Methods for the synthesis of diazabicyclo[6.2.0]decane-related compounds

Abstract

This provides a method for synthesizing diazabicyclo[6.2.0]decane compounds. [Solution] The synthesis of diazabicyclo[6.2.0]decane compounds proceeds by stereoselective synthesis of chiral lactones, followed by azetidine formation via a series of chemoselective reactions. Bicyclization occurs with the formation of diazobicyclo[6.2.0]decane-related compounds.

Claims

1. Formula I: 【Chemistry 1】 (In the formula, R １ is -I, -Cl, -Br, or 【Chemistry 2】 And; R ２ is C(O)R ３ And; R ３ is, -O － And a positive counterion forms an ionic bond with formula I; P １ (This is a nitrogen protecting group.) A method for forming a solid compound represented by formula II 【Transformation 3】 A method comprising the steps of reacting a reactant with a base, and dividing a racemic mixture by crystallization using a chiral reagent.

2. R １ but, 【Chemistry 4】 The method according to claim 1.

3. P １ is selected from the group consisting of -C(O)CF ３ , -C(O)OC(C H ３ ), ３ and -C(O)OCH ２ Ph, the method according to claim 2.

4. P １ However, -C(O)CF ３ The method according to claim 3.

5. The step of reacting with the aforementioned base is lithium diisopropylamine, and ZnCl ２ The method according to claim 4, in the presence of

6. The method according to claim 5, wherein the chiral reagent is (R)-(+)-1-phenylethylamine.

7. Formula I: 【Transformation 5】 (In the formula, R １ is -I, -Cl, -Br, or 【Transformation 6】 And; R ２ is C(O)R ３ And; R ３ It is an -O alkyl group; P １ (This is a nitrogen protecting group.) A method for forming a compound represented by formula III 【Transformation 7】 (In the formula, X １ (It is a halogen atom.) A method comprising the step of reacting a reactant with a chiral sulfinylimine.

8. R １ and X １ However, each is -Br, The aforementioned chiral sulfinylimine, 【Transformation 8】 (In the formula, R ４ and R ５ (These are linear or branched alkyl groups.) That is, The method according to claim 7.

9. R ４ However, -C(CH ３ ) ３ And R ５ However, -CH ２ CH ３ The method according to claim 8.

10. The method according to claim 9, wherein the reaction step is performed in the presence of Zn.

11. Formula IV 【Chemistry 9】 (In the formula, R １ is -I, -Cl, -Br, or 【Chemistry 10】 And; P １ and P ２ (These are the same or different groups, and represent nitrogen protecting groups.) A method for forming a compound represented by formula V 【Chemistry 11】 The lactone of formula I 【Chemistry 12】 (In the formula, R ２ is C(O)R ３ And; R ３ is -OH, -O alkyl, -O － And; R ３ ga-O － In this case, the positive counterion forms an ionic bond with formula I; P １ (This is a nitrogen protecting group.) A step of forming from a compound; The lactone of formula V is converted to formula VI 【Chemistry 13】 The step of reducing to the compound; and A method comprising the step of forming an intermediate that reacts with a nitrogen nucleophile to generate a compound of formula IV by converting an alcoholic group covalently bonded to the unsaturated carbon of formula VI into a leaving group.

12. The method according to claim 11, wherein the nitrogen nucleophile is phthalimide.

13. R １ but, 【Chemistry 14】 And R ２ ga-C(O)O － P １ However, -C(O)CF ３ The method according to claim 12.

14. The method according to claim 13, wherein the lactone of formula V is formed by reacting the compound of formula I with an electropositive halogen source in a polar solvent.

15. The aforementioned electropositive source of halogen is I ２ The polar solvent is CH ３ The method according to claim 14, wherein the CN is an aqueous mixture.

16. The lactone of formula V is used to form compound I. ２ The first product is formed by reacting it with a polar solvent, and the first product is converted into NaN ３ The method according to claim 13, wherein the compound of formula V is formed by reacting with [another compound].

17. The aforementioned reduction step is NaBH ４ The method according to claim 16, which is carried out using

18. The leaving group is a mesylate group, and the intermediate has the following structure: 【Chemistry 15】 The method according to claim 17, as shown by one or both of the above.

