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EP-4735444-A1 - BENZYL (3-(METHYL(7H-PYRROLO[2,3-D]PYRIMIDIN-4YL)AMINO)CYCLOBUTYL) CARBAMATE OR A SALT THEREOF, METHOD FOR THE PREPARATION THEREOF, AND USE THEREOF IN THE SYNTHESIS OF ABROCITINIB

EP4735444A1EP 4735444 A1EP4735444 A1EP 4735444A1EP-4735444-A1

Abstract

Benzyl (3-(methyl(7h-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclobutyl)carbamate or a salt thereof, method for the preparation thereof, and use thereof in the synthesis of abrocitinib The present invention relates to a new intermediate useful in the synthesis of abrocitinib, to a method for obtaining same, to the use of said intermediate for preparing abrocitinib, and to a method for preparing abrocitinib using said intermediate.

Inventors

  • ARE, Celeste
  • RAMÓN ÚBEDA, Oscar
  • BALLETTE, Roberto

Assignees

  • Moehs Ibérica, S.L.

Dates

Publication Date
20260506
Application Date
20240626

Claims (20)

  1. 1. A compound of formula (I) or a salt thereof wherein the bonds represented by a wavy line are in the c/s configuration.
  2. 2. The compound according to claim 1 , characterized in that it has an X-ray powder diffractogram measured with CuKa radiation comprising peaks at 12.0, 13.3, 14.4, 17.8, 19.8, and 23.9 20, all of them with a margin of error of ± 0.2° 20.
  3. 3. The compound according to any of claims 1 and 2, characterized in that it has an X-ray powder diffractogram measured with CuKa radiation essentially like the one of Figure 1.
  4. 4. The compound according to any of claims 1 to 3, characterized in that it has a differential scanning calorimetry (DSC) diagram comprising an endothermic peak having a threshold temperature of about 180.5°C ± 2°C.
  5. 5. Use of a compound of formula (I) or a salt thereof according to any of claims 1 to 4 in the preparation of abrocitinib.
  6. 6. A method of preparing a compound of formula (I) according to any of claims 1 to 4 which comprises step (a) of reacting a compound of formula (II), wherein the bonds represented by a wavy line are in the c/s configuration, or a salt thereof, with a compound of formula (III) or a salt thereof,
  7. 7. The method according to claim 8, characterized in that step (a) is carried out in the presence of an aqueous base solution, preferably an alkaline salt of carbonate, and/or at a temperature of between 50°C and 70°C, preferably about 60°C.
  8. 8. The method according to any of claims 6 to 7, characterized in that it comprises the previous step (b) of preparing the compound of formula (II), wherein said step (b) comprises: (b-1) reacting a compound of formula (IV) with methylamine to convert the carbonyl group of the compound of formula (IV) into a methylimine group or a salt thereof, and (b-2) reacting the product of step (b-1) to convert the methylimine group or a salt thereof into a methylamine group.
  9. 9. The method according to claim 8, characterized in that step (b-2) is carried out by means of catalytic hydrogenation.
  10. 10. The method according to claim 9, characterized in that the catalyst of step (b-2) is platinum.
  11. 11. The method according to any of claims 8 to 10, characterized in that it comprises the previous step (c) of preparing the compound of formula (IV), wherein said step (c) comprises reacting a compound of formula (V) to form a compound of formula (IV)
  12. 12. The method according to claim 11 , characterized in that step (c) is carried out by means of the acid hydrolysis of the compound of formula (V).
  13. 13. The method according to any of claims 11 to 12, characterized in that it comprises the previous step (d) of preparing the compound of formula (V), wherein said step (d) comprises reacting a compound of formula (VI) to form a compound of formula (V)
  14. 14. The method according to claim 13, characterized in that step (d) comprises: (d-1) reacting a compound of formula (VI) to convert the -CONHOH group into an isocyanate group, and (d-2) reacting the product of step (d-1) with benzyl alcohol.
  15. 15. The method according to claim 14, characterized in that step (d-1) comprises reacting a compound of formula (VI) with carbonyldiimidazole.
  16. 16. The method according to any of claims 13 to 15, characterized in that it comprises the previous step (e) of preparing the compound of formula (VI), wherein said step (e) comprises: (e-1) reacting 3-oxocyclobutane-1 -carboxylic acid with trimethyl orthoformate to provide a compound of formula (VII) (e-2) reacting the compound of formula (VII) resulting from step (e-1) with hydroxylamine or a salt thereof to produce a compound of formula (VI).
  17. 17. A method for preparing /V-[c/s-3-(methyl-7/7-pyrrolo[2,3-d]pyrimidin-4-ylamino)cyclobutyl]- 1 -propanesulfonamide (abrocitinib), or a salt thereof, characterized in that it comprises: (f) reacting a compound of formula (I) or a salt thereof according to any of claims 1 to 4 to remove the benzyloxycarbonyl -CChCF^Ph group, obtaining an amino -NH2 group; and (g) reacting the compound resulting from step (f) to convert the amino group formed from the benzyl carbamate group of the compound of formula (I) or the salt thereof into a group of formula -NHSO2CH2CH2CH3.
  18. 18. The method according to claim 17, characterized in that step (f) is a catalytic hydrogenation step.
  19. 19. The method according to claim 18, characterized in that the catalyst of step (f) is palladium on carbon.
  20. 20. The method according to any of claims 18 to 19, characterized in that step (f) is carried out in the presence of methanol.

