Br;

[0017] (b) Formula 5 compound is subjected to deprotection to selectively remove the ethoxyethyl group, thereby obtaining Formula 1 compound.

[0018] In step (a), the method and conditions of the Kumada coupling reaction can be the conventional method and conditions of this reaction in the art. According to common knowledge in the art, the Kumada coupling reaction is carried out in the presence of a catalyst. The catalyst is preferably a nickel-based catalyst. The nickel-based catalyst is preferably one or more of NiCl2(dppf), NiCl2(dppp) and NiCl2(dppe), and more preferably NiCl2(dppf). The molar ratio of the Formula 4 compound to the catalyst is preferably 10:1 to 20:1.

[0019] In step (a), the solvent of the Kumada coupling reaction is preferably tetrahydrofuran and / or 2-methyltetrahydrofuran, and more preferably tetrahydrofuran.

[0020] In step (a), the reaction temperature of the Kumada coupling reaction is preferably 20°C to 60°C, more preferably 30°C to 40°C.

[0021] In step (a), after the Kumada coupling reaction is completed, the post-treatment operation of conventional extraction, washing and concentration can be performed according to common knowledge in the art.

[0022] In step (a), the compound of formula 3 is preferably prepared by the following method:

[0023]

[0024] The Grignard exchange reaction of the compound of formula 2 is performed in the presence of an alkyl magnesium halide, wherein R is I or Br.

[0025] Preferably, the alkyl magnesium halide is one or more of isopropyl magnesium chloride, isopropyl magnesium chloride-lithium chloride, isopropyl magnesium bromide, methyl magnesium chloride, methyl magnesium bromide, ethyl magnesium chloride and ethyl magnesium bromide, more preferably isopropyl magnesium chloride-lithium chloride.

[0026] The amount of the compound of formula 2 and the alkyl magnesium halide can be conventional in the art. In some embodiments of the present application, the molar ratio of the compound of formula 2 to the alkyl magnesium halide is 1:1 to 1:1.2, more preferably 1:1.1 to 1:1.2.

[0027] Preferably, the solvent of the Grignard exchange reaction is one or more of tetrahydrofuran, 2-methyltetrahydrofuran and toluene, more preferably tetrahydrofuran.

[0028] Preferably, the temperature of the Grignard exchange reaction is -10°C to 30°C, more preferably -5°C to 0°C.

[0029] In a preferred embodiment of the present application, the compound of formula 5 is prepared by one-pot method, i.e. the Grignard exchange reaction and step (a) are performed continuously.

[0030] In step (b), the method and conditions of the deprotection can be conventional method and conditions for such reaction in the art, as long as the ethoxyethyl group can be selectively removed. Preferably, the deprotection is performed in the presence of an acid. Preferably, the acid is one or more of sulfuric acid, hydrochloric acid and phosphoric acid.

[0031] In step (b), the temperature of the deprotection is preferably 10°C to 45°C, more preferably 25°C to 30°C.

[0032] In step (b), after the deprotection reaction is completely finished, the post-treatment operation of conventional filtration, washing and purification can be performed according to common knowledge in the art.

[0033] The above-mentioned preferred conditions can be combined arbitrarily to obtain preferred embodiments of the present application without departing from the common knowledge in the art.

[0034] The positive progress effect of the present application is that:

[0035] (1) The Kumada reaction is applied to the preparation of the compound of formula 5, the reaction condition is mild, the coupling can be realized by a cheap nickel-based catalyst, the yield is high, the cost is low, and the production is safe.

[0036] (2) The compound of formula 3 can be prepared by Grignard exchange method with mild reaction condition, avoiding the use of traditional hazardous Grignard reaction which is flammable and explosive.

[0037] (3) The overall reaction route is simple, environmentally friendly, the raw materials are simple and easy to obtain, the production cost is low, the disadvantages of high production cost of the compound of formula 1 are solved, and the method has high economic value. DETAILED DESCRIPTION

[0038] The inventors of the present application have made extensive and in-depth research, and for the first time, a new synthesis method of the compound of formula 1 is accidentally developed, which is easy to obtain raw materials, simple operation, environmentally friendly, and cost-competitive. On this basis, the present application is completed.

