(S)-lenalidomide-5-position derivatives, synthesis method and application thereof

Abstract

The application discloses an (S)-lenalidomide-5-position derivative, a synthetic method and application thereof, and the application comprises the following steps: removing a tert-butyloxycarbonyl protective group of a compound 1 under acidic conditions to obtain a compound 2; in the presence of an organic amine, the compound 2 is provided with a benzyloxy carbonyl protective group to obtain a compound 3; the compound 3 is subjected to an amination reduction reaction with L-glutamine tert-butyl ester to obtain a compound 4; the compound 4 is subjected to ring closing under acidic conditions to obtain a compound 5; the compound 5 is subjected to a hydrogenation debenzyl-oxy carbonyl reaction with hydrogen under the action of an acid condition and a hydrogenation catalyst to obtain a compound 6; the compound 6 and 7 are subjected to an amination reduction reaction to obtain a compound 8; and the compounds 5, 6 and 8 are (S)-lenalidomide 5-position derivatives. The synthetic method is simple in post-treatment, less in racemization, high in yield, free of toxic pollutants, and safe and environmentally friendly.

Description

A (S)-lenalidomide-5-position derivative and its synthesis method and application Technical Field

[0001] The present invention belongs to the technical field of drug synthesis, and in particular relates to a (S)-lenalidomide-5-position derivative and a synthesis method and application thereof. Background Art

[0002] Lenalidomide, chemical name is 3-(7-amino-3-oxo-1H-isoindol-2-yl)piperidine-2,6-dione, molecular formula is C 13 H 13 N3O3 is an anti-tumor drug developed by Celgene Biopharmaceutical Company in the United States. It has multiple effects such as anti-tumor, immunomodulatory and anti-angiogenesis.

[0003] (S)-Lenalidomide-5-position derivatives are widely used in PROTAC (Proteolysis-targeting chimera) technology as chiral highly active ligands for cereblon E3 ubiquitin ligase.

[0004] US10836749B1 and others have successively reported a method for synthesizing lenalidomide-5-piperazine derivatives by ring closure of H-Glu(OtBu)-NH2 using tert-butoxycarbonyl as a piperazine protecting group.

[0005] Although the lenalidomide-5-piperazine derivative in the structural formula given by this method is of S configuration, the inventors found that the product had a racemization problem when synthesizing it according to this method, resulting in a decrease in the chiral purity of the final product, which was difficult to meet the requirements. In order to obtain a product with higher chiral purity, it is necessary to add a chiral purification operation, which increases the cost of the method.

[0006] Summary of the Invention

[0007] The present invention provides a (S)-lenalidomide-5-position derivative, a synthesis method and application thereof. When the (S)-lenalidomide-5-position derivative is used as a key intermediate for synthesizing lenalidomide and its derivatives, the purity of the product can be effectively improved and the cost can be reduced.

[0008] The technical solutions of the present invention are as follows:

[0009] A (S)-lenalidomide-5-position derivative is a compound represented by formula (II):

[0010] In formula (II), R is

[0011] Wherein X is CH2, NH, PG-N, O or S, PG is an N protecting group, and Z is CH2, C=O.

[0012] in, Indicates a replacement position.

[0013] As preferred, the R is

[0014] Wherein X is CH2, NH, PG-N, O or S, and PG is an N protecting group.

[0015] Preferably, the PG is Cbz-, Boc-, Fmoc-, Tos- or Trt-.

[0016] The present invention also provides a method for synthesizing the (S)-lenalidomide-5-position derivative, comprising: performing an amination-reduction reaction on compound I and L-glutamine tert-butyl ester (H-Gln-OtBu) to obtain compound II;

[0017] The reaction formula is as follows:

[0018] R is defined as above.

[0019] Preferably, the reducing agent used in the amination reduction reaction is one or more of sodium borohydride, sodium triacetoxyborohydride, potassium borohydride, hydrogen and sodium cyanoborohydride.

