Preparation method of JAK inhibitor intermediate

Abstract

The invention provides a preparation method of a JAK inhibitor intermediate, and particularly relates to a preparation method of a baricitinib or ruxolitinib intermediate. The method does not use precious metal reagents, the reagents are cheap and easy to obtain, post-treatment is simple, and the method is suitable for large-scale industrial production.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical technology, and particularly relates to a preparation method of a JAK inhibitor intermediate. Background Art

[0002] Ruxolitinib is a small molecule inhibitor of protein kinases JAK1 and JAK2, and is the first drug approved by the FDA for the treatment of myelofibrosis. Baricitinib is an oral selective reversible Janus kinase (JAKs) inhibitor, and the FDA has approved it for the treatment of adult patients with moderate to severe active rheumatoid arthritis who are insufficiently responsive to other disease-modifying antirheumatic drugs (DMARDs), including TNF antagonist therapies. Their structural formulas are as follows:

[0003]

[0004] The key preparation intermediates of ruxolitinib and baricitinib have the following structures:

[0005]

[0006] The existing synthetic routes of 4-(1H-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine mainly include:

[0007] (1) Patent CN104024256B reported the following synthetic method.

[0008]

[0009] Using compound I as a raw material, the N-terminus is protected with a SEM protecting group, and then it undergoes a coupling reaction with III-1 under the catalysis of tetrakis(triphenylphosphine)palladium to obtain compound IV-2. Finally, the protecting group at the N-terminus of the pyrazole ring is removed to obtain compound V.

[0010] (2) Patent CN114044777B reported the following synthetic method.

[0011]

[0012] Using compound I as a raw material, the N-terminus is protected with a SEM protecting group, and then it reacts with a Grignard reagent and a borate ester to generate compound III-2. Finally, it undergoes a Suzuki coupling with IV-2 under the catalysis of an organometallic catalyst Ni(PCy3)2Cl2 to obtain compound V.

[0013] (3) Patent CN111320633B reported the following synthetic method.

[0014]

[0015] Using compound I as a raw material, the SEM protecting group is introduced at the N-terminus, and then it is coupled with (1H-pyrazol-4-yl)boronic acid pinacol ester under the catalysis of Pd(ddf)Cl2 to obtain compound V.

[0016] In summary, the synthetic methods for preparing compound V from compound I disclosed in the existing patents all involve the coupling reaction step, and precious metal reagents are used as catalysts in the reaction, such as palladium reagents or nickel reagents. Moreover, whether the synthetic raw materials are boronic esters or bromides, their prices are relatively high, resulting in generally high production costs and being not suitable for large-scale production. Therefore, in order to further reduce the production cost, there is still a need in the art to develop a new synthetic method with inexpensive reagents, simple operation, and easy purification of the product. Summary of the Invention

[0017] The present invention discloses a preparation method for an intermediate of a JAK inhibitor.

[0018] A preparation method for a structure represented by formula (E):

[0019]

[0020] Wherein:

[0021] X - is selected from Cl - 、ClO4 - 、BF4 - 、PF6 - 、AsF6 - 、SbF6 - ;

[0022] P is an amino protecting group;

[0023] The structure represented by formula (D) or its salt reacts with hydrazine hydrate to obtain the structure represented by formula (E).

[0024] In one embodiment, the structure represented by formula (D) or its salt is prepared by the following method:

[0025]

[0026] X ’ is a halogen, preferably F, Cl or Br, more preferably Br.

[0027] In one embodiment, P is SEM, Boc, Cbz, Tos or Bn.

[0028] In one embodiment, The structure shown reacts with hydrazine hydrate to obtain the structure represented by formula (E-1).

[0029] In one embodiment, the structure represented by formula (D-1) is prepared by the following method:

[0030]

[0031] Step 1-1: The structure shown in formula (A) reacts with 2-(trimethylsilyl)ethoxymethyl chloride under the action of sodium tert-butoxide to obtain the structure shown in formula (B-1);

[0032] Step 2-1: Under a nitrogen atmosphere, the structure shown in formula (B-1) reacts with iron(III) acetylacetonate and methylmagnesium chloride to obtain the structure shown in formula (C-1)

[0033] Step 3-1: The structure shown in formula (C-1) reacts with oxalyl chloride to obtain the structure shown in formula (D-1).

