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EP-4737437-A1 - DPP1 INHIBITOR INTERMEDIATE, AND PREPARATION METHOD THEREFOR AND USE THEREOF IN MEDICINES

EP4737437A1EP 4737437 A1EP4737437 A1EP 4737437A1EP-4737437-A1

Abstract

The present disclosure relates to a compound as represented by formula (I) and a method for preparing an intermediate thereof. The method uses inexpensive starting materials and multi-step telescoping reactions, is simple and convenient in terms of post-treatment operation, achieves a high yield, is high in terms of the chemical and chiral purity of a product, and is suitable for large-scale industrial production.

Inventors

  • FAN, JIANG
  • ZHU, Fengfei
  • DOU, Ying

Assignees

  • Haisco Pharmaceuticals Pte. Ltd.

Dates

Publication Date
20260506
Application Date
20240625

Claims (14)

  1. A method for preparing a compound as represented by formula (I), comprising wherein X is a leaving group, such as F, Cl, Br, I or OTf; a: the compound as represented by formula (I) is prepared from a compound of formula (II).
  2. The preparation method according to claim 1, wherein the method further comprises the following steps: wherein X is a leaving group, such as F, Cl, Br, I or OTf; b: a compound of formula (II-1) is prepared from a compound of formula (III); c: the compound of formula (II) is prepared from the compound of formula (II-1).
  3. A method for preparing a compound as represented by formula (II), comprising wherein X is a leaving group, such as F, Cl, Br, I or OTf; b: a compound of formula (II-1) is prepared from a compound of formula (III); c: the compound of formula (II) is prepared from the compound of formula (II-1).
  4. The preparation method according to claim 2 or 3, wherein the method further comprises the following steps: wherein X is a leaving group, such as F, Cl, Br, I or OTf; d: the compound of formula (III) is prepared from a compound of formula (IV).
  5. A method for preparing a compound as represented by formula (III), comprising wherein X is a leaving group, such as F, Cl, Br, I or OTf; d: the compound of formula (III) is prepared from a compound of formula (IV).
  6. The preparation method according to claim 4 or 5, wherein the method further comprises the following steps: wherein X is a leaving group, such as F, Cl, Br, I or OTf; g: a compound of formula (VI) is prepared from a compound of formula (VII-1) and a compound of formula (VII-2); f: a compound of formula (V-1) is prepared from the compound of formula (VI); e: the compound of formula (IV) is prepared from the compound of formula (V-1) and a compound of formula (V-2).
  7. A method for preparing a compound as represented by formula (IV), comprising wherein X is a leaving group, such as F, Cl, Br, I or OTf; g: a compound of formula (VI) is prepared from a compound of formula (VII-1) and a compound of formula (VII-2); f: a compound of formula (V-1) is prepared from the compound of formula (VI); e: the compound of formula (IV) is prepared from the compound of formula (V-1) and a compound of formula (V-2).
  8. The preparation method according to any one of claims 1, 2, 4 and 6, wherein a: the compound as represented by formula (II) is reacted in the presence of an organic solvent and a base to obtain the compound as represented by formula (I), wherein the organic solvent is preferably one or more of dichloromethane, ethyl acetate, isopropyl acetate, toluene, dioxane, tetrahydrofuran, methyltetrahydrofuran, MTBE, (Boc) 2 O or n-heptane, more preferably one or more of dichloromethane, MTBE, (Boc) 2 O or n-heptane; the base is preferably one or more of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, potassium phosphate, potassium hydroxide, lithium hydroxide, sodium hydroxide, triethylamine, DIPEA or DBU, more preferably sodium carbonate.
  9. The preparation method according to any one of claims 2, 3, 4 and 6, wherein b: the compound of formula (III) is reacted in the presence of an organic solvent and an acid to obtain the compound of formula (II-1), wherein the organic solvent is preferably one or more of dichloromethane, ethyl acetate, isopropyl acetate, toluene, dioxane, tetrahydrofuran, methyltetrahydrofuran, MTBE, methanol, ethanol or isopropanol, more preferably ethanol or MTBE; the acid is preferably one or more of HCl, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid or trifluoroacetic acid, more preferably HCl; c: the compound of formula (II-1) is reacted in the presence of a chiral acid solvent to obtain the compound of formula (II), wherein the chiral acid solvent is preferably one or more of tartaric acid, malic acid, camphoric acid, camphorsulfonic acid, lactic acid, diacetone-L-gulonic acid, mandelic acid or phenoxypropionic acid, more preferably L(-)-tartaric acid.
  10. The preparation method according to any one of claims 4-6, wherein d: the compound of formula (IV) is reacted in the presence of a solvent, a cyanating reagent and a base to obtain the compound of formula (III), wherein the solvent is preferably one or more of DCM, DMF, THF, n-heptane, ACN, toluene or DMSO, more preferably DCM or toluene; the cyanating reagent is preferably one or more of TMSCN, sodium cyanide, potassium cyanide or lithium cyanide, more preferably TMSCN; the base is preferably one or more of CsF, KF, TBAF, Na 2 CO 3 , K 3 PO 4 or Ti(OEt) 4 , more preferably CsF or KF, even more preferably CsF.