[0039] The present application will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present application and not to limit the scope of the present application, and the preferred implementation methods and materials described herein are only used as an example. The following examples are described in detail.

[0040] In the following examples, unless otherwise specified, the percentage of the concentration or content of the substance is expressed as a mass percentage.

[0041] Example 1

[0042] Step 1: Preparation of compound 5

[0043]

[0044] Into a reactor was added compound 2-1 (70.00 g, 0.26 mol) and anhydrous tetrahydrofuran (500 mL) under nitrogen protection, and the mixture was cooled to -10 °C. Isopropyl magnesium chloride (2 mol / L 150 mL, 0.3 mol) was added dropwise while the temperature was controlled at -5-0 °C, and the mixture was reacted for 0.5 h. NiCl2(dppf) (6.80 g, 0.01 mol) was added, and the temperature was raised to 20-25 °C. A tetrahydrofuran (400 mL) solution of compound 4 (56.70 g, 0.20 mol) was added dropwise. After the addition was completed, the temperature was raised to 30-40 °C, and the mixture was reacted for 4 h. The mixture was cooled to 5-15 °C, and purified water (500 mL) was added. The mixture was extracted with isopropyl acetate (300 mL), and the water phase was extracted with isopropyl acetate (200 mL). The combined organic phase was washed with 10% sodium chloride (200 mL) and purified water (200 mL) in sequence. The organic phase was collected, and concentrated under reduced pressure at 40-50 °C (-0.09 MPa) to obtain a brown oil. The product was directly used in the next step.

[0045] Second Step: Preparation of Compound 1

[0046]

[0047] Into a reactor was added tetrahydrofuran (80 mL), and the mixture was stirred to dissolve at 20-30 °C. 10% Hydrochloric acid (400 mL) was added, and the mixture was stirred at room temperature for 4 h. A 35% sodium hydroxide solution (sodium hydroxide 50.00 g, water 93.00 g) was added dropwise while the temperature was maintained below 30 °C. After the addition was completed, the temperature was raised to 25-30 °C, and the mixture was stirred for 2 h. The solid was filtered under vacuum, and washed with water twice (50 mL*2). The wet product was filtered to obtain a light brown crude product. The wet product was added with ethyl acetate (120 mL), and the mixture was heated to reflux for 0.5 h. The temperature was slowly lowered to 0-5 °C, and the mixture was maintained for 3 h. The mixture was filtered, and the white solid was dried under reduced pressure at 40 °C for 5 h (-0.09 MPa) to obtain 39.10 g of a white solid. The HPLC purity was 99.12%.

[0048] 1 H NMR (400 MHz, DMSO) δ ppm 13.41 (bs, 1H), 8.74 (s, 1H), 8.67 (bs, 1H), 8.35 (bs, 1H), 7.72 (d, 1H, J = 3.7 Hz), 7.10 (d, 1H, J = 3.7 Hz), 5.61 (s, 2H), 3.51 (t, 2H, J = 8.2 Hz), 0.81 (t, 2H, J = 8.2 Hz), 0.13 (s, 9H).

[0049] The total yield of the first and second steps was 62.00%.

[0050] Example 2

[0051] First Step: Preparation of Compound 5

[0052]

[0053] Into the reactor was added compound 2-2 (70.00 g, 0.32 mol) and anhydrous tetrahydrofuran (400 mL) under nitrogen protection, and isopropyl magnesium chloride-lithium chloride (1.3 mol / L 280.0 mL, 0.36 mol) was added dropwise while the temperature was controlled at 20-30 °C, and the reaction was maintained for 10 hours. NiCl2(dppp) (6.53 g, 0.012 mol) was added, the temperature was raised to 25-30 °C, and a tetrahydrofuran (420 mL) solution of compound 4 (59.50 g, 0.21 mol) was added dropwise. After the dropwise addition was completed, the temperature was raised to 30-40 °C, and the reaction was maintained for 5 hours. The temperature was lowered to 5-15 °C and purified water (450 mL) was added. Isopropyl acetate (280 mL) was added for extraction, and the water phase was extracted with isopropyl acetate (210 mL). The organic phases were combined, washed with 10% sodium chloride (210 mL) and purified water (210 mL) in sequence, and the organic phase was collected. The organic phase was concentrated under reduced pressure at 40-50 °C (-0.09 MPa) to obtain a brown oil, which was directly used in the next step.