[0034] In one embodiment,

[0035] The present invention also discloses the structure shown in formula (D) or its salt;

[0036]

[0037] X- is selected from Cl-, ClO4 - , BF4-, PF6 - , AsF6 - , SbF6 - ;

[0038] P is an amino protecting group.

[0039] In one embodiment, P is SEM, Boc, Cbz, Tos or Bn.

[0040] In one embodiment, the compound or its salt is selected from the following structures:

[0041]

[0042]

[0043] The use of the compound or its salt described in any embodiment for the preparation of ruxolitinib and baricitinib.

[0044] The beneficial technical effects of the present invention: The route of the present invention does not involve the catalysis of precious metal reagents. The route of the present invention has low cost and high yield, and is suitable for large-scale industrial production. Detailed implementation manners

[0045] Example 1: Preparation method of compound (E-1)

[0046]

[0047] Dissolve sodium tert-butoxide (15.0 g) in DMF (50 mL); dissolve compound (A) (20.0 g) in DMF (50 mL), and cool the temperature to 0 ± 5 °C; dropwise add the prepared DMF solution of sodium tert-butoxide under stirring; after the addition, react for 1 hour; dropwise add 2-(trimethylsilyl)ethoxymethyl chloride (26.0 g); after the addition, continue stirring for 2 hours; add water to the reaction solution, extract with ethyl acetate, wash the organic phase with saturated brine after liquid separation, dry the organic phase, and concentrate to dryness; purify the crude product by silica gel column chromatography to obtain the crude product of compound (B-1) with a yield of 100%, which is directly used for the next step.

[0048]

[0049] Dissolve the crude product of compound (B-1) (37.0 g) in tetrahydrofuran (300 mL), and cool the temperature to 0 - 5 °C; add Fe(acac)3 (2.3 g) to the reaction solution; dropwise add methylmagnesium chloride (65 mL) under nitrogen protection, and after the addition, let it rise to room temperature naturally and stir overnight; dropwise add saturated ammonium chloride solution to the reaction system, add MTBE and stir evenly, pad with diatomaceous earth, and filter under reduced pressure. For the obtained filtrate, after liquid separation, concentrate the organic phase; perform column chromatography (ethyl acetate / n-heptane = 1 / 20 to 1 / 4) to obtain the oily compound (C-1) (26.8 g); yield: 78%.

[0050]

[0051] Dissolve oxalyl chloride (29.1 g) in acetonitrile (130 mL), and cool the temperature to 0 - 5 °C; slowly add dropwise DMF (96.8 g) to the reaction solution, and keep the temperature below 10 °C; after the addition is complete, raise the temperature to room temperature and stir for 1 hour; add compound (C-1) (26.8 g) to the reaction system, and stir to mix evenly; raise the temperature to 85 - 90 °C and react for 1 hour; cool to room temperature, add hydrazine hydrate (9.6 g), and continue to stir overnight; concentrate the reaction solution, add saturated brine, extract with ethyl acetate, dry the organic phase, and concentrate to dryness; slurry with ethyl acetate / n-heptane (=1 / 4, 250 mL); filter under reduced pressure to obtain the crude product of compound (E-1) (23.0 g); add the crude product of compound (E-1) to a reaction flask, add ethyl acetate (100 mL), heat to 70 °C, and reflux for 4 hrs; after cooling to room temperature, filter under reduced pressure, wash the filter cake with ethyl acetate (20 mL), and dry the filter cake to obtain compound (E-1) (16.2 g); Yield: 50%. 1H NMR (DMSO-d6, 400 MHz): 13.30 (bs, 1H), 8.76 (s, 1H), 8.66 (bs, 1H), 8.36 (bs, 1H), 7.74 (d, 1H), 7.11 (d, 1H), 5.62 (s, 2H), 3.51 (t, 2H), 0.82 (t, 2H), 0.15 (s, 9H).