19. P １ However, -C(O)CF ３ From the following structure: 【Chemistry 16】 The method according to claim 18, which is converted to

20. R １ However, it is -Br, and R ２ is -C(O)OCH ２ CH ３ P １ However, -S(O)C(CH ３ ) ３ The method according to claim 11.

21. P １ However, -S(O)C(CH ３ ) ３ The structure is as follows: 【Chemistry 17】 The method according to claim 20, which is converted to

22. The lactone of formula V reacts with the compound of formula I in a polar solvent with an electropositive source of a halide to form a first product, and the first product is converted into NaN ３ The method according to claim 21, wherein the compound of formula V is formed by reacting with [another compound].

23. The lactone in formula V is NaBH ４ The following compounds are reduced using: [Chemistry 18] The method according to claim 22, which forms

24. The leaving group is a mesylate group, and the intermediate has the following structure: 【Chemistry 19】 The method according to claim 23, as shown by one or both of the above.

25. The following structure 【Chemistry 20】 (In the formula, R １ is -I, -Cl, -Br, or 【Chemistry 21】 And; R ６ and R ７ These are independently the same or different, selected from -H, alkyl, -O alkyl, or R ６ and R ７ They form a ring together with the atoms to which they are bonded; R ８ and R ９ These are independently the same or different, -H, -alkyl, -C(O)alkyl, -S(O) ２ Selected from alkyl groups, or R ８ and R ９ Together with the N to which they are bonded, they form a monocyclic or bicyclic ring system; R １０ These are -H, linear or branched alkyl, -C(O)alkyl, -C(O)O-alkyl, -C(O)NH-alkyl, -C(O)aryl, -C(O)O-aryl, -C(O)NH-aryl, -C(O)heteroaryl, -C(O)O-heteroaryl, and -C(O)N-heteroaryl; The alkyl, aryl, and heteroaryl atoms are optionally substituted with one or more halogen, oxygen, nitrogen, or sulfur atoms. A method for producing a compound represented by formula IV 【Chemistry 22】 A method comprising the steps of reacting a compound represented by with a substituted γ-hydroxyaldehyde, and achieving bicyclization.

26. The aforementioned γ-hydroxyaldehyde has the following structure: 【Chemistry 23】 (In the formula, R １１ is a -H or oxygen protecting group; R １２ is -H or -CH ２ (OH) The method according to claim 25, as shown by [referencing].

27. The aforementioned γ-hydroxyaldehyde is 【Chemistry 24】 The compound of formula VIII is the following intermediate: 【Chemistry 25】 The method according to claim 26, which is produced through the process described above.

28. The process involves an oxidation step, and the compound of formula VIII is obtained as the following intermediate: 【Chemistry 26】 The method according to claim 27, which is produced through the process described above.

29. The process includes a reduction step and a bicyclization step, and the compound of formula VIII is the following intermediate: 【Chemistry 27】 The method according to claim 28, which is produced through the process described above.

30. Further reduction steps are involved, and the compound of formula VIII yields the following intermediate: 【Chemistry 28】 The method according to claim 29, which is manufactured through the process described above.

31. The compound of formula XIII reacts with 4-methoxyphenyl isocyanate to form the compound of formula VIII, which has the following structure: 【Chemistry 29】 The method according to claim 30, as shown by [representation].

32. Formula IV 【Transformation 30】 (In the formula, R １ is -I, -Cl, -Br, or 【Chemistry 31】 And; P １ and P ２ (These are the same or different groups, and represent nitrogen protecting groups.) A method for forming a compound represented by formula VI 【Chemistry 32】 A method comprising the step of forming an intermediate that reacts with a nitrogen nucleophile to produce a compound of formula IV by converting an alcoholic group covalently bonded to an unsaturated carbon to a leaving group.

33. The leaving group is a mesylate group, and the intermediate has the following structure: 【Transformation 33】 The method according to claim 32, as shown by one or both of the above.

