阅读说明：本技术 合成方法和合成中间体 (Synthetic method and synthetic intermediate ) 是由 S·古恩 F-A·康 N·杰恩 A·K·帕希 R·波纳亚 A·K·索尼 S·R·R·阿图 于 2018-03-30 设计创作，主要内容包括：本发明提供了可用于制备抗菌剂TXA709的合成中间体和合成方法：<Image he="346" wi="700" file="DDA0002256399580000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The invention provides a synthetic intermediate and a synthetic method for preparing an antibacterial agent TXA 709:)

1. A method of making TXA 709:

the method comprises reacting an amide of formula 9:

converted to TXA 709.

2. The method of claim 1, further comprising preparing the compound of formula 9 by:

the mode is that the compound of the formula 3:

with a compound of formula 8:

3. the method of claim 2, further comprising preparing the compound of formula 3 by: reacting a compound of formula 2:

with a compound of the formula:

4. the method of claim 3, further comprising preparing the compound of formula 2 by: reducing a nitro compound of formula 1:

to provide the compound of formula 2.

5. The method of claim 4, further comprising preparing the compound of formula 1 by: reacting a compound of the formula:

with a compound of the formula:

to provide the compound of formula 1.

6. The method of any one of claims 2-5, further comprising preparing the compound of formula 8 by: reacting a compound of formula 7:

to said compound of formula 8.

7. The method of claim 6, further comprising preparing the compound of formula 7 by: reacting a compound of formula 6:

to said compound of formula 7.

8. The method of claim 7, further comprising preparing the compound of formula 6 by: a carboxylated compound of formula 5:

9. the method of claim 8, further comprising preparing the compound of formula 5 by: benzylating a phenol of formula 4:

10. a process for preparing a compound of formula 9:

the method comprises reacting a compound of formula 3:

with a compound of formula 8:

to provide the compound of formula 9.

11. A process for preparing a compound of formula 8:

the method comprises reacting a compound of formula 7:

to the compound of formula 8.

12. The process of claim 11, wherein the compound of formula 7 is converted to the compound of formula 8 by hydrogenation.

13. The process of claim 11, wherein the compound of formula 7 is converted to the compound of formula 8 by hydrogenation using palladium on carbon as a catalyst.

14. The method of any one of claims 11-13, wherein the compound of formula 7 is converted to the compound of formula 8 in the presence of a non-polar solvent.

15. The method of any one of claims 11-14, wherein the compound of formula 7 is converted to the compound of formula 8 at a temperature in the range of about-78 ℃ to about 65 ℃.

16. A method of preparing a salt of formula 11:

the method includes transmitting TXA 709:

to the salt of formula 11.

17. A salt of formula 11:

Background

International patent application publication No. WO 2014/074932 describes compounds of formula (I):

the compounds of formula (I) are useful as antimicrobial agents. One of these compounds TXA 709:

has been selected as an antibacterial agent for clinical development.

Currently, there is a need for improved synthetic methods and synthetic intermediates that can be used to prepare TXA709 in higher yields on a commercial (e.g., kg) scale.

Disclosure of Invention

The present invention provides synthetic methods and synthetic intermediates useful for preparing TXA709 in higher yield on a commercial (e.g., kg) scale.

Accordingly, one embodiment provides a compound of formula 9:

another embodiment provides a salt of formula 11:

another embodiment provides a method of preparing a compound of formula 8:

the method comprises reacting a compound of formula 7:

to the compound of formula 8.

Another embodiment provides a process for preparing TXA709 comprising reacting an amide of formula 9:

converted to TXA 709.

Another embodiment provides a method of preparing a compound of formula 9:

the method comprises reacting a compound of formula 3:

with a compound of formula 8:

to provide the compound of formula 9.

Another embodiment provides a method of preparing a salt of formula 11:

the method comprises converting TXA709 to a salt of formula 11.

Drawings

Figure 1 shows the preparation of synthetic intermediate 3.

Figure 2 illustrates the preparation of synthetic intermediate 8.

Figure 3 shows the preparation of TXA709 from synthetic intermediates 3 and 8.

Figure 4 illustrates the preparation of salt 10.

