A synthetic method for a Pevonedistat intermediate

Abstract

The present invention discloses a method for synthesizing a pevonedistat intermediate, comprising the following steps: adding compound I, triethyl orthoformate and a catalyst into a reaction vessel to react and generate compound II; performing a crystallization operation and filtering the reaction solution to obtain a crude compound II; adding the crude compound II and (S)-(+)-1-aminoindene into a solvent to react and generate compound III; adding a nucleophilic substance into the reaction solution, performing a reflux reaction, and causing compound III to undergo a Dimroth rearrangement to generate a crude compound IV; and recrystallizing the crude compound IV to obtain a refined compound IV. The method for synthesizing the pevonedistat intermediate provided by the present invention uses compound I as a raw material to generate N-(S)-(+)-1-aminoindene as a pevonedistat intermediate in two steps. 6 -Indenyl-7-deazaadenine; the synthesis method shortens the production cycle, has mild synthesis conditions, and low raw material prices, which is conducive to industrial production.

Description

Technical Field

[0001] The present invention relates to the technical field of antitumor drug synthesis, in particular to a method for synthesizing a Pevonedistat intermediate. Background Art

[0002] Pevonedistat, chemical name: [(1S,2S,4R)-4-[4-[[(1S)-2,3-dihydro-1H-inden-1-yl]amino]-7H-pyrrolo[2,3-D]pyrimidin-7-yl]-2-hydroxycyclopentyl]methylsulfamic acid ester, CAS: 905579-51-3, is a NEDD8 activating enzyme (NAE) inhibitor developed by Takeda Pharmaceuticals for the treatment of high-risk myelodysplastic syndromes (HR-MDS). Preclinical studies have demonstrated that pevonedistat's inhibition of NAE blocks the modification of specific proteins, thereby disrupting cell cycle progression and cell survival, leading to cancer cell death.

[0003]

[0004] The structure of Pevonedistat can be divided into fragment A, fragment B, and fragment C as follows.

[0005]

[0006] Currently, the following two synthetic routes of Pevonedistat are disclosed in relevant literature:

[0007] 1. Org.ProcessRes.Dev.2015,19,1299-1307 discloses a synthetic route of Pevonedistat:

[0008]

[0009] 2. Patent document US2012 / 330013 reports another synthetic route for Pevonedistat:

[0010]

[0011] The above-mentioned synthetic route 1 first synthesizes a substance containing a C fragment structure, and uses the substance containing a C fragment structure as the reaction basis for a series of subsequent reactions; in this route, the substance containing a C fragment structure reacts with a substance containing a B fragment structure to obtain a BC fragment joint structure, and the BC fragment joint structure further reacts with a substance containing an A fragment structure to obtain Pevonedistat. The chiral structure of the C fragment is complex, difficult to synthesize, and expensive, so using a substance containing a C fragment structure as the structural basis for synthesizing Pevonedistat will greatly increase production costs. Compared with synthetic route 1, the above-mentioned synthetic route 2 introduces N 6 -Indenyl-7-deazaadenine reacts with substances containing C fragment structure, N 6 -Indenyl-7-deazaadenine is an AB fragment combination structure, thus avoiding the process of using a substance containing a C fragment structure as a reaction basis to generate a BC fragment combination structure, which can reduce the consumption of substances containing a C fragment structure and reduce production costs.

[0012]

[0013] It can be seen that N 6 -Indenyl-7-deazaadenine, also known as N-[(1S)-2,3-dihydro-1H-inden-1-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine, CAS: 905580-86-1, is an important intermediate in the synthesis of Pevonedistat; however, there is currently little research on the synthesis path of this Pevonedistat intermediate in China, and the existing synthesis method has defects such as expensive raw materials and harsh reaction conditions; therefore, the present application provides a synthesis method of Pevonedistat intermediate, which is of great significance to the overall synthesis of Pevonedistat and the study of the properties of Pevonedistat. Summary of the Invention

[0014] In order to improve the problems in the background technology, the present invention provides a method for synthesizing a Pevonedistat intermediate, comprising the following steps:

[0015] 1) Compound I, triethyl orthoformate, and a catalyst are added to a reaction vessel to react to produce Compound II; crystallization is performed, and the reaction solution is filtered to obtain a crude product of Compound II;

[0016] 2) Adding crude compound II and (S)-(+)-1-aminoindene to a solvent to react to produce compound III; adding a nucleophilic substance to the reaction solution and refluxing the solution to cause compound III to undergo Dimroth rearrangement to produce compound IV; performing a crystallization operation, filtering the reaction solution to obtain crude compound IV; and recrystallizing the crude compound IV to obtain refined compound IV;

[0017] The reaction path is as follows:

[0018]

[0019] Wherein, Nu is a nucleophile. The chemical name of compound I is: 2-amino-1H-pyrrole-3-carbonitrile.