Description

DESCRIPTION BENZYL (3-(METHYL(7/7-PYRROLO[2,3-D]PYRIMIDIN-4YL)AMINO)CYCLOBUTYL) CARBAMATE OR A SALT THEREOF, METHOD FOR THE PREPARATION THEREOF, AND USE THEREOF IN THE SYNTHESIS OF ABROCITINIB FIELD OF THE INVENTION The present invention relates to a new intermediate useful in the synthesis of abrocitinib, to a method for obtaining same, to the use of said intermediate for preparing abrocitinib, and to a method for preparing abrocitinib using said intermediate. BACKGROUND OF THE INVENTION Abrocitinib, the chemical name of which is /V-[c/s-3-(methyl-7/7-pyrrolo[2,3-d]pyrimidin-4- ylamino)cyclobutyl]-1 -propanesulfonamide, is a Janus kinase JAK1 -inhibiting pharmaceutical active ingredient indicated for the treatment of moderate to severe atopic dermatitis in adult candidates for systemic therapy. Abrocitinib is a compound of formula (VIII) Abrocitinib was approved for medical use in the United States in January 2022 and in Europe in December 2021. Several synthetic routes have been described for the preparation of abrocitinib (VIII), see for example, documents EP 2 958 921 B1 and WO 2020/008391A. Document EP 2958921 B1 describes five alternative methods for the preparation of abrocitinib analogs. In particular, scheme 2 describes the following method: In said method, benzyl cis-[3-(methylamino)cyclobutyl]carbamate is designated as the synthetic intermediate which reacts with 2,4-dichloro-7-H-pyrrolo-(2,3-d)pyrimidine through an aromatic nucleophilic substitution reaction. After the deprotection of the benzyl carbamate, which proceeds together with the dechlorination of the pyrimidine ring, formation of the desired sulfonamide takes place in the presence of trimethylsilane derivatives, which are used in superstoichiometric amounts. Document WO 2020/008391A describes an alternative synthetic route for abrocitinib which proceeds according to the following synthetic scheme: A key step of this synthetic route is the Lossen rearrangement that allows preparing amine E from hydroxylamide D, the preparation of which is described with an overall yield of 38% for conversion steps A to D. The preparation of abrocitinib from compound D has an overall yield of 59.87%. Vazquez et al., Journal of Medicinal Chemistry 2018, 61 , 1130-1152, describe a method of preparing abrocitinib through aromatic nucleophilic substitution following a route similar to the one described in document EP2 958 921 B1 , but using a derivative in which nitrogen of the pyrrole ring is protected by a tosyl group (compound 25 is prepared from compound 48a). A synthetic route is described for abrocitinib analogs using an unprotected heterocyclic system and following a route similar to the one described in document EP2 958 921 B1 : According to this document, the 98% yield of the aromatic nucleophilic substitution step is due to the presence of the chlorine atom in position 2 of the pyrimidine ring which activates the chlorine atom in position 4 of said ring as a leaving group. Following this method, the sulfonamide formation step takes place with yields of between 21 and 65% according to the sulfonyl chloride compound used in said step. Connor et al., Organic Process Research and Development 2021 , 25, 608-615, describe the development of a commercial method for the synthesis of abrocitinib based on a nitrene group rearrangement reaction, describing the Curtius, Hoffmann, and Lossen rearrangement reactions for introducing amino group in cyclobutyl moiety. In particular, the synthetic route described is the same as the one described in document WO 2020/008391 A and is described with the following yields: There is a need in the state of the art for methods for obtaining abrocitinib with a reduced number of synthetic steps and/or a higher overall synthetic yield. SUMMARY OF THE INVENTION The inventors have discovered a new abrocitinib synthetic intermediate which allows preparing abrocitinib with a higher yield and savings in atoms. In particular, the abrocitinib synthetic intermediate of the invention, which is a compound of formula (I), allows abrocitinib to be prepared with a high yield in two steps and with an overall yield of 78.6%, according to the following scheme Abrocitinib yield 78.6% The overall yield of said synthesis is surprisingly higher compared to that described in the state of the art using benzyl (cis-3-((2-chloro-7/7-pyrrolo[2,3-d]pyrimidin-4- yl)(methyl)amino)cyclobutyl)carbamate as the starting product, for which a yield of 76% is described for the step of benzyl carbamate group deprotection, which is lower than the overall yield observed using the synthetic intermediate of the invention. Furthermore, as shown in the examples, the compound of formula (I) can be prepared through aromatic nucleophilic substitution by means of the following reaction with a yield of 98.3%: It is surprising because the presence of a Cl atom in position 2 of the pyrimidine ring system is known to activate the Cl atom in position 4 as a leaving group