[0020] Preferably, the amination reduction reaction is carried out in an organic solvent, which is a mixture of one or more of a halogenated hydrocarbon solvent, a nitrile solvent or an alkyl alcohol, wherein the carbon chain in the halogenated hydrocarbon solvent, nitrile solvent or alkyl alcohol molecule contains 1 to 5 carbon atoms; more preferably, it is a mixture of one or more of dichloromethane, chloroform, acetonitrile, methanol and ethanol; and even more preferably, it is a mixture of one or more of dichloromethane, acetonitrile and methanol.

[0021] Preferably, sodium acetate and acetic acid are added as additives in the amination-reduction reaction.

[0022] The present invention also provides an application of the (S)-lenalidomide-5-derivative, comprising:

[0023] Compound II undergoes a ring-closing reaction under acidic conditions to obtain chiral compound III;

[0024] R is defined as above.

[0025] Preferably, the acid used in the acidic condition is one or more of benzenesulfonic acid, benzenesulfonic acid, acetic acid and hydrochloric acid;

[0026] The ring-closure reaction is carried out in an organic solvent, which is at least one of an ether solvent, a C1-C4 nitrile solvent or a C1-C4 alkyl alcohol, and more preferably at least one of tetrahydrofuran, acetonitrile and isopropanol.

[0027] Preferably, the application also includes a preparation process of compound II;

[0028] The compound II was obtained according to the method described above.

[0029] Furthermore, the specific steps of the present invention are as follows:

[0030] A method for synthesizing a 5-piperazine derivative of (S)-lenalidomide comprises the following steps:

[0031] Step A: Compound 1 is subjected to a deprotection reaction under acidic conditions to obtain compound 2;

[0032] The reaction formula is as follows:

[0033] Step B: Compound 2 is protected at N by benzyl chloroformate in the presence of an organic amine to obtain compound 3;

[0034] The reaction formula is as follows:

[0035] Step C: Compound 3 is subjected to an amination reduction reaction with L-glutamine tert-butyl ester (H-Gln-OtBu) to obtain compound 4;

[0036] The reaction formula is as follows:

[0037] Step D: Compound 4 is ring-closed under acidic conditions to obtain chiral compound 5;

[0038] The reaction formula is as follows:

[0039] Step E: Compound 5 is subjected to a hydrogenation debenzyloxycarbonylation reaction with hydrogen under acidic conditions and a hydrogenation catalyst to obtain chiral compound 6;

[0040] The reaction formula is as follows:

[0041] Step F: Compounds 6 and 7 are subjected to an amination reduction reaction to obtain chiral compound 8; the reaction formula is as follows:

[0042] Preferably, in step A, the deprotection reaction is carried out in an organic solvent I, wherein the organic solvent I is dioxane or tetrahydrofuran;

[0043] In step A, the acid used in the acidic condition is one or more of HCl, HBr and trifluoroacetic acid, most preferably hydrochloric acid.

[0044] Furthermore, the acid can be pre-mixed with the organic solvent by acid gas, or the acid gas can be introduced into the reaction system during the reaction.

[0045] In step A, the deprotection reaction temperature is 20-40° C., and the reaction time is 3-10 h.

[0046] In step A, after the reaction is completed, the product is directly filtered and washed to obtain compound 2.

[0047] Preferably, in step B, the organic amine is selected from at least one of triethylamine, diethylamine, diisopropylethylamine, and pyridine, preferably triethylamine or diisopropylethylamine;

[0048] The protection is carried out in a mixed system of organic solvent II and water, and the organic solvent II is at least one of dioxane and acetone.

[0049] In step B, the reaction temperature is 20-40° C., and the reaction time is 10-15 h.

[0050] In step B, after the reaction is completed, ethyl acetate and saturated brine are added, the liquids are separated, the organic phase is collected, concentrated under reduced pressure, and then purified by column chromatography to obtain compound 3.

[0051] Preferably, in step C, the reducing agent is one or more of sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, potassium borohydride, and hydrogen;

[0052] The amination reduction reaction is carried out in an organic solvent III, which is a mixture of one or more of dichloromethane, acetonitrile, and methanol.

[0053] In step C, when the reducing agent is hydrogen, the reduction is carried out in the presence of a catalyst; the catalyst is selected from at least one of palladium carbon and Raney nickel.