Detailed Description

Unless otherwise stated, the following definitions are used: halo is fluoro, chloro, bromo, or iodo. Alkyl, alkoxy, alkenyl, alkynyl, and the like each represent both straight-chain and branched groups; however, reference to an individual group such as propyl encompasses only straight chain groups, branched chain isomers such as isopropyl are specifically mentioned. Aryl represents phenyl, or a mono-edge fused bicyclic carbocyclic group having about nine to ten ring atoms in which at least one ring is aromatic. Heteroaryl groups encompass: a monocyclic aromatic ring radical containing five or six ring atoms consisting of carbon and one to four heteroatoms, each selected from the group consisting of: non-peroxide oxygen, sulfur and N (X), wherein X is absent or is H, O, (C)₁-C₄) Alkyl, phenyl or benzyl; and a mono-edge fused bicyclic heterocyclic group having about eight to ten ring atoms containing one to four heteroatoms, each selected from the group consisting of: non-peroxide oxygen, sulfur and N (X).

It will be appreciated by those skilled in the art that the compounds of the invention having chiral centers may exist and be isolated in optically active and racemic forms. Some compounds may exhibit polymorphism. It is to be understood that the present invention encompasses any racemic, optically-active, polymorphic, or stereoisomeric form, or mixtures thereof, of a compound of the invention, which form possesses the useful properties described herein, it being well known in the art how to prepare optically-active forms (e.g., resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase).

When a bond in a formula of a compound herein is drawn in a non-stereochemical manner (e.g., flat), the atom to which the bond is attached includes all stereochemical possibilities. When a bond in a formula of a compound herein is drawn in a defined stereochemical manner (e.g., bold wedge, dashed line, or dashed wedge), it is understood that the atom to which the stereochemical bond is attached is enriched in the absolute stereoisomer depicted, unless otherwise indicated. In one embodiment, the compound may be at least 51% of the absolute stereoisomer depicted. In another embodiment, the compound may be at least 60% of the absolute stereoisomer depicted. In another embodiment, the compound may be at least 80% of the absolute stereoisomer depicted. In another embodiment, the compound may be at least 90% of the absolute stereoisomer depicted. In another embodiment, the compound may be at least 95% of the absolute stereoisomer depicted. In another embodiment, the compound may be at least 99% of the absolute stereoisomer depicted.

The specific values for the radicals, substituents, and ranges set forth below are for illustration only; they do not exclude other defined values or other values within the defined range of radicals and substituents.

In one embodiment the invention provides a process for preparing a compound of formula 8:

the method comprises reacting a compound of formula 7:

to the compound of formula 8. In one embodiment, the conversion may be carried out by hydrogenation. In one embodiment, the hydrogenation may be carried out in a polar solvent, such as a solvent comprising methanol, ethanol or ethyl acetate. In one embodiment, the hydrogenation may be carried out using a metal-containing catalyst, such as palladium on carbon. In one embodiment, the hydrogenation may be carried out in a non-polar solvent, such as a solvent comprising benzene, tetrahydrofuran or toluene. In one embodiment, the conversion may be carried out at a temperature in the range of from about-78 ℃ to about 65 ℃.

In one embodiment, the present invention provides a process for preparing TXA709 comprising reacting an amide of formula 9:

converted to TXA 709. In one embodiment, the conversion may be carried out in a polar solvent (such as a solvent comprising dichloromethane DCM, dimethylformamide DMF, or dichloroethane DCE). In one embodiment, the conversion is carried out at a temperature in the range of from about 0 ℃ to about 40 ℃. In one embodiment, the conversion is carried out in dichloromethane using an edc.hcl/DMAP system as the coupling agent at a temperature in the range of from about 35 ℃ to about 40 ℃.

In one embodiment, the present invention provides a process for preparing an amide of formula 9:

the method is carried out by reacting a compound of formula 3:

with a compound of formula 8:

in one embodiment, the reaction may be carried out at a temperature in the range of from about 0 ℃ to about 50 ℃. In one embodiment, the reaction may be in a polar solvent (such as, for example, comprising TH)F. Solvents of DMF, acetyl nitrile ACN, or dimethyl sulfoxide DMSO). In one embodiment, the reaction may be carried out in a suitable base, such as an amine base (e.g., a hindered amine base, such as N, N-diisopropyl-N-ethylamine), or an inorganic base (e.g., NaH, KH, NaOH, KOH, K)₂CO₃Or NaO^tBu)) in the presence of a catalyst. In one embodiment, the reaction may use K in acetonitrile₂CO₃As a base at a temperature in the range of from about 0 ℃ to about 30 ℃.