  11. The preparation method according to claim 6 or 7, wherein g: the compound of formula (VII-1) and the compound of formula (VII-2) are reacted in the presence of a base to obtain the compound of formula (VI), wherein the base is preferably one or more of LiHMDS, NaHMDS, KHMDS, LDA, BuLi or potassium tert-butoxide, more preferably LiHMDS, NaHMDS or KHMDS, even more preferably LiHMDS; f: the compound of formula (VI) is reacted in the presence of an acid and an organic solvent to obtain the compound of formula (V-1), wherein the acid is preferably one or more of TsOH, methanesulfonic acid, camphorsulfonic acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, oxalyl chloride or trimethylchlorosilane, more preferably TsOH; the organic solvent is preferably one or more of dichloromethane, ethyl acetate, isopropyl acetate, toluene, dioxane, tetrahydrofuran, methyltetrahydrofuran, methyl tert-butyl ether, acetonitrile, methanol, ethanol or isopropanol, more preferably toluene; e: the compound of formula (V-1) and the compound of formula (V-2) are reacted in the presence of an organic solvent and a dehydration reagent to obtain the compound of formula (IV), wherein the organic solvent is preferably one or more of toluene, dichloromethane, ethyl acetate, isopropyl acetate, dioxane, tetrahydrofuran, methyltetrahydrofuran, acetic acid or acetonitrile, more preferably toluene; the dehydration reagent is preferably one or more of anhydrous CuSO 4 , Zn(OAc) 2 , Co(OAc) 2 · 4H 2 O, Na 2 SO 4 , MgSO 4 , Ti(Oi-Pr) 4 , DCC/DMAP, EDCI/DMAP or HOAc/molecular sieve, more preferably anhydrous CuSO 4 or HOAc/molecular sieve.
  12. A method for preparing a compound as represented by formula (C7), comprising wherein g: C1 is reacted in the presence of an organic solvent and a base to obtain C2; f: C2 is reacted in the presence of an organic solvent and an acid to obtain C3; e: C3 is reacted in the presence of an organic solvent and a dehydration reagent to obtain C4; d: C4 is reacted in the presence of a solvent, a base and a cyanating reagent to obtain C5-1; b: C5-1 is reacted in the presence of an acid to obtain C6; c: C6 is reacted in the presence of an organic solvent, a base and a chiral acid to obtain C6-b; a: C6-b is reacted in the presence of an organic solvent and a base to obtain C7.
  13. The preparation method according to claim 12, wherein g: the organic solvent is selected from one or more of tetrahydrofuran, dichloromethane, MTBE or n-heptane; the base is selected from one or more of LiHMDS, NaHMDS or KHMDS, preferably LiHMDS; f: the acid is selected from one or more of TsOH, methanesulfonic acid, camphorsulfonic acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, oxalyl chloride or trimethylchlorosilane, preferably TsOH; the organic solvent is selected from one or more of dichloromethane, ethyl acetate, isopropyl acetate, toluene, dioxane, tetrahydrofuran, methyltetrahydrofuran, methyl tert-butyl ether, acetonitrile, methanol, ethanol or isopropanol, preferably toluene; e: the organic solvent is selected from one or more of toluene, dichloromethane, ethyl acetate, isopropyl acetate, dioxane, tetrahydrofuran, methyltetrahydrofuran, acetic acid or acetonitrile, preferably toluene; and the dehydration reagent is selected from one or more of anhydrous CuSO 4 , Zn(OAc) 2 , Co(OAc) 2 · 4H 2 O, Na 2 SO 4 , MgSO 4 , Ti(Oi-Pr) 4 , DCC/DMAP, EDCI/DMAP or HOAc/molecular sieve, preferably anhydrous CuSO 4 or HOAc/molecular sieve; d: the solvent is selected from one or more of DCM, DMF, THF, n-heptane, ACN, toluene or DMSO, preferably DCM or toluene; the cyanating reagent is selected from one or more of TMSCN, sodium cyanide, potassium cyanide or lithium cyanide, preferably TMSCN; and the base is selected from one or more of CsF, KF, TBAF, Na 2 CO 3 , K 3 PO 4 or Ti(OEt) 4 , preferably CsF or KF, even more preferably CsF; b: the organic solvent is selected from one or more of dichloromethane, ethyl acetate, isopropyl acetate, toluene, dioxane, tetrahydrofuran, methyltetrahydrofuran, MTBE, methanol, ethanol or isopropanol, preferably ethanol or MTBE; and the acid is selected from one or more of HCl, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid or trifluoroacetic acid, preferably HCl; c: the chiral acid solvent is selected from one or more of tartaric acid, malic acid, camphoric acid, camphorsulfonic acid, lactic acid, diacetone-L-gulonic acid, mandelic acid or phenoxypropionic acid, preferably L(-)-tartaric acid; a: the organic solvent is selected from one or more of dichloromethane, ethyl acetate, isopropyl acetate, toluene, dioxane, tetrahydrofuran, methyltetrahydrofuran, MTBE, (Boc) 2 O or n-heptane, more preferably one or more of dichloromethane, MTBE, (Boc) 2 O or n-heptane; and the base is selected from one or more of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, potassium phosphate, potassium hydroxide, lithium hydroxide, sodium hydroxide, triethylamine, DIPEA or DBU, preferably sodium carbonate.
  14. The preparation method according to claim 12 or 13, wherein g: the organic solvent is tetrahydrofuran, and the base is LiHMDS; f: the acid is TsOH, and the organic solvent is toluene; e: the dehydration reagent is selected from anhydrous CuSO 4 or HOAc/molecular sieve; d: the cyanating reagent is TMSCN, and the base is CsF; b: the organic solvent is selected from ethanol or MTBE, and the acid is HCl; c: the chiral acid solvent is L(-)-tartaric acid; a: the organic solvent is selected from one or more of dichloromethane, MTBE, (Boc) 2 O or n-heptane; and the base is sodium carbonate.

