阅读说明：本技术 制备取代的2-[2-(苯基)乙基氨基]烷酰胺衍生物的方法 (Process for preparing substituted 2- [2- (phenyl) ethylamino ] alkanamide derivatives ) 是由 W·里昂 兰东晓 张伟芳 方项 吴思忠 于 2020-04-14 设计创作，主要内容包括：本发明涉及一种制备式(I)的化合物或其药学上可接受的盐的方法：其中R是(C-(3)-C-(10))烷基、或ω-三氟(C-(3)-C-(10))烷基；R-(1)和R-(2)独立地是氢、羟基、(C-(1)-C-(8))烷氧基、(C-(1)-C-(8))烷硫基、卤代、三氟甲基或2,2,2-三氟乙基；或R-(1)和R-(2)之一是在R-O-基团的邻位处,且与该同一R-O-一起代表式(A)基团,其中R-(0)是(C-(2)-C-(9))烷基；R-(3)和R-(4)独立地是氢、(C-(1)-C-(4))烷基；或R-(4)是氢且R-(5)是选自-CH-(2)-OH、-CH-(2)-O-(C-(1)-C-(6))烷基、-CH(CH-(3))-OH、-(CH-(2))-(2)-S-CH-(3)、苄基及4-羟苄基的基团；或R-(4)和R-(5)与相邻碳原子一起形成(C-(3)-C-(6))环烷基残基；R-(5)和R-(6)独立地是氢或(C-(1)-C-(6))烷基；或与相邻氮原子一起形成5-6元单环饱和杂环,其任选含有一个选自-O-、-S-及-NR-(7)-的另外的杂原子,其中R-(7)是氢或(C-(1)-C-(6))烷基；且其中任选地,基团R、R-(1)、R-(2)、R-(3)、R-(4)、R-(5)和R-(6)优选R基团中的一或多个氢原子可被氘原子取代。(The present invention relates to a process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof: wherein R is (C) 3 ‑C 10 ) Alkyl, or omega-trifluoro (C) 3 ‑C 10 ) An alkyl group; r 1 And R 2 Independently hydrogen, hydroxy, (C) 1 ‑C 8 ) Alkoxy group, (C) 1 ‑C 8 ) Alkylthio, halo, trifluoromethyl or 2,2, 2-trifluoroethyl; or R 1 And R 2 One at the ortho position of the R-O-group and together with the same R-O-represents a group of formula (A) whereinR 0 Is (C) 2 ‑C 9 ) An alkyl group; r 3 And R 4 Independently of each other, hydrogen, (C) 1 ‑C 4 ) An alkyl group; or R 4 Is hydrogen and R 5 Is selected from-CH 2 ‑OH、‑CH 2 ‑O‑(C 1 ‑C 6 ) Alkyl, -CH (CH) 3 )‑OH、‑(CH 2 ) 2 ‑S‑CH 3 Benzyl and 4-hydroxybenzyl groups; or R 4 And R 5 Together with adjacent carbon atoms to form (C) 3 ‑C 6 ) A cycloalkyl residue; r 5 And R 6 Independently is hydrogen or (C) 1 ‑C 6 ) An alkyl group; or together with the adjacent nitrogen atom form a 5-6 membered monocyclic saturated heterocycle optionally containing one member selected from the group consisting of-O-, -S-and-NR 7 A further heteroatom of (A), wherein R 7 Is hydrogen or (C) 1 ‑C 6 ) An alkyl group; and wherein optionally, the group R, R 1 、R 2 、R 3 、R 4 、R 5 And R 6 Preferably, one or more hydrogen atoms in the R group may be replaced by deuterium atoms.)

1. A process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof,

wherein R is (C)₃-C₁₀) Alkyl, or omega-trifluoro (C)₃-C₁₀) An alkyl group;

R₁and R₂Independently hydrogen, hydroxy, (C)₁-C₈) Alkoxy group, (C)₁-C₈) Alkylthio, halo, trifluoromethyl or 2,2, 2-trifluoroethyl; or R₁And R₂One at the ortho position of the R-O-group and together with the same R-O-representsGroup, wherein R₀Is (C)₂-C₉) An alkyl group;

R₃and R₄Independently of each other, hydrogen, (C)₁-C₄) An alkyl group; or R₄Is hydrogen and R₅Is selected from-CH₂-OH、-CH₂-O-(C₁-C₆) Alkyl, -CH (CH)₃)-OH、-(CH₂)₂-S-CH₃Benzyl and 4-hydroxybenzyl groups; or R₄And R₅Together with adjacent carbon atoms to form (C)₃-C₆) A cycloalkyl residue;

