阅读说明：本技术 用于制备杀微生物的噁二唑衍生物的方法 (Process for the preparation of microbicidal oxadiazole derivatives ) 是由 T·J·霍夫曼 R·J·G·蒙迪埃 E·戈迪诺 W·施图茨 S·K·戈雷 A·贾瓦莱卡尔 于 2020-04-16 设计创作，主要内容包括：本发明涉及一种根据方案1制备适合用作例如活性成分的杀微生物的具有式(I)的5-三氟甲基-1,2,4-噁二唑衍生物的方法,所述噁二唑衍生物具有杀微生物活性,特别是杀真菌活性。(The present invention relates to a process for the preparation of 5-A method of producing trifluoromethyl-1, 2, 4-oxadiazole derivatives having microbiocidal activity, in particular fungicidal activity.)

1. a process for preparing a compound having formula (I):

wherein

A is A-1 or A-2:

wherein each of A-1 and A-2 is optionally substituted with 1 or 2 substituents independently selected from halogen, C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy and C_1-4Substituted with a halo alkoxy group;

n is 0, 1 or 2;

R¹and R²Independently selected from hydrogen, halogen, cyano, hydroxy, C_1-4Alkyl radical, C_1-4Alkoxy and C_1-4A haloalkyl group; or

R¹And R²Together with the carbon atom to which they are bonded form a cyclopropyl ring;

z is Z¹Or Z²：

Z¹Is hydrogen, halogen, cyano, -OH, or-SH;

Z²is C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy radical, C_1-4Haloalkoxy, -COOH, -C (═ W) -X, -NR³R⁴、-NR³-C(＝W)-X、-S(＝O)₂-R⁵or-NR³-S(＝O)₂-R⁵(ii) a Or

Z²Is C_3-8Cycloalkyl radical, C_3-8Cycloalkyl radical C_1-2Alkyl, heterocyclic radical C_1-2Alkyl, phenyl C_1-2Alkyl, heteroaryl C_1-2Alkyl, or heterodiaryl, wherein the heterocyclyl moietyIs a compound containing 1,2 or 3 of the compounds individually selected from O, S, N, NR⁶C (O) and S (O)₂A 4-to 7-membered non-aromatic ring of a heteroatom or group of (a), and the heteroaryl moiety is a 5-or 6-membered monocyclic aromatic ring comprising 1,2, 3 or 4 heteroatoms independently selected from N, O and S; wherein any of said cycloalkyl, heterocyclyl, phenyl, heteroaryl or heterodiaryl is optionally substituted with 1 or 2 substituents selected from R⁷May be the same or different;

w is O or S;

x is halogen, -NR³R⁴、R⁵、-NR³-[CR⁸R⁹]_m-CR¹⁰(＝NR⁵)、-C(＝O)-NR³R⁴、-C(＝O)-R⁵、-C(＝N-C_1-4Alkoxy) -R⁵OR-OR¹¹；

R³And R⁴Independently selected from hydrogen, C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy, hydroxy C_1-4Alkyl radical, C_1-4Alkoxy radical C_1-4Alkyl radical, C_1-4Haloalkoxy, C_1-2Halogenoalkoxy radical C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-6Alkynyl, C_3-4Alkenyloxy radical, C_3-4Alkynyloxy, C_1-4Alkylcarbonyloxy, N-C_1-4Alkylamino and N, N-di-C_1-4An alkylamino group; or

R³And R⁴Independently selected from C_3-8Cycloalkyl radical, C_3-8Cycloalkyl radical C_1-2Alkyl, heterocyclic radical C_1-2Alkyl, phenyl C_1-2Alkyl, heteroaryl and heteroaryl C_1-2Alkyl wherein the heterocyclyl moiety is one containing 1,2 or 3 substituents independently selected from O, S, N, NR⁶C (O) and S (O)₂A 4-to 6-membered non-aromatic ring of a heteroatom or group of (a), and the heteroaryl moiety is a 5-or 6-membered monocyclic aromatic ring comprising 1,2, 3 or 4 heteroatoms independently selected from N, O and S; wherein any of said cycloalkyl, heterocyclyl, phenyl, or heteroaryl is optionally substituted with 1 or 2 substituents selected from R⁷May be the same or different; or