[0054] In step C, sodium acetate and acetic acid are further added as additives in the amination reduction reaction.

[0055] In step C, the reaction temperature is 20-40° C., and the reaction time is 15-25 h.

[0056] In step C, after the reaction is completed, the organic solvent III is removed by concentration under reduced pressure, and then ethyl acetate and water are added, the layers are separated, and the organic phase is collected and concentrated under reduced pressure to obtain compound 4.

[0057] Preferably, in step D, the acid used in the acidic condition is one or more of benzenesulfonic acid, benzenesulfonic acid, acetic acid and hydrochloric acid;

[0058] The ring-closing reaction is carried out in an organic solvent IV, which is at least one of tetrahydrofuran, acetonitrile and isopropanol.

[0059] In step D, the reaction temperature is 20-40° C., and the reaction time is 10-15 h.

[0060] In step D, after the reaction is completed, ethyl acetate and saturated water are added, the liquids are separated, the organic phase is collected, concentrated under reduced pressure, and then purified by column chromatography to obtain compound 5.

[0061] Preferably, in step E, the acid used in the acidic condition is one or more of benzenesulfonic acid, benzenesulfonic acid, acetic acid and hydrochloric acid, and the hydrogenation catalyst is palladium on carbon or Raney nickel;

[0062] The hydrodebenzyloxycarbonylation reaction is carried out in an organic solvent V, which is at least one of tetrahydrofuran, methanol, and isopropanol.

[0063] In step E, the reaction temperature is 20-40° C., and the reaction time is 5-10 h.

[0064] In step E, after the reaction is completed, methanol is added to dissolve the product, the product is filtered to remove palladium carbon, and methanol is removed by rotary evaporation under reduced pressure to obtain compound 6.

[0065] Preferably, in step F, the reducing agent is at least one of sodium borohydride, potassium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, and hydrogen;

[0066] The amination reduction reaction is carried out in an organic solvent VI, which is at least one of tetrahydrofuran, dichloromethane, methanol, and isopropanol.

[0067] In step F, the reaction temperature is 20-40° C., and the reaction time is 3-10 h.

[0068] In step F, after the reaction is completed, the solvent is removed by rotary evaporation under reduced pressure, and then ethyl acetate and water are added, the liquids are separated, the aqueous phase is collected, and then neutralized with a base, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and the filtrate is rotary dried to obtain compound 8.

[0069] In the method for synthesizing the (S)-lenalidomide-5-derivative described in the present invention, unless otherwise specified, the amount of the reaction raw materials is not strictly limited, and the reaction is generally carried out according to the stoichiometric ratio, and the reaction can also be carried out in excess. The amount of the reaction solvent and reaction reagent in each step is not strictly limited and can be adjusted according to the amount of the reaction raw materials. The amount of the reaction solvent and reaction reagent can be increased if the reaction raw materials are large, and reduced if the reaction raw materials are small. The reaction solvent in each step can be selected according to the knowledge of those skilled in the art, such as water, alcohols, ketones, ethers, etc.; the post-treatment method in each step can be selected according to the knowledge of those skilled in the art, such as extraction, distillation, etc.

[0070] Compared with the prior art, the present invention has the following advantages:

[0071] The (S)-lenalidomide-5-position derivative is prepared by the route of the present invention, which is simple to operate, simple to post-process, and has readily available raw materials and is environmentally friendly. The prepared product has high chiral purity, good stability, high total yield, low production cost, and is suitable for large-scale industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0072] FIG1 is a hydrogen spectrum of compound 4 obtained in step C of Example 1;

[0073] FIG2 is a carbon spectrum of compound 4 obtained in step C of Example 1;

[0074] FIG3 is a mass spectrum of compound 4 obtained in step C of Example 1 in LCMS;

[0075] FIG4 is a hydrogen spectrum of compound 5 obtained in step D of Example 1;

[0076] FIG5 is a carbon spectrum of compound 5 obtained in step D of Example 1;

[0077] FIG6 is a mass spectrum of compound 5 obtained in step D of Example 1 in LCMS;

[0078] FIG7 is a chiral LC spectrum of the control racemate of compound 5;