[0020] Preferably, in step 1), the reaction of compound I, triethyl orthoformate and the catalyst uses triethyl orthoformate as solvent; the molar ratio of compound I to triethyl orthoformate is 1.0:6.0.

[0021] Preferably, in step 1), the reaction of compound I, triethyl orthoformate and the catalyst is carried out in tetrahydrofuran; the molar ratio of compound I to triethyl orthoformate is 1.0:1.0-2.0.

[0022] Preferably, in step 1), the molar ratio of compound I to triethyl orthoformate is 1.0:1.5.

[0023] Preferably, in step 1), the catalyst is selected from one or more of p-toluenesulfonic acid, trifluoroacetic acid, and acetic acid.

[0024] Preferably, in step 2), the molar ratio of compound I to (S)-(+)-1-aminoindene is 1.0:1.0-1.6.

[0025] Preferably, in step 2), the molar ratio of compound I to (S)-(+)-1-aminoindene is 1.0:1.3.

[0026] Preferably, in step 2), the solvent is selected from one or more of DMF, ethanol, and 1,4-dioxane.

[0027] Preferably, in step 2), the nucleophilic substance is selected from water or sodium ethoxide.

[0028] Preferably, in step 2), the solvent used for recrystallization is ethyl acetate; activated carbon is added to the ethyl acetate as an impurity adsorbent and decolorizer, and the ratio of activated carbon to ethyl acetate is 0.1 g / ml.

[0029] In summary, the present invention has the following beneficial effects:

[0030] The present invention provides a method for synthesizing a Pevonedistat intermediate, wherein compound I, triethyl orthoformate and (S)-(+)-1-aminoindene are used as raw materials and reacted in two steps to produce the desired Pevonedistat intermediate N 6-Indenyl-7-deazaadenine. Using this route to synthesize the aforementioned Pevonedistat intermediate can shorten the production cycle. Furthermore, the synthetic route has mild conditions and low raw material prices, which is conducive to industrial production and has good industrial prospects. DETAILED DESCRIPTION

[0031] The present invention is described in detail below with reference to the embodiments, but the present invention is not limited to these embodiments.

[0032] Example 1

[0033] This embodiment provides a method for synthesizing a Pevonedistat intermediate, which is synthesized by the following steps:

[0034] 1) Weigh 21.4 g (0.2 mol) of compound I into a reaction flask, add 150 ml of tetrahydrofuran and stir to dissolve; add 44.4 g (0.3 mol) of triethyl orthoformate and 3.44 g (0.02 mol) of p-toluenesulfonic acid in sequence; heat and control the reflux reaction until the raw materials are completely reacted, and monitor the process by TLC (EA:PE = 1:4); after the reaction is completed, concentrate under reduced pressure to near dryness to obtain 40.4 g of crude compound II (solid) with a yield of 124.5%, which is used directly in the next reaction without purification;

[0035] 2) The crude compound II from step 1) was dissolved in 200 ml of DMF, and 34.58 g (0.26 mol) of (S)-(+)-1-aminoindene was added with stirring. The mixture was heated and refluxed for 45 minutes. 300 mL of water was slowly added dropwise to the reaction solution, and reflux was continued until the reaction of compound II was complete. The reaction time was approximately 8 hours, and the process was monitored by TLC (EA:PE = 1:2). After the reaction was completed, the mixture was cooled to room temperature, stirred, and crystallized completely. After filtration, crude compound IV was obtained. The crude compound IV was recrystallized from ethyl acetate, with activated carbon added as an impurity adsorbent and decolorizer. The ratio of activated carbon to ethyl acetate was 0.1 g / ml. Recrystallization yielded 36.2 g of purified compound IV, with a combined yield of 71.5% for both steps and a purity of 99.882% by HPLC.