34. The method according to claim 33, wherein the nitrogen nucleophile is phthalimide.

35. Compound of formula XV: 【Transformation 34】 [In the formula, R １ is -I, -Cl, -Br, or 【Chemistry 35】 And, Z is, 【Transformation 36】 (In the formula, P １ and P ２ (which are the same or different, and are nitrogen protecting groups or -H) or their pharmaceutically acceptable salts; 【Chemistry 37】 (wherein, R ６ and R ７ are independently the same or different and are selected from -H, alkyl, -Oalkyl, or R ６ and R ７ together with the atom to which they are attached form a ring; R ８ and R ９ are independently the same or different and are selected from -H, -alkyl, -C(O)alkyl, -S(O) ２ alkyl, or R ８ and R ９ together with the N to which they are attached form a monocyclic or bicyclic ring system; R １０ is -H, linear or branched alkyl, -C(O)alkyl, -C(O)O-alkyl, -C(O)NH-alkyl, -C(O)aryl, -C(O)O-aryl, -C(O)NH-aryl, -C(O)heteroaryl, -C(O)O-heteroaryl, and -C(O)N-heteroaryl, and alkyl, aryl and heteroaryl are substituted by one or more halogen atoms, hydrogen atoms, oxygen atoms, nitrogen atoms or sulfur atoms) or a pharmaceutically acceptable salt thereof; 【Transformation 38】 (wherein, R ８ and R ９ are independently the same or different and are selected from -H, -alkyl, -C(O)alkyl, -S(O) ２ alkyl, or R ８ and R ９ together with the N to which they are attached form a monocyclic ring or bicyclic ring system, and the alkyl is substituted by one or more halogen atoms, hydrogen atoms, oxygen atoms, nitrogen atoms or sulfur atoms) or a pharmaceutically acceptable salt thereof; 【Chemistry 39】 (In the formula, R ８ and R ９ These are independently the same or different, -H, -alkyl, -C(O)alkyl, -S(O) ２ Selected from alkyl groups, or R ８ and R ９ (The alkyl groups, together with the nitrogen atoms to which they are bonded, form a monocyclic or bicyclic ring system, and the alkyl group is substituted with one or more halogen atoms, hydrogen atoms, oxygen atoms, nitrogen atoms, or sulfur atoms) or pharmaceutically acceptable salts thereof; 【Chemistry 40】 (In the formula, R ８ and R ９ These are independently the same or different, -H, -alkyl, -C(O)alkyl, -S(O) ２ Selected from alkyl groups, or R ８ and R ９ (The alkyl groups, together with the N to which they are bonded, form a monocyclic or bicyclic ring system, and the alkyl group is substituted with one or more halogen atoms, hydrogen atoms, oxygen atoms, nitrogen atoms, or sulfur atoms) or pharmaceutically acceptable salts thereof; and 【Chemistry 41】 (In the formula, R ８ and R ９ These are independently the same or different, -H, -alkyl, -C(O)alkyl, -S(O) ２ Selected from alkyl groups, or R ８ and R ９ (These atoms, together with the nitrogen atoms to which they are bonded, form a monocyclic or bicyclic ring system, and the alkyl group is optionally substituted with one or more halogen atoms, hydrogen atoms, oxygen atoms, nitrogen atoms, or sulfur atoms) or a pharmaceutically acceptable salt thereof. [A substituted four-membered nitrogen-containing heterocycle selected from the group consisting of the following:]

36. Formula IV: 【Chemistry 42】 (In the formula, R １ is -I, -Cl, -Br, or 【Chemistry 43】 P １ and P ２ (These are the same or different, and are nitrogen protecting groups or -H.) The compound or pharmaceutically acceptable salt thereof according to claim 35.

37. Formula VIII: 【Chemistry 44】 (In the formula, R １ is -I, -Cl, -Br, or 【Chemistry 45】 And; R ６ and R ７ These are independently the same or different, selected from -H, alkyl, -O alkyl, or R ６ and R ７ They form a ring together with the atoms to which they are bonded; R ８ and R ９ These are independently the same or different, -H, -alkyl, -C(O)alkyl, -S(O) ２ Selected from alkyl groups, or R ８ and R ９ Together with the N to which they are bonded, they form a monocyclic or bicyclic ring system; R １０ These are -H, linear or branched alkyl, -C(O)alkyl, -C(O)O-alkyl, -C(O)NH-alkyl, -C(O)aryl, -C(O)O-aryl, -C(O)NH-aryl, -C(O)heteroaryl, -C(O)O-heteroaryl, and -C(O)N-heteroaryl, where alkyl, aryl, and heteroaryl are substituted with one or more halogen atoms, hydrogen atoms, oxygen atoms, nitrogen atoms, or sulfur atoms. The compound or pharmaceutically acceptable salt thereof according to claim 35.

38. Formula X: 【Chemistry 46】 (In the formula, R １ is -I, -Cl, -Br, or 【Chemistry 47】 And; R ８ and R ９ These are independently the same or different, -H, -alkyl, -C(O)alkyl, -S(O) ２ Selected from alkyl groups, or R ８ and R ９ (The alkyl groups, together with the nitrogen atoms to which they are bonded, form a monocyclic or bicyclic ring system, and the alkyl group is substituted with one or more halogen atoms, hydrogen atoms, oxygen atoms, nitrogen atoms, or sulfur atoms.) The compound or pharmaceutically acceptable salt thereof according to claim 35.