In one embodiment, the present invention provides a process for preparing a compound of formula 3:

the method is carried out by reacting a compound of formula 2:

with a compound of the formula:

to provide the compound of formula 3. In one embodiment, the reaction may be carried out at a temperature in the range of from about 50 ℃ to about 55 ℃. In one embodiment, the reaction may be carried out at a temperature in the range of from about 45 ℃ to about 60 ℃. In one embodiment, the reaction may be carried out in a polar solvent. In one embodiment, the reaction may be carried out in a solvent comprising ethyl acetate, a chlorinated hydrocarbon (e.g., dichloromethane), or an aromatic hydrocarbon (e.g., toluene).

In one embodiment, the present invention provides a process for preparing a compound of formula 2:

the process is carried out by reducing the corresponding nitro compound of formula 1:

in one embodiment, the reduction may be carried out at a temperature in the range of from about 65 ℃ to about 70 ℃. In one embodiment, the reduction may be carried out at a temperature in the range of from about 60 ℃ to about 80 ℃. In one embodiment, the reduction may be carried out in a polar solvent. In one embodiment, the reduction may be performed in a solvent comprising ethyl acetate. In one embodiment, the reduction may be carried out in the presence of a suitable reducing agent (e.g., iron/acetic acid, or zinc chloride/ammonium chloride).

In one embodiment, the present invention provides a process for preparing a compound of formula 1:

the method is carried out by reacting a compound of the formula:

with a compound of the formula:

in one embodiment, the reaction may be carried out at a temperature in the range of from about 50 ℃ to about 55 ℃. In one embodiment, the reaction may be carried out at a temperature in the range of from about 40 ℃ to about 60 ℃. In one embodiment, the reaction may be carried out in a protic solvent. In one embodiment, the reaction may be carried out in a solvent comprising methanol, isopropanol, or ethanol.

In one embodiment, the present invention provides a process for preparing a compound of formula 7

The method is carried out by reacting a compound of formula 6:

to the compound of formula 7. In one embodiment, the conversion may be carried out at a temperature in the range of from about 25 ℃ to about 30 ℃. In one embodiment, the conversion may be carried out at a temperature in the range of from about 20 ℃ to about 40 ℃. In one embodiment, the conversion may be carried out in a polar solvent. In one embodiment, the conversion may be carried out in a solvent comprising DMF or THF. In one embodiment, the conversion may be carried out in the presence of a suitable base (e.g., aqueous ammonia).

In one embodiment, the present invention provides a process for preparing a compound of formula 6:

the method is by carboxylating a compound of formula 5:

in one embodiment, carboxylation may be conducted at a temperature in the range of about-75 ℃ to about 0 ℃. In one embodiment, carboxylation may be conducted at a temperature in the range of about-80 ℃ to about 0 ℃. In one embodiment, the carboxylation may be carried out in a polar solvent. In one embodiment, carboxylation may be carried out in a solvent comprising an ether (e.g., THF, diethyl ether, or methyl tert-butyl ether MTBE). In one embodiment, carboxylation may be carried out in the presence of a suitable base (e.g., n-butyl lithium).

In one embodiment, the present invention provides a process for preparing a compound of formula 5:

the process is carried out by benzylating a phenol of formula 4:

in one embodiment, the benzylation reaction may be carried out at a temperature in the range of from about 55 ℃ to about 60 ℃. In one embodiment, the benzylation reaction may be carried out at a temperature in the range of from about 40 ℃ to about 65 ℃. In one embodiment, the benzylation reaction may be carried out in a polar solvent (e.g., a solvent comprising acetone or acetonitrile) or in a protic solvent (e.g., a solvent comprising methanol or ethanol). In one embodiment, the benzylation reaction may be carried out in the presence of a suitable base (e.g. potassium carbonate or sodium carbonate).

The invention will now be illustrated by the following non-limiting examples.