[0036] Example 2

[0037] This embodiment provides a method for synthesizing a Pevonedistat intermediate, which is synthesized by the following steps:

[0038] 1) Weigh 21.4 g (0.2 mol) of compound I into a reaction flask, add 150 ml of tetrahydrofuran and stir to dissolve; add 29.6 g (0.2 mol) of triethyl orthoformate and 3.44 g (0.02 mol) of p-toluenesulfonic acid in sequence; heat and control the reflux reaction until the reaction of the raw materials is complete, and monitor the process by TLC (EA:PE = 1:4); after the reaction is completed, concentrate under reduced pressure to near dryness to obtain 35.68 g of crude compound II (solid) with a yield of 110.0%, which is used directly in the next reaction without purification;

[0039] 2) The crude compound II from step 1) was dissolved in 200 ml of DMF, and 34.58 g (0.26 mol) of (S)-(+)-1-aminoindene was added with stirring. The mixture was heated and refluxed for 45 minutes. 300 mL of water was slowly added dropwise to the reaction solution, and reflux was continued until the reaction of compound II was complete. The reaction time was approximately 8 hours, and the process was monitored by TLC (EA:PE = 1:2). After the reaction was completed, the mixture was cooled to room temperature and stirred until crystallization was complete. After filtration, crude compound IV was obtained. The crude compound IV was recrystallized from ethyl acetate, with activated carbon added as an impurity adsorbent and decolorizer. The ratio of activated carbon to ethyl acetate was 0.1 g / ml. Recrystallization yielded 30.0 g of purified compound IV, with a combined yield of 59.3% for both steps and a purity of 99.662% by HPLC.

[0040] Example 3

[0041] This embodiment provides a method for synthesizing a Pevonedistat intermediate, which is synthesized by the following steps:

[0042] 1) Weigh 21.4 g (0.2 mol) of compound I into a reaction flask, add 150 ml of tetrahydrofuran and stir to dissolve; then add 59.2 g (0.4 mol) of triethyl orthoformate and 3.44 g (0.02 mol) of p-toluenesulfonic acid in sequence; heat and control the reflux reaction until the reaction of the raw materials is complete, and monitor the process by TLC (EA:PE = 1:4); after the reaction is completed, concentrate under reduced pressure to near dryness to obtain 46.7 g of crude compound II (solid) with a yield of 143.9%, which is used directly in the next reaction without purification;

[0043] 2) The crude compound II from step 1) was dissolved in 200 ml of DMF, and 34.58 g (0.26 mol) of (S)-(+)-1-aminoindene was added with stirring. The mixture was heated and refluxed for 45 min. 300 mL of water was slowly added dropwise to the reaction solution, and reflux was continued until the reaction of compound II was complete. The reaction time was approximately 8 hrs, and the reaction was monitored by TLC (EA:PE = 1:2). After the reaction was completed, the mixture was cooled to room temperature, stirred, and crystallized completely. After filtration, crude compound IV was obtained. The crude compound IV was recrystallized from ethyl acetate, with activated carbon added as an impurity adsorbent and decolorizer. The ratio of activated carbon to ethyl acetate was 0.1 g / ml. Recrystallization yielded 35.6 g of purified compound IV, with a combined yield of 70.3% for both steps and a purity of 99.641% by HPLC.

[0044] Example 4

[0045] This embodiment provides a method for synthesizing a Pevonedistat intermediate, which is synthesized by the following steps:

[0046] 1) Weigh 21.4 g (0.2 mol) of compound I into a reaction flask, add 150 ml of tetrahydrofuran and stir to dissolve; add 44.4 g (0.3 mol) of triethyl orthoformate and 3.44 g (0.02 mol) of p-toluenesulfonic acid in sequence; heat and control the reflux reaction until the raw materials react completely, and monitor the process by TLC (EA:PE = 1:4); after the reaction is completed, concentrate under reduced pressure to near dryness to obtain 41.0 g of crude compound II (solid) with a yield of 126.3%, which is used directly in the next reaction without purification;

[0047] 2) The crude compound II from step 1) was dissolved in 200 ml of DMF, and 26.6 g (0.20 mol) of (S)-(+)-1-aminoindene was added with stirring. The mixture was heated and refluxed for 45 min. 300 mL of water was slowly added dropwise to the reaction solution, and the reflux reaction was continued after the addition. The process was monitored by TLC (EA:PE = 1:2). In this example, the reaction of compound II was incomplete, and 10% (S)-(+)-1-aminoindene was added after 8 hours, but the effect was not significant. After the reaction was completed, the mixture was cooled to room temperature, stirred, and crystallized completely. After filtration, crude compound IV was obtained. The crude compound IV was recrystallized from ethyl acetate, with activated carbon added as an impurity adsorbent and decolorizer. The ratio of activated carbon to ethyl acetate was 0.1 g / ml. Recrystallization yielded 31.9 g of purified compound IV, with a combined yield of 63.1% for the two steps and a purity of 99.679% by HPLC.