R₅and R₆Independently is hydrogen or (C)₁-C₆) An alkyl group; or together with the adjacent nitrogen atom form a 5-6 membered monocyclic saturated heterocycle optionally containing one member selected from the group consisting of-O-, -S-and-NR₇A further heteroatom of (A), wherein R₇Is hydrogen or (C)₁-C₆) An alkyl group;

and whereinOptionally, a group R, R₁、R₂、R₃、R₄、R₅And R₆Preferably one or more hydrogen atoms in the R group may be replaced by deuterium atoms;

the method comprises the following steps:

a) reacting a compound of formula (II):

r, R therein₁And R₂Is as defined above in that the process is carried out,

with a compound of formula (III) in the presence of a strong base,

[(R₉)₃PCH₂OR₈]⁺X^-

(III)

wherein

R₉Is aryl, preferably phenyl, tolyl, or (C1-C6) alkyl, preferably methyl, ethyl or n-propyl;

x is Cl, Br or I, preferably Cl and Br;

R₈is (C)₁-C₆) Alkyl groups preferably methyl, ethyl or n-propyl, or aryl groups preferably phenyl or tolyl;

to obtain a compound of formula (IV):

r, R therein₁、R₂And R₈Is as defined above, and

b) hydrolyzing the obtained compound of formula (IV) to obtain a compound of formula (V):

r, R therein₁And R₂Is as defined above, and

c) reacting the obtained compound of formula (V) with a compound of formula (VI) or a salt thereof,

wherein R is₃、R₄、R₅And R₆Is as defined above and G is hydrogen or a protecting group for an amino group,

to obtain a condensation compound;

d) reducing the obtained condensation compound to obtain a compound of formula (I)

Or

c') directly reacting a compound of formula (IV) as defined above with a compound of formula (VI) as defined above and reducing the obtained condensation compound to obtain a compound of formula (I); and

e) optionally converting the obtained compound of formula (I) into a pharmaceutically acceptable salt thereof.

2. The process of claim 1, which is used to obtain a compound of formula (Γ):

r, R therein₁、R₂、R₃、R₄、R₅And R₆Is as defined in claim 1.

3. A process according to any one of the preceding claims for obtaining a compound of formula (I) as defined in claim 1 or formula (Γ) as defined in claim 2, wherein:

r is (C)₄-C₆) Alkyl or CD₃-CD₂-(C₂-C₄) An alkyl group;

R₁and R₂Independently hydrogen or halo, preferably fluoro;

R₃and R₄Are all hydrogen; and is

R₅And R₆Independently is hydrogen or (C)₁-C₃) An alkyl group.

4. The process according to any one of the preceding claims, for obtaining a compound of formula (I) as defined in claim 1 or formula (Γ) as defined in claim 2, wherein R is n-butyl or CD₃-CD₂-CH₂-CH₂-, and R₁、R₂、R₃、R₄、R₅And R₆Is hydrogen.

5. The process according to any one of the preceding claims, wherein the strong base of step a) is selected from the group consisting of alkyl lithium, lithium hexamethyldisilazide, lithium isopropylamide, potassium tert-butoxide.

6. The method of claim 5, wherein the strong base is lithium hexamethyldisilazide.

7. The process of any one of the preceding claims, wherein the by-product formed in step a) is wherein R₉Is (R) as defined in claim 1₉)₃P is oxidized to (R)₉)₃PO was removed.

8. The method of claim 7 wherein (R) is removed by filtration₉)₃PO。

9. The process according to claim 7 or 8, wherein the product (IV) obtained is purified by chromatography.

10. The process according to any one of the preceding claims, wherein the hydrolysis of step b) is carried out in aqueous acidic conditions.

11. The process of claim 10, wherein the hydrolysis of step b) is carried out in acetonitrile and aqueous hydrochloric acid.

12. The process of any of the preceding claims, wherein G in the compound of formula (VI) is hydrogen.

13. The process of any one of claims 1 to 11, wherein G in the compound of formula (VI) is an amino protecting group selected from: carbamates N-carboxyalkyl, N-tert-Butylcarbamate (BOC), N-benzylcarbamate (Cbz), bromobenzylcarbamate, p-chlorobenzylcarbamate and 9-fluorenylmethylcarbamate (Fmoc).

14. The process according to any one of the preceding claims, wherein the reducing agent used in step d) is selected from sodium borohydride, sodium triacetoxyborohydride (STAB-H), Pd/H₂And NaBH3 CN.

15. The process according to any of the preceding claims, wherein the reducing agent used in step d) is sodium triacetoxyborohydride (STAB-H).

16. The process according to any one of the preceding claims, wherein steps b), c) and d) are carried out without isolation of intermediates.

17. The process of claim 16, wherein steps b), c) and d) are carried out in acetonitrile and aqueous hydrochloric acid.

18. The process according to any of the preceding claims, wherein the pharmaceutically acceptable acid of step e) is selected from HCl, HBr, CH₃SO₃H. P-toluenesulfonic acid and phosphoric acid.

19. The method of any one of the preceding claims, wherein R, R is the most important among the above₁And R₂Is a compound of the formula (II) as defined in claim 1Prepared by alkylation of a compound of formula (II) wherein R is hydrogen by reaction with a compound of formula RY wherein R is as defined in claim 1 and Y is a leaving group.

20. The method of claim 19, wherein Y is selected from the group consisting of chloride, bromide, mesylate, p-toluenesulfonate, p-bromobenzenesulfonate, m-nitrobenzenesulfonate and phosphate.