39. Formula XI: 【Chemistry 48】 (In the formula, R １ is -I, -Cl, -Br, or 【Chemistry 49】 And; R ８ and R ９ These are independently the same or different, -H, -alkyl, -C(O)alkyl, -S(O) ２ Selected from alkyl groups, or R ８ and R ９ (The alkyl groups, together with the nitrogen atoms to which they are bonded, form a monocyclic or bicyclic ring system, and the alkyl group is substituted with one or more halogen atoms, hydrogen atoms, oxygen atoms, nitrogen atoms, or sulfur atoms.) The compound or pharmaceutically acceptable salt thereof according to claim 35.

40. Equation XII: [Transformation 50] (In equation XII, R １ is -I, -Cl, -Br, or 【Chemistry 51】 And; R ８ and R ９ These are independently the same or different, -H, -alkyl, -C(O)alkyl, -S(O) ２ Selected from alkyl groups, or R ８ and R ９ (The alkyl groups, together with the nitrogen atoms to which they are bonded, form a monocyclic or bicyclic ring system, and the alkyl group is substituted with one or more halogen atoms, hydrogen atoms, oxygen atoms, nitrogen atoms, or sulfur atoms.) The compound or pharmaceutically acceptable salt thereof according to claim 35.

41. Equation XIII: 【Chemistry 52】 (In the formula, R １ is -I, -Cl, -Br, or 【Chemistry 53】 And; R ８ and R ９ These are independently the same or different, -H, -alkyl, -C(O)alkyl, -S(O) ２ Selected from alkyl groups, or R ８ and R ９ These atoms, together with the nitrogen atoms to which they are bonded, form a monocyclic or bicyclic ring system, and the alkyl group is optionally substituted with one or more halogen atoms, hydrogen atoms, oxygen atoms, nitrogen atoms, or sulfur atoms. The compound or pharmaceutically acceptable salt thereof according to claim 35.

42. Formula XV: 【Chemistry 54】 [In the formula, R １ is -I, -Cl, -Br, or 【Transformation 55】 And; Z is, 【Transformation 56】 (In the formula, R ２ is C(O)R ３ And; R ３ is, -O － Therefore, the positive counterion forms an ionic bond with formula XVI, or R ３ is -OH; P １ (is a nitrogen protecting group or -H); 【Chemistry 57】 (In the formula, P １ (is a nitrogen protecting group or -H); 【Transformation 58】 (In the formula, P １ (is a nitrogen protecting group or -H); 【Chemistry 59】 (In the formula, P １ (is a nitrogen protecting group or -H); and 【Transformation 60】 (In the formula, P １ (where is a nitrogen protecting group or -H) or a pharmaceutically acceptable salt thereof Selected from the group consisting of: A compound having or a pharmaceutically acceptable salt thereof.

43. Formula I: 【Chemistry 61】 (In the formula, R １ teeth, 【Transformation 62】 And; R ２ is C(O)R ３ And; R ３ is, -O － Therefore, the positive counterion forms an ionic bond with formula I, or R ３ is -OH; P １ (This is a nitrogen protecting group or -H) The compound or pharmaceutically acceptable salt thereof according to claim 42.

44. Formula V: 【Transformation 63】 (In the formula, R １ is -I, -Cl, -Br, or 【Chemistry 64】 P １ (This is a nitrogen protecting group or -H) The compound or pharmaceutically acceptable salt thereof according to claim 42.

45. Formula VI: 【Transformation 65】 (In the formula, R １ is -I, -Cl, -Br, or 【Chemical Formula 66】 P １ (This is a nitrogen protecting group or -H) The compound or pharmaceutically acceptable salt thereof according to claim 42.

46. Formula VII: 【Transformation 67】 (In the formula, R １ is -I, -Cl, -Br, or 【Transformation 68】 P １ (This is a nitrogen protecting group or -H) The compound or pharmaceutically acceptable salt thereof according to claim 42.

47. Equation VIIb: 【Transformation 69】 (In the formula, R １ is -I, -Cl, -Br, or 【Transformation 70】 P １ (This is a nitrogen protecting group or -H) The compound or pharmaceutically acceptable salt thereof according to claim 42.

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