[0054] Second Step: Preparation of Compound 1

[0055]

[0056] Into the reactor was added tetrahydrofuran (70 mL), and the solution was dissolved by stirring at 20-30 °C. 30% Sulfuric acid (200 mL) was added, and stirring was performed at room temperature for 4 hours. A 37% sodium hydroxide solution (sodium hydroxide 55.00 g, water 93.00 g) was added dropwise while the temperature was maintained below 30 °C. After the dropwise addition was completed, the temperature was raised to 25-30 °C, and stirring was performed for 2 hours. The solid was filtered under vacuum, washed with water twice (60 mL*2), and filtered to obtain light brown crude wet product. The wet product was heated to reflux for 0.5 hours with the addition of ethyl acetate (140 mL), the temperature was slowly lowered to 0-5 °C, and the mixture was maintained for 3 hours. The mixture was filtered, and the white solid was dried under reduced pressure at 40 °C (-0.09 MPa) for 5.5 hours to obtain 41.66 g of white solid. The HPLC purity was 99.34%.

[0057] 1 H NMR (400 MHz, DMSO) δ ppm 13.41 (bs, 1H), 8.74 (s, 1H), 8.67 (bs, 1H), 8.35 (bs, 1H), 7.72 (d, 1H, J = 3.7 Hz), 7.10 (d, 1H, J = 3.7 Hz), 5.61 (s, 2H), 3.51 (t, 2H, J = 8.2 Hz), 0.81 (t, 2H, J = 8.2 Hz), 0.13 (s, 9H).

[0058] The total yield of the first and second steps was 63.0%.

[0059] Example 3

[0060] Step 1: Preparation of compound 5

[0061]

[0062] Into the reactor was added compound 2-2 (35.00 g, 0.16 mol) and anhydrous tetrahydrofuran (200 mL) under nitrogen protection, and isopropyl magnesium bromide (3 mol / L 60.0 mL, 0.18 mol) was added dropwise while the temperature was controlled at 20-30 °C, and the reaction was maintained for 10 hours. NiCl2(dppe) (5.42 g, 0.01 mol) was added, and the temperature was raised to 25-30 °C, and a tetrahydrofuran (210 mL) solution of compound 4 (30.00 g, 0.11 mol) was added dropwise. After the dropwise addition was completed, the temperature was raised to 30-40 °C, and the reaction was maintained for 7.0 hours. The temperature was lowered to 5-15 °C, and purified water (230 mL) was added, followed by extraction with isopropyl acetate (150 mL), and the water phase was extracted with isopropyl acetate (100 mL). The combined organic phases were washed with 10% sodium chloride (100 mL) and purified water (100 mL) in sequence, and the organic phase was collected and concentrated under reduced pressure at 40-50 °C (-0.09 MPa) to obtain a brownish red oil, which was directly used in the next step.

[0063] Step 2: Preparation of compound 1

[0064]

[0065] Into the reactor was added tetrahydrofuran (40 mL), and the solution was dissolved by stirring at 20-30 °C. A 30% phosphoric acid (40 mL) was added, and the temperature was controlled at room temperature while stirring for 6 hours. A 35% sodium hydroxide solution (sodium hydroxide 20.00 g, water 37.00 g) was added dropwise while the temperature was maintained below 30 °C. After the dropwise addition was completed, the temperature was raised to 25-30 °C, and the stirring was maintained for 2 hours. The solid was filtered under vacuum, and washed with water twice (30 mL*2). The wet product was filtered to obtain a light brown crude product. The wet product was added to ethyl acetate (60 mL), and refluxed for 0.5 hours. The temperature was slowly lowered to 0-5 °C, and the stirring was maintained for 3 hours. The product was filtered, and dried under reduced pressure at 40 °C (-0.09 MPa) for 6.0 hours to obtain a white solid 20.60 g. The HPLC purity was 99.38%.

[0066] 1H NMR (400 MHz, DMSO) δ ppm 13.41 (bs, 1H), 8.74 (s, 1H), 8.67 (bs, 1H), 8.35 (bs, 1H), 7.72 (d, 1H, J = 3.7 Hz), 7.10 (d, 1H, J = 3.7 Hz), 5.61 (s, 2H), 3.51 (t, 2H, J = 8.2 Hz), 0.81 (t, 2H, J = 8.2 Hz), 0.13 (s, 9H).