[0079] FIG8 is a chiral LC spectrum of compound 5 obtained in step D of Example 1;

[0080] FIG9 is a hydrogen spectrum of compound 8 obtained in step F of Example 1;

[0081] FIG10 is a carbon spectrum of compound 8 obtained in step F of Example 1;

[0082] FIG11 is a mass spectrum of compound 8 obtained in step F of Example 1 in LCMS;

[0083] Figure 12 is a chiral LC spectrum of the reference racemate of compound 8;

[0084] FIG13 is a chiral LC spectrum of compound 8 obtained in step F of Example 1. DETAILED DESCRIPTION

[0085] The present invention will be further described below with reference to specific embodiments. The following specific embodiments are provided for a better understanding of the technical solutions of the present invention. However, those skilled in the art should recognize that the present invention is not limited to these embodiments. Those skilled in the art may make various modifications to the present invention without departing from the spirit and scope of the present invention, and such equivalent modifications also fall within the scope of protection of the present invention.

[0086] Example 1

[0087] Step A: To a 50 mL four-necked flask, add a solution of HCl in 1,4-dioxane (26 mL, 1.0 eq.). Add a solution of compound 1 (6.50 g, 1.0 eq.) in 1,4-dioxane (13 mL) at 30 ± 5°C and stir at 30 ± 5°C until solid precipitates. After stirring for 4 hours, complete conversion of compound 1 was confirmed by TLC. Filter the reaction mixture, and wash the filter cake with 6.5 mL of 1,4-dioxane to obtain 12.51 g of a yellow solid product, compound 2. This can be used directly as feed for the next step.

[0088] Step B: Add compound 2 (0.82 g, 1.0 eq.), 1,4-dioxane (8.2 mL), triethylamine (1.17 g, 4.0 eq.), and water to a reaction flask and stir to dissolve. Cool to 0±5°C, add benzyl chloroformate (0.74 g, 1.5 eq.), stir for 10 minutes, then raise the temperature to 30±5°C and stir for 12 hours. TLC monitoring indicates complete conversion of compound 2. Add 10 mL of ethyl acetate and 10 mL of saturated brine, separate the layers, and collect the upper organic phase. After concentration under reduced pressure, purify by column chromatography (Hex / EA = 1 / 1) to obtain 0.87 g of a yellow solid product, compound 3, in a 79% yield. MS (ESI, m / z) = 383 [M+H] + .

[0089] Step C: To a 100 mL reaction flask, add H-Gln-OtBu.HCl (1.87 g, 1.0 eq.), methanol (60 mL), and sodium acetate (1.93 g, 3.0 eq.), stir at 30±5°C for 0.5 h, then add compound 3 (3.0 g, 1.0 eq.) and acetic acid (0.71 g, 1.5 eq.). Stir for 1 h, then cool to 0±5°C, slowly add sodium cyanoborohydride (3.0 eq.), then raise the temperature to 30±5°C, stir and react for 20 h. TLC monitoring shows complete conversion of the starting material with obvious product formation. After the reaction was complete, the methanol was removed by concentration under reduced pressure. 30 mL of water and 30 mL of ethyl acetate were added, and the separated liquids were extracted. The upper organic phase was collected, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure to obtain 5.71 g of a light yellow viscous substance, which was compound 4. A portion of the product was purified (2.33 g was separated by column to obtain 1.42 g of the product, with a yield of 82.7%). The hydrogen spectrum, carbon spectrum, and MS spectrum are shown in Figures 1 to 3, respectively. This was used directly as the feed for the next step. MS (ESI, m / z) = 537 [M+H] + .

[0090] Step D: Compound 4 (1.12 g, 1.0 eq.) and acetonitrile (23 mL) were added to a 50 mL four-necked flask and stirred at 30°C until dissolved. Benzenesulfonic acid (0.66 g, 2.0 eq.) was then added and stirred under nitrogen. After 16 h of reaction, TLC and MS monitoring indicated complete conversion of the starting material. 20 mL of ethyl acetate and 20 mL of water were added and stirred thoroughly. The mixture was separated and the upper organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. Purification by column chromatography (DCM / MeOH = 50 / 1) afforded 0.55 g of an off-white solid, compound 5, with a total yield of 77% for both steps. The H, C, and MS spectra are shown in Figures 4-6, respectively. MS (ESI, m / z) = 463.2 [M+H] + , ee value: 93% (Figure 8).