[0048] Example 5

[0049] This embodiment provides a method for synthesizing a Pevonedistat intermediate, which is synthesized by the following steps:

[0050] 1) Weigh 21.4 g (0.2 mol) of compound I into a reaction flask, add 150 ml of tetrahydrofuran and stir to dissolve; add 44.4 g (0.3 mol) of triethyl orthoformate and 3.44 g (0.02 mol) of p-toluenesulfonic acid in sequence; heat and control the reflux reaction until the reaction of the raw materials is complete, and monitor the process by TLC (EA:PE = 1:4); after the reaction is completed, concentrate under reduced pressure to near dryness to obtain 40.1 g of crude compound II (solid) with a yield of 123.5%, which is used directly in the next reaction without purification;

[0051] 2) The crude compound II from step 1) was dissolved in 200 ml of DMF, and 42.56 g (0.32 mol) of (S)-(+)-1-aminoindene was added with stirring. The mixture was heated and refluxed for 45 min. 300 mL of water was slowly added dropwise to the reaction solution, and reflux was continued until the reaction of compound II was complete. The reaction time was approximately 8 hrs, and the reaction was monitored by TLC (EA:PE = 1:2). After the reaction was completed, the mixture was cooled to room temperature, stirred, and crystallized completely. After filtration, crude compound IV was obtained. The crude compound IV was recrystallized from ethyl acetate, with activated carbon added as an impurity adsorbent and decolorizer. The ratio of activated carbon to ethyl acetate was 0.1 g / ml. Recrystallization yielded 35.5 g of purified compound IV, with a combined yield of 70.2% for both steps and a purity of 99.815% by HPLC.

[0052] Example 6

[0053] This embodiment provides a method for synthesizing a Pevonedistat intermediate, which is synthesized by the following steps:

[0054] 1) Weigh 21.4 g (0.2 mol) of compound I into a reaction flask, add 150 ml of tetrahydrofuran and stir to dissolve; add 44.4 g (0.3 mol) of triethyl orthoformate and 2.28 g (0.02 mol) of trifluoroacetic acid in sequence; heat and control the reflux reaction until the raw materials are completely reacted, and monitor the process by TLC (EA:PE = 1:4); after the reaction is completed, concentrate under reduced pressure to near dryness to obtain 38.6 g of crude compound II (solid) with a yield of 118.9%, which is used directly in the next reaction without purification;

[0055] 2) The crude compound II from step 1) was dissolved in 200 ml of DMF, and 34.58 g (0.26 mol) of (S)-(+)-1-aminoindene was added with stirring. The mixture was heated and refluxed for 45 min. 300 mL of water was slowly added dropwise to the reaction solution, and reflux was continued until the reaction of compound II was complete. The reaction time was approximately 6 hrs, and the process was monitored by TLC (EA:PE = 1:2). After the reaction was completed, the mixture was cooled to room temperature, stirred, and crystallized completely. After filtration, crude compound IV was obtained. The crude compound IV was recrystallized from ethyl acetate, with activated carbon added as an impurity adsorbent and decolorizer. The ratio of activated carbon to ethyl acetate was 0.1 g / ml. Recrystallization yielded 31.7 g of purified compound IV, with a combined yield of 63.3% for the two steps and a purity of 99.695% by HPLC.

[0056] Example 7

[0057] This embodiment provides a method for synthesizing a Pevonedistat intermediate, which is synthesized by the following steps:

[0058] 1) Weigh 21.4 g (0.2 mol) of compound I into a reaction flask, add 150 ml of tetrahydrofuran and stir to dissolve; add 44.4 g (0.3 mol) of triethyl orthoformate and 1.92 g (0.02 mol) of methanesulfonic acid in sequence; heat and control the reflux reaction until the reaction of the raw materials is complete, and monitor the process by TLC (EA:PE = 1:4); after the reaction is completed, concentrate under reduced pressure to near dryness to obtain 39.8 g of crude compound II (solid) with a yield of 122.6%, which is used directly in the next reaction without purification;

[0059] 2) The crude compound II from step 1) was dissolved in 200 ml of DMF, and 34.58 g (0.26 mol) of (S)-(+)-1-aminoindene was added with stirring. The mixture was heated and refluxed for 45 min. 300 ml of water was slowly added dropwise to the reaction solution, and reflux was continued until the reaction of compound II was complete. The reaction time was approximately 8 hrs, and the reaction was monitored by TLC (EA:PE = 1:2). After the reaction was completed, the mixture was cooled to room temperature and stirred until crystallization was complete. After filtration, crude compound IV was obtained. The crude compound IV was recrystallized from ethyl acetate, with activated carbon added as an impurity adsorbent and decolorizer. The ratio of activated carbon to ethyl acetate was 0.1 g / ml. Recrystallization afforded 33.7 g of purified compound IV, with a combined yield of 66.8% for both steps and a purity of 99.722% by HPLC.