[0067] The total yield of the first step and the second step was 61.8%.

[0068] Example 4

[0069] First Step: Preparation of Compound 5

[0070]

[0071] To the reactor was added compound 2-1 (35.00 g, 0.13 mol) and anhydrous tetrahydrofuran (220 mL) under nitrogen protection, and cooled to -5-0 °C. Ethyl magnesium bromide (2 mol / L 75 mL, 0.15 mol) was added dropwise, and the temperature was raised to 20-30 °C. The reaction was maintained for 12 hours. NiCl2(dppf) (3.40 g, 0.005 mol) was added, and the temperature was raised to 20-25 °C. A tetrahydrofuran (200 mL) solution of compound 4 (28.00 g, 0.10 mol) was added dropwise. After the addition was completed, the temperature was raised to 30-40 °C, and the reaction was maintained for 4 hours. The temperature was cooled to 5-15 °C. Purified water (250 mL) was added, and isopropyl acetate (150 mL) was extracted. The water phase was extracted with isopropyl acetate (100 mL). The organic phases were combined, washed with 10% sodium chloride (100 mL) and purified water (100 mL) in sequence. The organic phase was collected, and concentrated under reduced pressure at 40-50 °C (-0.09 MPa) to obtain brown oil. The product was directly used in the next step.

[0072] Second Step: Preparation of Compound 1

[0073]

[0074] To the reactor was added tetrahydrofuran (40 mL), and stirred to dissolve at 20-30 °C. 20% hydrochloric acid (120 mL) was added, and stirred at room temperature for 6 hours. A 35% sodium hydroxide solution (sodium hydroxide 30.00 g, water 56.00 g) was added dropwise while maintaining the temperature below 30 °C. After the addition was completed, the temperature was raised to 20-30 °C, and stirred for 3 hours. The solid was filtered under vacuum, and washed with water twice (30 mL*2). The wet product was filtered. The wet product was added with ethyl acetate (65 mL), and heated to reflux for 0.5 hours. The temperature was slowly lowered to 0-5 °C, and maintained for 3 hours. The product was filtered, and dried under reduced pressure at 40 °C (-0.09 MPa) for 5.5 hours to obtain white solid 20.16 g. The HPLC purity was 99.41%.

[0075] 1H NMR (400 MHz, DMSO) δ ppm 13.41 (bs, 1H), 8.74 (s, 1H), 8.67 (bs, 1H), 8.35 (bs, 1H), 7.72 (d, 1H, J = 3.7 Hz), 7.10 (d, 1H, J = 3.7 Hz), 5.61 (s, 2H), 3.51 (t, 2H, J = 8.2 Hz), 0.81 (t, 2H, J = 8.2 Hz), 0.13 (s, 9H).

[0076] Total yield of the first and second steps 64.0%.

[0077] Example 5

[0078] First step: Preparation of compound 5

[0079]

[0080] Into the reactor was added compound 2-1 (17.50 g, 0.062 mol) and anhydrous tetrahydrofuran (130 mL) under nitrogen protection and cooled to -10 °C. Ethyl magnesium chloride (2 mol / L 38 mL, 0.076 mol) was added dropwise while the temperature was controlled at 0-10 °C and the reaction was maintained for 0.5 h. NiCl2(dppp) (1.65 g, 0.003 mol) was added and the temperature was raised to 20-25 °C. A solution of compound 4 (14.20 g, 0.05 mol) in tetrahydrofuran (100 mL) was added dropwise. After the addition was completed, the temperature was raised to 30-40 °C and the reaction was maintained for 4 h. The temperature was lowered to 5-15 °C and purified water (130 mL) was added. The mixture was extracted with isopropyl acetate (80 mL) and the aqueous phase was extracted with isopropyl acetate (50 mL). The combined organic phases were washed successively with 10% sodium chloride (50 mL) and purified water (50 mL). The organic phase was collected and concentrated under reduced pressure at 40-50 °C (-0.09 MPa) to obtain a brown oil which was directly used in the next step.