Description

TECHNICAL FIELD The present disclosure relates to a method for preparing a compound as represented by formula (I) and an intermediate thereof. The method features low-cost reaction starting materials, multi-step telescoping reactions, straightforward workup procedures, high yield, and high chemical and chiral purity of the product, making it suitable for large-scale industrial production. BACKGROUND ART Dipeptidyl peptidase 1 (DPP1), also known as cathepsin C, is a cysteinyl protease of the lysosomal papain family involved in intracellular protein degradation. During neutrophil maturation, DPP1 activates neutrophil serine proteases (NSPs), including neutrophil elastase (NE), proteinase 3 (Pr3), and cathepsin G (CatG), by cleaving the N-terminal dipeptide of a target protein. DPP1 has been implicated in a variety of inflammatory diseases, including Wegener's granulomatosis, rheumatoid arthritis, lung inflammation, virus infection, etc. Studies have shown that the inhibition of DPP1 can have a good therapeutic effect on highly inflammatory lung diseases caused by neutrophils, such as bronchiectasis, chronic obstructive pulmonary disease (COPD) and acute lung injury. Therefore, inhibiting the over-activation of NSPs by targeting DPP1 may have a potential therapeutic effect on bronchiectasis. WO 2014140075A1 and WO 2016016242A1 recite a class of compounds having DPP1 activity, wherein the compound as represented by formula (C7) can be used as a key intermediate for the synthesis of this class of products. WO 2014140075A1 discloses intermediate I-1.1, which is prepared via Route 1 using R8 and R9 as starting materials. This preparation method mainly has problems such as expensive starting materials, the requirement for ultra-low reaction temperature, low reaction conversion efficiency, the necessity for purification by column chromatography, and the difficulty in industrial scale-up production. WO 2016016242A1 discloses another intermediate I-5.2.1, which is prepared via Route 2 using R14 as a starting material, as described below. This route mainly has problems such as the requirement for asymmetric reduction in the reaction, the high cost and susceptibility to deactivation of catalysts, the formation of dehalogenated by-products during the asymmetric reduction reaction, the necessity for purification by reversed-phase HPLC, high production costs, and the difficulty in scale-up production. Therefore, it is necessary to develop a route for preparing compound (I) that features mild reaction conditions, simple operation, high reaction yield, high chemical and chiral purity of the product, straightforward workup, low cost, and the suitability for industrial production. SUMMARY OF THE INVENTION The objective of the present disclosure is to provide a method for preparing a compound as represented by formula (I) and an intermediate thereof. The method of the present disclosure features low-cost reaction starting materials, multi-step telescoping reactions, straightforward workup procedures, high yield, and high chemical and chiral purity of the product, making it suitable for large-scale industrial production. The present disclosure provides a method for preparing a compound as represented by formula (I), wherein the compound as represented by formula (I) is prepared from a compound of formula (II), wherein X is a leaving group, such as F, Cl, Br, I or OTf. The method for preparing the compound as represented by formula (I) provided by the present disclosure may further comprise the following: a compound of formula (II-1) is prepared from a compound of formula (III); a compound of formula (II) is prepared from the compound of formula (II-1); and then the compound as represented by formula (I) is prepared from the compound of formula (II): wherein X is a leaving group, such as F, Cl, Br, I or OTf. The method for preparing the compound as represented by formula (I) provided by the present disclosure may further comprise the following: a compound of formula (III) is prepared from a compound of formula (IV); a compound of formula (II-1) is prepared from the compound of formula (III); a compound of formula (II) is prepared from the compound of formula (II-1); and then the compound as represented by formula (I) is prepared from the compound of formula (II): wherein X is a leaving group, such as F, Cl, Br, I or OTf. The method for preparing the compound as represented by formula (I) provided by the present disclosure may further comprise the following: a compound of formula (VI) is prepared from a compound of formula (VII-1) and a compound of formula (VII-2); a compound of formula (V-1) is prepared from the compound of formula (VI); a compound of formula (IV) is prepared from the compound of formula (V-1) and a compound of formula (V-2); a compound of formula (III) is prepared from the compound of formula (IV); a compound of formula (II-1) is prepared from the compound of formula (III); a compound of formula (II) is prep