R³And X and R³The attached nitrogen atom, and the group-C (═ W) together form a heterocyclic group, a heterocyclic group C_1-6Alkyl, heteroaryl C_1-2Alkyl or heterodiaryl wherein the heterocyclyl moiety is a cyclic moiety comprising 1,2 or 3 substituents independently selected from O, S, N, NR⁶C (O) and S (O)₂A 4-to 7-membered non-aromatic ring of a heteroatom or group of (a), and the heteroaryl moiety is a 5-or 6-membered monocyclic aromatic ring comprising 1,2, 3 or 4 heteroatoms independently selected from N, O and S; wherein any of said heterocyclyl, heteroaryl or heterodiaryl is optionally substituted with 1 or 2 substituents selected from R⁷May be the same or different;

R⁵is C_1-4Alkyl radical, C_1-4Haloalkyl, hydroxy C_1-4Alkyl, cyano C_1-4Alkyl radical, C₂-₄Alkenyl radical, C_2-6Alkynyl, C_1-4Alkoxy radical, C_1-4Haloalkoxy, or C_1-4Alkoxy radical C₁-₄Alkyl, or C_1-2Halogenoalkoxy radical C_1-4An alkyl group; or

R⁵Is C_3-8Cycloalkyl radical, C_3-8Cycloalkyl radical C_1-2Alkyl, heterocyclic radical C_1-2Alkyl, phenyl C_1-6Alkyl, heteroaryl C_1-2Alkyl, or heterodiaryl wherein the heterocyclyl moiety is a cyclic moiety comprising 1,2 or 3 substituents independently selected from O, S, N, NR⁶C (O) and S (O)₂A 4-to 6-membered non-aromatic ring of a heteroatom or group of (a), and the heteroaryl moiety is a 5-or 6-membered monocyclic aromatic ring comprising 1,2, 3 or 4 heteroatoms independently selected from N, O and S; wherein any of said cycloalkyl, heterocyclyl, phenyl, heteroaryl or heterodiaryl is optionally substituted with 1 or 2 substituents selected from R⁷May be the same or different;

R⁶is hydrogen, C_1-4Alkyl radical, C_1-4Alkoxy, formyl, C_1-4Alkylcarbonyl group, C_1-4Alkoxycarbonyl, N-C_1-4Alkylaminocarbonyl, N-di-C_1-4Alkylaminocarbonyl radical, C_1-4Alkyl radicalSulfonyl, N-C_1-4Alkylaminosulfonyl, or N, N-di-C_1-4An alkylaminosulfonyl group;

R⁷is halogen, cyano, hydroxy, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-6Alkynyl, C_1-4Haloalkyl, C_2-4Haloalkenyl, C_1-4Alkoxy radical, C_1-4Haloalkoxy, C_3-4Alkenyloxy radical, C_3-4Alkynyloxy, N-C_1-4Alkylamino, N-di-C_1-4Alkylamino radical, C_1-4Alkylcarbonyl group, C_1-4Alkoxycarbonyl, aminocarbonyl, C_1-4Alkylcarbonylamino group C_1-4Alkyl, N-C_1-4Alkylaminocarbonyl, N-di-C_1-4Alkylaminocarbonyl radical, C_1-4Alkoxycarbonylamino, N-C_1-4Alkoxyaminocarbonyl, N-C_1-4alkyl-N-C_1-4Alkoxyaminocarbonyl group, C_3-8Cycloalkylaminocarbonyl, N-C_3-8Cycloalkyl radical C_1-2Alkylaminocarbonyl, N-C_1-4Alkoxy radical C_1-4Alkylaminocarbonyl, N-C_1-4Alkoxy radical C_1-4Alkylimino radical, C_1-4Alkylsulfonyl, or C_1-4An alkylsulfanyl group;

m is 0, 1 or 2;