[0091] Step E: Compound 5 (0.2 g, 1.0 eq.), methanol (5 mL), tetrahydrofuran (5 mL), and dichloromethane (4 mL) were added to a 50 mL four-necked flask and stirred to dissolve completely. Benzenesulfonic acid (79 mg, 1.0 eq.) and 10% palladium on carbon (20 mg, 0.1 w / w) were then added. The atmosphere was replaced with hydrogen three times, a hydrogen balloon was installed, and the reaction was stirred at 30°C for 8 h. The reaction solution was monitored by TLC, indicating complete conversion of the starting material. After the reaction, a clear solid precipitated. 20 mL of methanol was added to dissolve the solid, filtered, and the palladium on carbon was removed. The methanol was then removed by rotary evaporation under reduced pressure to obtain 0.21 g of an off-white foamy solid, compound 6, with a crude yield of 100%. MS (ESI, m / z) = 329.1 [M+H] + .

[0092] Step F: Add compound 6 (0.2 g, 1.0 eq.) and methanol (5 mL) to a 50 mL four-necked flask and stir for 30 minutes to completely dissolve the material. Then, add compound 7 (88 mg, 1.0 eq.) and acetic acid (39 mg, 1.0 eq.) and stir at 30±5°C for 1 hour. Then cool to 0±5°C. Add sodium cyanoborohydride (82 mg, 1.0 eq.) and stir at 30±5°C for 6 hours. Monitor the reaction solution by TLC to confirm complete conversion of the starting material. Remove the methanol by vacuum rotary evaporation. Add 15 mL of water and 15 mL of ethyl acetate to dissolve the residue. Separate the layers and collect the lower aqueous phase. Wash the aqueous phase once more with 15 mL of ethyl acetate. The pH is measured to be 5.46. Adjust the pH of the aqueous phase to 7.02 with 1 mol / L sodium hydroxide solution. The adjusted aqueous phase was extracted three times with dichloromethane (15 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to obtain 0.21 g of an off-white solid product. The yield was 95%. The H-spectrum, C-spectrum, and MS spectra are shown in Figures 9-11, respectively. MS (ESI, m / z) = 516.2 [M+H] + .ee value: 88% (Figure 13).

[0093] Example 2

[0094] The conditions of steps A to C were the same as those in Example 1. Methanol was used as the solvent in step D. Other conditions were the same as those in step D of Example 1. The final results showed no reaction, and no post-treatment was performed.

[0095] Example 3

[0096] The conditions of steps A to C were the same as those in Example 1, and the reaction temperature of step D was 60° C. The results showed that no ring-closed product was obtained, and only a by-product of tert-butyl detachment was obtained.

[0097] Example 4

[0098] The conditions of steps A to E were the same as those in Example 1. In step F, the amount of sodium cyanoborohydride used was 3.0 eq, and the amount of acetic acid used was 1.5 eq. Other conditions were the same as those in step F of Example 1. A product was generated, but some of it was racemized.

[0099] Example 5

[0100] Steps A and B were the same as in Example 1, and step C referred to step C of Example 1, except that acetic acid was not added. As a result, the target product was not obtained and no post-treatment was performed.

[0101] Example 6

[0102] To a 100 mL reaction flask, H-Gln-OtBu.HCl (1.79 g, 1.0 eq.), methanol (30 mL), and sodium acetate (1.84 g, 3.0 eq.) were added and stirred at 30±5°C for 0.5 h. Compound 3a (1.23 g, 1.0 eq.) was then added. Stirring continued for 1 h, the temperature was lowered to 0±5°C, and sodium cyanoborohydride (3.0 eq.) was slowly added. The temperature was then raised to 30±5°C and stirred for 20 h. TLC monitoring indicated complete conversion of the starting material, with clear product formation. After completion of the reaction, the methanol was removed by concentration under reduced pressure. 30 mL of water and 30 mL of ethyl acetate were added, and the separated liquids were extracted. The upper organic phase was collected, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure to yield 2.38 g of a light yellow viscous product. HPLC analysis indicated a yield of nearly 100%.