[0052] Example 2: Preparation method of compound (E-1)

[0053]

[0054] Dissolve sodium methoxide (15.0 g) in DMF (50 mL); dissolve compound (A-1) (26.0 g) in DMF (55 mL), and cool the temperature to 5 ± 5 °C; add dropwise the prepared DMF solution of sodium methoxide with stirring; after the addition is complete, react for 2 hours; add dropwise 2-(trimethylsilyl)ethoxymethyl chloride (28.0 g); after the addition is complete, continue to stir for 2 hours; add 100 ml of water to the reaction solution, extract with 100 ml of ethyl acetate, wash the organic phase with 100 ml of saturated brine after liquid separation, dry the organic phase, and concentrate to dryness; obtain the crude product of compound (B-2) with a yield of 100%, which is directly used for the next step.

[0055]

[0056] Dissolve the crude product of compound (B-2) (43.1 g) in tetrahydrofuran (300 mL), and cool the temperature to 0 - 5 °C; add Fe(acac)3 (2.5 g) to the reaction solution; dropwise add methylmagnesium chloride (65 mL) under nitrogen protection. After the addition is complete, let it rise to room temperature naturally and stir overnight; add 50 mL of saturated ammonium chloride solution dropwise to the reaction system, add 100 mL of MTBE, stir evenly, then filter under reduced pressure. For the obtained filtrate, after liquid separation, concentrate the organic phase; obtain the oily compound (C-1) (26.6 g); yield: 76.9%

[0057]

[0058] Dissolve oxalyl chloride (34.8 g) in acetonitrile (150 mL), and cool the temperature to 0 - 5 °C; slowly dropwise add DMF (97.0 g) to the reaction solution, keeping the temperature below 10 °C; after the addition is complete, rise to room temperature and stir for 1 hour; add compound (C-1) (26.6 g) to the reaction system and stir to mix evenly; heat up to 80 - 85 °C and react for 1 hour; add 50 g of NaPF6 and continue to stir for 2 hours, cool to room temperature, add hydrazine hydrate (9.6 g), and continue to stir overnight; concentrate the reaction solution, add 100 mL of saturated brine, extract with 100 mL of ethyl acetate, dry the organic phase, and concentrate to dryness; slurry with ethyl acetate / n-heptane (=1 / 4, 250 mL); filter under reduced pressure to obtain the crude product of compound (E-1) (23.2 g); add the crude product of compound (E-1) to the reaction flask, add ethyl acetate (100 mL), heat to 70 °C, and reflux for 4 h; after cooling to room temperature, filter under reduced pressure, wash the filter cake with ethyl acetate (20 mL), and dry the filter cake to obtain compound (E-1) (16.3 g); yield: 51.2%.

[0059] Example 3: Preparation method of compound (E-2)

[0060]

[0061] Dissolve sodium methoxide (15.0 g) in DMF (50 mL); dissolve compound (A-2) (18.0 g) in DMF (55 mL), and cool the temperature to 5 ± 5 °C; dropwise add the prepared DMF solution of sodium methoxide with stirring; after the addition is complete, react for 2 hours; dropwise add di-tert-butyl dicarbonate (28.0 g); after the addition is complete, continue to stir for 2 hours; add 100 mL of water to the reaction solution, extract with 100 mL of ethyl acetate, after liquid separation, wash the organic phase with 100 mL of saturated brine, dry the organic phase, and concentrate to dryness; obtain the crude product of compound (B-3) with a yield of 100%, which is directly used for the next step.

[0062]

[0063] Dissolve the crude product of compound (B-3) (31.1 g) in tetrahydrofuran (300 mL), and cool the temperature to 0 - 5 °C; add Fe(acac)3 (2.5 g) to the reaction solution; under nitrogen protection, dropwise add methylmagnesium chloride (65 mL). After the addition is complete, naturally raise the temperature to room temperature and stir overnight; dropwise add saturated ammonium chloride solution to the reaction system, add 50 mL of MTBE, stir evenly, pad with diatomaceous earth, and filter under reduced pressure. For the obtained filtrate, after liquid separation, concentrate the organic phase; obtain the oily compound (C-2) (23.9 g); the yield is 78.2%.