[0060] Example 8

[0061] This embodiment provides a method for synthesizing a Pevonedistat intermediate, which is synthesized by the following steps:

[0062] 1) Weigh 21.4 g (0.2 mol) of compound I into a reaction flask, add 150 ml of tetrahydrofuran and stir to dissolve; add 44.4 g (0.3 mol) of triethyl orthoformate and 1.2 g (0.02 mol) of acetic acid in sequence; heat and reflux until the reaction is complete, and monitor the process by TLC (EA:PE = 1:4); after the reaction is completed, concentrate under reduced pressure to near dryness to obtain 29.9 g of crude compound II (solid) with a yield of 92.2%, which is used directly in the next reaction without purification;

[0063] 2) The crude compound II from step 1) was dissolved in 200 ml of DMF, and 34.58 g (0.26 mol) of (S)-(+)-1-aminoindene was added with stirring. The mixture was heated and refluxed for 45 min. 300 ml of water was slowly added dropwise to the reaction solution, and reflux was continued until the reaction of compound II was complete. The reaction time was approximately 10 hr, and the process was monitored by TLC (EA:PE = 1:2). After the reaction was completed, the mixture was cooled to room temperature, stirred, and crystallized completely. After filtration, crude compound IV was obtained. The crude compound IV was recrystallized from ethyl acetate, with activated carbon added as an impurity adsorbent and decolorizer. The ratio of activated carbon to ethyl acetate was 0.1 g / ml. Recrystallization yielded 27.5 g of purified compound IV, with a combined yield of 54.5% for both steps and a purity of 99.607% by HPLC.

[0064] Example 9

[0065] This embodiment provides a method for synthesizing a Pevonedistat intermediate, which is synthesized by the following steps:

[0066] 1) Weigh 21.4 g (0.2 mol) of compound I into a reaction flask, and add 133.2 g (1.2 mol) of triethyl orthoformate and 3.44 g (0.02 mol) of p-toluenesulfonic acid in sequence; heat to an internal temperature of 100°C, and distill off the generated ethanol during the reaction. Monitor the reaction by TLC until the reaction is complete (EA:PE = 1:4); after the reaction is completed, cool to room temperature, add 400 ml of petroleum ether (60-90°C), and further cool to an internal temperature of 0°C. Stir and crystallize for 4 hrs, and filter to obtain 29.32 g of crude compound II (solid) with a yield of 89.9%, which is used directly in the next reaction without purification;

[0067] 2) The crude compound II from step 1) was dissolved in 200 ml of DMF, and 34.58 g (0.26 mol) of (S)-(+)-1-aminoindene was added with stirring. The mixture was heated and refluxed for 45 minutes. 300 ml of water was slowly added dropwise to the reaction solution, and reflux was continued until the reaction of compound II was complete. The reaction time was approximately 8 hours, and the process was monitored by TLC (EA:PE = 1:2). After the reaction was completed, the mixture was cooled to room temperature and stirred until crystallization was complete. After filtration, crude compound IV was obtained. The crude compound IV was recrystallized from ethyl acetate, with activated carbon added as an impurity adsorbent and decolorizer. The ratio of activated carbon to ethyl acetate was 0.1 g / ml. Recrystallization yielded 28.6 g of purified compound IV, with a combined yield of 56.5% for both steps and a purity of 99.404% by HPLC.

[0068] Example 10

[0069] This embodiment provides a method for synthesizing a Pevonedistat intermediate, which is synthesized by the following steps:

[0070] 1) Weigh 21.4 g (0.2 mol) of compound I into a reaction flask, add 150 ml of tetrahydrofuran and stir to dissolve; then add 44.4 g (0.3 mol) of triethyl orthoformate and 3.44 g (0.02 mol) of p-toluenesulfonic acid in sequence; heat and reflux until the reaction is complete, monitoring the process by TLC (EA:PE = 1:4); after the reaction is complete, concentrate under reduced pressure to near dryness to obtain a crude solid of compound II, which is used directly in the next reaction without purification;

[0071] 2) The crude compound II from step 1) was dissolved in 200 ml of ethanol, and 34.58 g (0.26 mol) of (S)-(+)-1-aminoindene was added with stirring. The mixture was heated under controlled reflux for 3 hours. The mixture was cooled to room temperature for crystallization for 1 hour, filtered, and the filter cake was added with 200 ml of a 20% sodium ethoxide solution in ethanol. Heating was continued until the reaction was complete, and the reaction was monitored by TLC (EA:PE = 1:2). After the reaction, the solvent was evaporated under reduced pressure, and 300 ml of water was added to allow crystallization for 2 hours. The mixture was then filtered to obtain crude compound IV. The crude compound IV was recrystallized from ethyl acetate, with activated carbon added as an impurity adsorbent and decolorizer at a ratio of 0.1 g / ml to ethyl acetate. Recrystallization yielded 31.7 g of purified compound IV, with a combined yield of 63.3% for both steps and a purity of 99.592% by HPLC.