[0081] Second step: Preparation of compound 1

[0082]

[0083] Into the reactor was added tetrahydrofuran (20 mL) and the mixture was stirred to dissolve at 20-30 °C. 30% Phosphoric acid (22 mL) was added and the mixture was stirred at room temperature for 6 h. 35% Sodium hydroxide solution (sodium hydroxide 10.50 g, water 20.00 g) was added dropwise while the temperature was maintained below 30 °C. After the addition was completed, the temperature was raised to 20-30 °C and the mixture was stirred for 2 h. The solid was filtered under vacuum and washed twice with water (20 mL*2). The wet product was added to ethyl acetate (30 mL) and the mixture was heated to reflux for 0.5 h. The temperature was slowly lowered to 0-5 °C and the mixture was maintained for 3 h. The mixture was filtered and the white solid was dried under reduced pressure at 40 °C (-0.09 MPa) for 5.0 h. The yield was 9.78 g and the HPLC purity was 99.52%.

[0084] 1H NMR (400 MHz, DMSO) δ ppm 13.41 (bs, 1H), 8.74 (s, 1H), 8.67 (bs, 1H), 8.35 (bs, 1H), 7.72 (d, 1H, J = 3.7 Hz), 7.10 (d, 1H, J = 3.7 Hz), 5.61 (s, 2H), 3.51 (t, 2H, J = 8.2 Hz), 0.81 (t, 2H, J = 8.2 Hz), 0.13 (s, 9H).

[0085] Total yield of first and second steps 62.0%.

[0086] It is to be understood that while the present application has been described above with reference to specific embodiments, the application is not meant to be limited to the specifics of these embodiments but rather can be practiced with modifications within the scope of the appended claims.

Claims

1. A process for the preparation of a compound of formula 1, characterized in that, It comprises the following steps: (a) Kumada coupling reaction of a compound of formula 3 with a compound of formula 4 to obtain a compound of formula 5; X is Cl or Br; (b) deprotection of the compound of formula 5 to selectively remove the ethoxyethyl group to obtain the compound of formula 1; In step (a), the Kumada coupling reaction is carried out in the presence of a catalyst, which is a nickel-based catalyst.

2. The production method according to claim 1, wherein The nickel-based catalyst is one or more of NiCl2(dppf), NiCl2(dppp) and NiCl2(dppe).

3. The production method according to claim 1, wherein The molar ratio of the compound of formula 4 to the catalyst is 10:1 to 20:

1.

4. The production method according to claim 1, wherein In step (a), the solvent of the Kumada coupling reaction is tetrahydrofuran and / or 2-methyltetrahydrofuran; And / or, in step (a), the reaction temperature of the Kumada coupling reaction is 20°C to 60°C.

5. The production method according to claim 1, wherein In step (a), the reaction temperature of the Kumada coupling reaction is 30°C to 40°C.

6. The production method according to claim 1, wherein In step (a), the compound of formula 3 is prepared by the following method: The Grignard exchange reaction of the compound of formula 2 in the presence of an alkyl magnesium halide, wherein R is I or Br.

7. The production method according to claim 6, wherein The alkyl magnesium halide is one or more of isopropyl magnesium chloride, isopropyl magnesium chloride-lithium chloride, isopropyl magnesium bromide, methyl magnesium chloride, methyl magnesium bromide, ethyl magnesium chloride and ethyl magnesium bromide; And / or, the molar ratio of the compound of formula 2 to the alkyl magnesium halide is 1:1 to 1:1.

2.

8. The production method according to claim 6, wherein The solvent of the Grignard exchange reaction is one or more of tetrahydrofuran, 2-methyltetrahydrofuran and toluene; And / or, the temperature of the Grignard exchange reaction is -10°C to 30°C.

9. The production method according to claim 6, wherein The temperature of the Grignard exchange reaction is -5°C to 0°C.

10. The production method according to any one of claims 6 to 9, wherein The compound of formula 5 is prepared by one-pot method.

11. The production method according to claim 1, wherein In step (b), the deprotection is carried out in the presence of an acid; And / or, in step (b), the temperature of the deprotection is 10°C to 45°C.

12. The production method according to claim 11, wherein In step (b), the acid is one or more of sulfuric acid, hydrochloric acid and phosphoric acid.

13. The production method according to claim 1, wherein In step (b), the temperature of the deprotection is 25°C to 30°C.

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