[0103] The results of Example 5 and Example 6 show that the substituents on the benzene ring have a significant impact on the reaction results.

Claims

1. A (S)-lenalidomide-5-position derivative, characterized in that, Is a compound represented by formula (II): In formula (II), R is one of the following; wherein X is CH 2 , NH, PG-N, O or S, PG is an N-protecting group, Z is CH 2 , C═O.

2. The (S)-lenalidomide-5-position derivative according to claim 1, characterized in that, The said R is wherein X is CH 2 , NH, PG-N, O or S, and PG is an N-protecting group.

3. The (S)-lenalidomide-5-position derivative according to claim 1, characterized in that, the PG is Cbz-, Boc-, Fmoc-, Tos- or Trt-.

4. A method for synthesizing the (S)-lenalidomide-5-position derivative according to any one of claims 1 to 3, characterized in that, comprising: Performing an amination reduction reaction on compound I and L-glutamine tert-butyl ester to obtain compound II; The reaction formula is as follows: The definition of R is as described in any one of claims 1 to 3.

5. The method for synthesizing the (S)-lenalidomide-5-position derivative according to claim 4, characterized in that, the reducing agent used in the amination reduction reaction is one or more of sodium borohydride, sodium triacetoxyborohydride, potassium borohydride, hydrogen and sodium cyanoborohydride.

6. The method for synthesizing the (S)-lenalidomide-5-position derivative according to claim 4, characterized in that, the amination reduction reaction is carried out in an organic solvent, and the organic solvent is one or more mixtures of halogenated hydrocarbon solvents, nitrile solvents or alkyl alcohols, and the carbon chain in the halogenated hydrocarbon solvent, nitrile solvent or alkyl alcohol molecule contains 1 to 5 carbon atoms.

7. The method for synthesizing the (S)-lenalidomide-5-position derivative according to claim 4, characterized in that, sodium acetate and acetic acid are added as additives in the amination reduction reaction.

8. An application of the (S)-lenalidomide-5-position derivative according to any one of claims 1 to 3, characterized in that, comprising: Compound II undergoes a ring-closure reaction under acidic conditions to obtain chiral compound III; The definition of R is as described in any one of claims 1 to 3.

9. The application of the (S)-lenalidomide-5-position derivative according to claim 8, characterized in that, the acid used in the acidic condition is one or more of benzenesulfonic acid, benzenesulfonic acid, acetic acid and hydrochloric acid; The closed-loop reaction is carried out in an organic solvent, and the organic solvent is at least one of an ether solvent, a C 1 ~C 4 nitrile solvent or a C 1 ~C 4 alkyl alcohol.

10. An application of the (S)-lenalidomide-5-position derivative according to claim 8 or 9, characterized in that, it further includes the preparation process of compound II; The compound II is obtained according to the method described in any one of claims 4 to 7.

11. A method for synthesizing a (S)-lenalidomide 5-position piperazine derivative, characterized in that, comprising the following steps: Step A: Performing a deprotection reaction on compound 1 under acidic conditions to obtain compound 2; The reaction formula is as follows: Step B: Protecting N with benzyl chloroformate in the presence of an organic amine to obtain compound 3; The reaction formula is as follows: Step C: Performing an amination reduction reaction on compound 3 and L-glutamine tert-butyl ester to obtain compound 4; The reaction formula is as follows: Step D: Closing the ring of compound 4 under acidic conditions to obtain a chiral compound 5; The reaction formula is as follows: Step E: Performing a hydrogenation debenzylcarbonylation reaction on compound 5 with hydrogen under acidic conditions and in the presence of a hydrogenation catalyst to obtain a chiral compound 6; The reaction formula is as follows: Step F: The chiral compounds 6 and 7 undergo an ammoniation reduction reaction to obtain the chiral compound 8; the reaction formula is as follows:

Images