[0072] Example 11

[0073] This embodiment provides a method for synthesizing a Pevonedistat intermediate, which is synthesized by the following steps:

[0074] 1) Weigh 21.4 g (0.2 mol) of compound I into a reaction flask, add 150 ml of tetrahydrofuran and stir to dissolve; then add 44.4 g (0.3 mol) of triethyl orthoformate and 3.44 g (0.02 mol) of p-toluenesulfonic acid in sequence; heat and reflux until the reaction is complete, monitoring the process by TLC (EA:PE = 1:4); after the reaction is complete, concentrate under reduced pressure to near dryness to obtain a crude solid of compound II, which is used directly in the next reaction without purification;

[0075] 2) Dissolve the crude compound II from step 1) in 200 ml of 1,4-dioxane, and add 34.58 g (0.26 mol) of (S)-(+)-1-aminoindene with stirring. Heat the mixture under controlled reflux for 45 min. Slowly add 300 ml of water dropwise to the reaction solution, and continue refluxing until the reaction of compound II is complete. The reaction time is approximately 8 hours, monitored by TLC (EA:PE = 1:2). After the reaction is completed, cool to room temperature, stir, and crystallize completely. Filter to obtain crude compound IV. Crude compound IV is recrystallized from ethyl acetate, adding activated carbon as an impurity adsorbent and decolorizer. The ratio of activated carbon to ethyl acetate is 0.1 g / ml. Recrystallization yields 30.2 g of purified compound IV, with a combined yield of 59.6% for both steps and a purity of 99.186% by HPLC.

[0076] Example 12

[0077] This embodiment provides a method for synthesizing a Pevonedistat intermediate, which is synthesized by the following steps:

[0078] 1) Add 15 L of tetrahydrofuran to a 50 L glass reactor, stir, and add 2.14 kg (20.0 mol) of Compound I. After stirring and dissolving, add 4.44 kg (30.0 mol) of triethyl orthoformate and 344.0 g (2.0 mol) of p-toluenesulfonic acid in that order. Heat and reflux the reaction until the starting materials are completely reacted, monitoring the process by TLC (EA:PE = 1:4). After the reaction is complete, concentrate under reduced pressure to near dryness, and evaporate the solvent and ethanol generated to obtain a crude solid of Compound II, which is used directly in the next reaction without purification.

[0079] 2) The crude compound II from step 1) was added to 18 L of DMF, stirred, and 3.46 kg (26.0 mol) of (S)-(+)-1-aminoindene was added. The mixture was heated and refluxed for 1 hour. 27 L of water was added dropwise to the reaction solution at a constant rate. After completion of the addition, the mixture was refluxed until the reaction of compound II was complete, monitored by TLC (EA:PE = 1:2). After the reaction was completed, the mixture was cooled to room temperature and stirred for 1 hour to crystallize. The temperature was then further lowered to an internal temperature of 0-5°C and stirred for 1 hour to crystallize. The mixture was discharged and centrifuged to dryness to obtain crude compound IV.

[0080] To a 30.0 L glass reactor was added 20.0 L of ethyl acetate, and the crude compound IV was added with stirring. After stirring, 2 kg of activated carbon was added, and the reaction mixture was heated to reflux and maintained at reflux for 1 hr. The mixture was then hot filtered, and the filtrate was allowed to cool naturally to room temperature, then cooled to an internal temperature of 0-5°C, and stirred for crystallization for 2 hrs. The mixture was discharged and centrifuged to dryness. The mixture was then dried with forced air at 60°C to obtain 3.71 kg of refined compound IV, with a total yield of 73.2% for the two steps and a HPLC purity of 99.775%.

[0081] Example 13

[0082] This embodiment provides a method for synthesizing a Pevonedistat intermediate, which is synthesized by the following steps:

[0083] 1) Weigh 10.7 g (0.1 mol) of compound I into a reaction flask, add 75 ml of tetrahydrofuran, and stir until dissolved; then add 22.2 g (0.15 mol) of triethyl orthoformate and 1.72 g (0.01 mol) of p-toluenesulfonic acid in sequence; heat and reflux the mixture until the reaction is complete, monitored by TLC (EA:PE = 1:4); the reaction time is approximately 0.5 hr; after completion of the reaction, the reaction solution is placed on a rotary evaporator to evaporate the solvent to obtain 20.0 g of crude compound II (yield 123.3%), which is used directly in the next step without purification;