[0064]

[0065] Dissolve oxalyl chloride (35.0 g) in acetonitrile (150 mL), and cool the temperature to 0 - 5 °C; slowly dropwise add DMF (97.0 g) to the reaction solution, keeping the temperature below 10 °C; after the addition is complete, raise the temperature to room temperature and stir for 1 hour; add compound (C-2) (23.9 g) to the reaction system and stir to mix evenly; raise the temperature to 90 - 95 °C and react for 1 hour, add NaClO4 (39 g) and continue to stir for 2 hours; cool to room temperature, add hydrazine hydrate (9.6 g), and continue to stir overnight; concentrate the reaction solution, add 100 mL of saturated brine, extract with 100 mL of ethyl acetate, dry the organic phase, and concentrate to dryness; slurry with ethyl acetate / n-heptane (=1 / 3, 320 mL); filter under reduced pressure to obtain the crude product of compound (E-2) (23.5 g); add the crude product of compound (E-2) to the reaction flask, add ethyl acetate (100 mL), heat to 70 °C, and reflux for 4 h; after cooling to room temperature, filter under reduced pressure, wash the filter cake with ethyl acetate (20 mL), and dry the filter cake to obtain compound (E-2) (17.1 g); the yield: 58.5%.

[0066] Example 4: Preparation method of compound (E-3)

[0067]

[0068] Dissolve sodium tert-butoxide (16.0 g) in DMF (60 mL); dissolve compound (A-1) (26.0 g) in DMF (55 mL), and cool the temperature to 0 ± 5 °C; dropwise add the prepared DMF solution of sodium tert-butoxide with stirring; after the addition is complete, react for 2 hours; dropwise add p-toluenesulfonyl chloride (28.0 g); after the addition is complete, continue to stir for 2 hours; add 100 mL of water to the reaction solution, extract with 100 mL of ethyl acetate, after liquid separation, wash the organic phase with 100 mL of saturated brine, dry the organic phase, and concentrate to dryness; obtain the crude product of compound (B-4) with a yield of 100%, which is directly used for the next step.

[0069]

[0070] Dissolve the crude product of compound (B-4) (46.1 g) in tetrahydrofuran (300 mL), and cool the temperature to 0-5 °C; add Fe(acac)3 (2.5 g) to the reaction solution; under nitrogen protection, dropwise add methylmagnesium chloride (65 mL). After the addition is complete, naturally warm up to room temperature and stir overnight; add saturated ammonium chloride solution dropwise to the reaction system. After adding 50 mL of MTBE and stirring evenly, filter under reduced pressure. For the obtained filtrate, after liquid separation, concentrate the organic phase; obtain the oily compound (C-3) (29.1 g); yield: 77.4%.

[0071]

[0072] Dissolve oxalyl chloride (36.0 g) in acetonitrile (150 mL), and cool the temperature to 0-5 °C; slowly dropwise add DMF (97.0 g) to the reaction solution, keeping the temperature below 10 °C; after the addition is complete, warm up to room temperature and stir for 1 hour; add the compound (C-3) (29.1 g) to the reaction system and stir to mix evenly; heat up to 90-95 °C and react for 2 hours, then add NaSbF6 (58.0 g) and continue stirring for 3 hours; cool to room temperature, add hydrazine hydrate (9.6 g), and continue stirring overnight; concentrate the reaction solution, add 100 mL of saturated brine, extract with 100 mL of ethyl acetate, dry the organic phase, and concentrate to dryness; slurry with ethyl acetate / n-heptane (=1 / 4, 250 mL); filter under reduced pressure to obtain the crude product of compound (E-3) (25.4 g); add the crude product of compound (E-3) to the reaction flask, add ethyl acetate (100 mL), heat to 70 °C, and reflux for 4 h; after cooling to room temperature, filter under reduced pressure, wash the filter cake with ethyl acetate (20 mL), and dry the filter cake to obtain compound (E-3) (17.9 g); yield: 52.1%.

[0073] Example 5: Preparation method of compound (E-4)

[0074]

[0075] Dissolve sodium tert-butoxide (16.0 g) in DMF (60 mL); dissolve compound (A-1) (26.0 g) in DMF (55 mL), and cool the temperature to 0±5 °C; dropwise add the prepared DMF solution of sodium tert-butoxide with stirring; after the addition is complete, react for 2 hours; dropwise add p-benzyl chloride (24.0 g); after the addition is complete, continue stirring for 2 hours; add 100 mL of water to the reaction solution, extract with 100 mL of ethyl acetate, after liquid separation, wash the organic phase with 100 mL of saturated brine, dry the organic phase, and concentrate to dryness; obtain the crude product of compound (B-5) with a yield of 100%, which is directly used for the next step.