R⁸and R⁹Independently selected from hydrogen, halogen, cyano, C_1-4Alkyl, and C_1-4A haloalkyl group; or

R⁸And R⁹Together with the carbon atom to which they are bonded form a cyclopropyl ring;

R¹⁰is hydrogen, C_1-6Alkyl radical, C_2-4Alkenyl radical, C_2-6Alkynyl, C_1-4Haloalkyl, C_3-8Cycloalkyl, or phenyl;

R¹¹is C_1-8Alkyl radical, C_1-4Haloalkyl, hydroxy C_1-6Alkyl radical, C_1-4Alkoxy radical C_1-6Alkyl radical, C_1-2Halogenoalkoxy radical C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-6Alkynyl, or C_1-4Alkylcarbonyloxy C₁-C₄An alkyl group;

the method comprises reacting a compound having the formula (II):

wherein A, n, R¹、R²And Z is a step of reaction with a compound having formula (III) as defined for a compound having formula (I):

wherein R is¹²Is C_1-4An alkyl group.

2. The process of claim 1, wherein the process is carried out in the presence of at least one base.

3. The method of claim 2, wherein the base is selected from the group consisting of: alkali metal C_1-6Alkoxylates and alkaline earth metals C_1-6An alkoxylate.

4. A process according to claim 2 or 3, wherein the base is sodium tert-butoxide or potassium tert-butoxide.

5. The method of any one of claims 1 to 4, further comprising reacting a compound having formula (VII):

wherein A, n, R¹、R²And Z is as defined in said compound having formula (I), a step of reacting with hydroxylamine or a salt thereof to obtain said compound having formula (II).

6. The method according to any one of claims 1 to 5, wherein, in the compound of formula (I), n is 0 or 1.

7. The method of any one of claims 1 to 6, further comprising reacting an intermediate compound having the formula (I-B), wherein Z is Z¹To obtain a compound having the formula (I-A), wherein Z is Z²。

8. The method of any one of claims 1 to 7, further comprising reacting the compound having formula (I-B), wherein Z is¹Is halogen, with an amine having the formula (V):

wherein R is³Is as defined in said compound of formula (I) to obtain a compound of formula (I-a) or a salt thereof:

wherein A, n, R¹、R²And R³Is as defined in said compound having formula (I).

9. The method of claim 8, further comprising reacting the compound having formula (I-a), or a salt thereof, with a compound having formula (VI):

wherein X and W are as defined for said compound of formula (I) and T is halogen, hydroxy or C_1-4Alkoxy radical to obtain a compound havingA step of using a compound having formula (I-A):

wherein A, n, R¹、R²、R³X and W are as defined for the compounds of formula (I).

10. The method of any one of claims 1 to 6, comprising reacting a compound having formula (II-A):

wherein A, n, R¹、R²、R³X and W are as defined in said compound of formula (I), with a compound of formula (III) wherein R is¹²Is C_1-4Alkyl to obtain a compound having formula (I-A):

wherein A, n, R¹、R²、R³X and W are as defined for the compounds of formula (I).

11. The method of claim 10, further comprising reacting a compound having formula (VII-a):

wherein A, n, R¹、R²、R³X and W are as defined in said compound of formula (I), with hydroxylamine or a salt thereof to obtain said compound of formula (II-A)The step (2).

12. The method of claim 10 or 11, further comprising reacting a compound having formula (VII-a):

wherein A, n, R¹、R²And R³Is as defined in said compound having formula (I), with a compound having formula (VI):

wherein X and W are as defined for said compound of formula (I) and T is halogen, hydroxy or C_1-4Alkoxy group to obtain the compound having formula (VII-A).

13. The method of any one of claims 1 to 12, further comprising the step of isolating the compound having formula (I) using an aqueous acidic medium.

14. The method of claim 13, wherein the aqueous acidic medium comprises citric acid.

15. The process according to claim 13 or 14, wherein the pH of the aqueous acidic medium is from 2.0 to 6.0.