[0084] 2) The crude, unpurified Compound II from step 1) was dissolved in 100 ml of DMF, and 17.3 g (0.13 mol) of (S)-(+)-1-aminoindene was added with stirring. The mixture was heated under reflux for 45 min. 150 mL of deionized water was then slowly added dropwise to the reaction solution, and reflux was continued until Compound II was completely reacted. The reaction time was approximately 7-8 hr, monitored by TLC (EA:PE = 1:2). After the reaction, the mixture was cooled and crystallized, and filtered to obtain crude Compound IV. The crude Compound IV was recrystallized from ethyl acetate, with activated carbon added as an impurity adsorbent and decolorizer. The ratio of activated carbon to ethyl acetate was 0.1 g / ml. Recrystallization afforded 14.2 g of purified Compound IV, with a yield of 69.5% and a purity of 99.816% by HPLC.

[0085] Comparative Example 1

[0086] This embodiment provides a method for synthesizing a Pevonedistat intermediate, which is synthesized by the following steps:

[0087] 1) Weigh 21.4 g (0.2 mol) of compound I into a reaction flask, add 150 ml of tetrahydrofuran and stir to dissolve; add 44.4 g (0.3 mol) of triethyl orthoformate and 2.67 g (0.02 mol) of anhydrous aluminum chloride in sequence; heat and reflux until the reaction is complete, and monitor the process by TLC (EA:PE = 1:4); after the reaction is completed, concentrate under reduced pressure to near dryness to obtain 43.78 g of crude compound II (solid), with a yield of 135.0%, which is used directly in the next reaction without purification;

[0088] 2) The crude compound II from step 1) was dissolved in 200 ml of DMF, and 34.58 g (0.26 mol) of (S)-(+)-1-aminoindene was added with stirring. The mixture was heated and refluxed for 45 min. 300 ml of water was slowly added dropwise to the reaction solution, and reflux was continued until the reaction of compound II was complete. The reaction was monitored by TLC (EA:PE = 1:2). After the reaction was completed, the mixture was cooled to room temperature and stirred until crystallization was complete. After filtration, crude compound IV was obtained. The crude compound IV was recrystallized from ethyl acetate, with activated carbon added as an impurity adsorbent and decolorizer. The ratio of activated carbon to ethyl acetate was 0.1 g / ml. Recrystallization yielded 18.4 g of purified compound IV, with a combined yield of 36.5% for both steps and a purity of 95.585% by HPLC.

[0089] Comparative Example 2

[0090] This embodiment provides a method for synthesizing a Pevonedistat intermediate, which is synthesized by the following steps:

[0091] 1) Weigh 21.4 g (0.2 mol) of compound I into a reaction flask, add 150 ml of tetrahydrofuran and stir to dissolve; add 44.4 g (0.3 mol) of triethyl orthoformate and 1.96 g (0.02 mol) of concentrated sulfuric acid in sequence; heat and control the reflux reaction until the raw materials are completely reacted, and monitor the process by TLC (EA:PE = 1:4); after the reaction is completed, concentrate under reduced pressure to near dryness to obtain 34.38 g of crude compound II (solid) with a yield of 106.0%, which is used directly in the next reaction without purification;

[0092] 2) Dissolve the crude compound II from step 1) in 200 ml of DMF, and add 34.58 g (0.26 mol) of (S)-(+)-1-aminoindene with stirring. Heat and control the reflux reaction for 45 min. Slowly add 300 ml of water dropwise to the reaction solution, and continue to reflux until the reaction of compound II is complete. Monitor the reaction by TLC (EA:PE = 1:2). After the reaction is completed, cool to room temperature, stir, and crystallize completely. Filter to obtain crude compound IV. Crude compound IV is recrystallized from ethyl acetate, adding activated carbon as an impurity adsorbent and decolorizer. The ratio of activated carbon to ethyl acetate is 0.1 g / ml. Recrystallization yields 15.4 g of purified compound IV, with a combined yield of 30.5% for both steps and 83.799% purity by HPLC.