[0076]

[0077] The crude product of compound (B-5) (37.8 g) was dissolved in tetrahydrofuran (300 mL), and the temperature was lowered to 0 - 5 °C; Fe(acac)3 (2.5 g) was added to the reaction solution; methylmagnesium chloride (65 mL) was added dropwise under nitrogen protection. After the addition was complete, the temperature was naturally raised to room temperature, and the mixture was stirred overnight; 50 mL of saturated ammonium chloride solution was added dropwise to the reaction system, 50 mL of MTBE was added and stirred evenly, then filtered under reduced pressure. The obtained filtrate was separated, and the organic phase was concentrated; an oily compound (C-4) (22.7 g) was obtained; yield: 77.5%.

[0078]

[0079] Oxalyl chloride (36.0 g) was dissolved in acetonitrile (150 mL), and the temperature was lowered to 0 - 5 °C; DMF (97.0 g) was slowly added dropwise to the reaction solution while maintaining the temperature below 10 °C; after the addition was complete, the temperature was raised to room temperature and stirred for 2 hours; compound (C-4) (22.7 g) was added to the reaction system and stirred to mix evenly; the temperature was raised to 90 - 95 °C and reacted for 2 hours, then NaAsF6 (46.0 g) was added and stirred for 1 hour; cooled to room temperature, hydrazine hydrate (9.6 g) was added, and stirring was continued overnight; the reaction solution was concentrated, 100 mL of saturated brine was added, and extracted with 100 mL of ethyl acetate. The organic phase was dried and concentrated to dryness; a crude product of compound (E-4) (25.4 g) was obtained; the crude product of compound (E-4) was added to a reaction flask, 100 mL of ethyl acetate was added, and heated to 70 °C and refluxed for 3 h; after cooling to room temperature, filtered under reduced pressure, and the filter cake was dried to obtain compound (E-4) (16.2 g); yield: 57.9%.

Claims

1. A method for preparing a structure represented by formula (E): in: X - Selected from Cl - 、ClO4 - 、BF4 - PF6 - 、AsF6 - 、SbF6 - ; P is an amino protecting group; The structure represented by formula (D) or its salt reacts with hydrazine hydrate to obtain the structure represented by formula (E).

2. According to the preparation method of claim 1, the structure represented by formula (D) or its salt is prepared by the following method: X ’ is halogen, preferably F, Cl or Br, more preferably Br.

3. The preparation method according to claim 2; P is SEM, Boc, Cbz, Tos or Bn.

4. A method for preparing a structure represented by formula (E-1):, characterized in that: The structure represented by formula (D-1) reacts with hydrazine hydrate to obtain the structure represented by formula (E-1).

5. According to the preparation method of claim 4, the structure represented by formula (D-1) is prepared by the following method: Step 1-1: The structure shown in formula (A) reacts with 2-(trimethylsilyl)ethoxymethyl chloride under the action of sodium tert-butoxide to obtain the structure shown in formula (B-1); Step 2-1: Under nitrogen environment, the structure shown in formula (B-1) reacts with triacetylacetonate iron and methylmagnesium chloride to obtain the structure shown in formula (C-1) step3-1: The structure shown in formula (C-1) reacts with oxalyl chloride to obtain the structure shown in formula (D-1).

6. The preparation method according to claim 1, characterized in that:

7. The structure represented by formula (D) or a salt thereof; X - Selected from Cl - 、ClO4 - 、BF4 - PF6 - 、AsF6 - 、SbF6 - ; P is an amino protecting group.

8. The structure represented by formula (D) or a salt thereof according to claim 7, P is SEM, Boc, Cbz, Tos or Bn.

9. A compound or a salt thereof selected from the following structures:

10. Use of the structure or salt thereof according to any one of claims 7 to 9 for preparing ruxolitinib and baricitinib.

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