[0093] Comparative Example 3

[0094] This embodiment provides a method for synthesizing a Pevonedistat intermediate, which is synthesized by the following steps:

[0095] 1) Weigh 21.4 g (0.2 mol) of compound I into a reaction flask, add 150 ml of tetrahydrofuran and stir to dissolve; add 44.4 g (0.3 mol) of triethyl orthoformate and 2.09 g (0.02 mol) of concentrated hydrochloric acid in sequence; heat and control the reflux reaction until the raw materials are completely reacted, and monitor the process by TLC (EA:PE = 1:4); after the reaction is completed, concentrate under reduced pressure to near dryness to obtain 37.28 g of crude compound II (viscous material) with a yield of 115.0%, which is used directly in the next reaction without purification;

[0096] 2) The crude compound II from step 1) was dissolved in 200 ml of DMF (200 ml), and 34.58 g (0.26 mol) of (S)-(+)-1-aminoindene was added with stirring. The mixture was heated and refluxed for 45 min. 300 ml of water was slowly added dropwise to the reaction solution, and reflux was continued until the reaction of compound II was complete. The reaction was monitored by TLC (EA:PE = 1:2). After the reaction was completed, the mixture was cooled to room temperature, stirred until crystallization was complete, and filtered to obtain crude compound IV. The crude compound IV was recrystallized from ethyl acetate, with activated carbon added as an impurity adsorbent and decolorizer. The ratio of activated carbon to ethyl acetate was 0.1 g / ml. Recrystallization yielded 20.1 g of purified compound IV, with a combined yield of 39.7% for both steps and a purity of 96.015% by HPLC.

[0097] Comparative Example 4

[0098] This embodiment provides a method for synthesizing a Pevonedistat intermediate, which is synthesized by the following steps:

[0099] 1) Weigh 21.4 g (0.2 mol) of compound I into a reaction flask, add 150 ml of tetrahydrofuran and stir to dissolve; then add 44.4 g (0.3 mol) of triethyl orthoformate and 3.44 g (0.02 mol) of p-toluenesulfonic acid in sequence; heat and reflux until the reaction is complete, monitoring the process by TLC (EA:PE = 1:4); after the reaction is complete, concentrate under reduced pressure to near dryness to obtain a crude solid of compound II, which is used directly in the next reaction without purification;

[0100] 2) The crude compound II from step 1) was dissolved in 200 ml of ethanol and stirred, followed by the addition of 34.58 g (0.26 mol) of (S)-(+)-1-aminoindene. The mixture was heated under controlled reflux for 3 hours, cooled to room temperature for crystallization for 1 hour, filtered, and the filter cake was added to 400 ml of ethanol. 30.0 g (0.5 mol) of glacial acetic acid was added under stirring and continued heating until the reaction was complete. The reaction was monitored by TLC (EA:PE = 1:2). After the reaction, the solvent was evaporated under reduced pressure, and 300 ml of water was added, stirred for crystallization for 2 hours, and filtered to obtain crude compound IV. The crude compound IV was recrystallized from ethyl acetate with activated carbon added as an impurity adsorbent and decolorizer. The ratio of activated carbon to ethyl acetate was 0.1 g / ml. Recrystallization yielded 22.36 g of purified compound IV, with a combined yield of 44.7% for both steps and a purity of 98.819% by HPLC.

[0101] The above are all preferred embodiments of the present invention, and are not intended to limit the scope of protection of the present invention. Therefore, any equivalent changes made based on the structure, shape, and principle of the present invention should be included in the scope of protection of the present invention.

Claims

1. A method for synthesizing a Pevonedistat intermediate, characterized in that: The steps include: 1) Compound I, triethyl orthoformate, and a catalyst are added to a reaction vessel to react to produce Compound II; crystallization is performed, and the reaction solution is filtered to obtain a crude product of Compound II; 2) Adding crude compound II and (S)-(+)-1-aminoindene to a solvent to react to produce compound III; adding a nucleophile to the reaction solution and refluxing the solution to cause compound III to undergo a Dimroth rearrangement to produce compound IV; performing a crystallization operation, filtering the reaction solution to obtain crude compound IV; and recrystallizing the crude compound IV to obtain refined compound IV; The reaction path is as follows: Among them, Nu is a nucleophile; In step 1), the catalyst is p-toluenesulfonic acid; the reaction of compound I, triethyl orthoformate and the catalyst is carried out in tetrahydrofuran; the molar ratio of compound I to triethyl orthoformate is 1.0:1.5; In the step 2), the nucleophilic substance is water, the solvent is DMF, and the molar ratio of compound I to (S)-(+)-1-aminoindene is 1.0:1.0-1.

6.

2. A method for synthesizing a Pevonedistat intermediate according to claim 1, characterized in that: In the step 2), the molar ratio of compound I to (S)-(+)-1-aminoindene is 1.0:1.

3.

3. A method for synthesizing a Pevonedistat intermediate according to claim 1, characterized in that: In step 2), the solvent used for recrystallization is ethyl acetate; activated carbon is added to the ethyl acetate as an impurity adsorbent and decolorizer, and the ratio of activated carbon to ethyl acetate is 0.1 g / ml.

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