阅读说明：本技术 一种GnRH受体拮抗剂关键中间体及其制备方法 (GnRH receptor antagonist key intermediate and preparation method thereof ) 是由 于立国 朱怡君 钱凯 张锡予 孙光祥 王兵 于 2020-07-10 设计创作，主要内容包括：本发明医药技术领域,具体涉及一种GnRH受体拮抗剂关键中间体及其制备方法,包括以下步骤：化合物2与手性助剂(<I>S</I>)-叔丁基亚磺酰胺在缩合剂的作用下进行缩合反应生成亚胺化合物3；在还原剂作用下,步骤(1)中所得亚胺化合物3还原得到化合物4；化合物4经酸水解得到化合物1的盐,经碱处理得到化合物1。通过引入手性助剂诱导手性,克服了已有的手性源方法,该法操作简单,条件温和,收率良好,化学纯度和光学纯度均较高,适合于工业化生产。(The invention belongs to the technical field of medicines, and particularly relates to a GnRH receptor antagonist key intermediate and a preparation method thereof, which comprise the following steps: compound 2 and chiral auxiliary: ( S ) -tert-butyl sulfenamide is subjected to condensation reaction under the action of a condensing agent to generate an imine compound 3; reducing the imine compound 3 obtained in the step (1) under the action of a reducing agent to obtain a compound 4; hydrolyzing the compound 4 with acid to obtain a salt of the compound 1, and treating with alkali to obtain the compound 1. The method overcomes the defects of the existing chiral source method by introducing the chiral auxiliary agent to induce chirality, has simple operation, mild conditions, good yield and higher chemical purity and optical purity, and is suitable for industrial production.)

1. A process for the preparation of a key intermediate of a GnRH receptor antagonist, characterized in that it comprises the steps of:

(1) carrying out condensation reaction on the compound 2 and chiral auxiliary agent (S) -tert-butyl sulfenamide under the action of a condensing agent to generate an imine compound 3;

(2) reducing the imine compound 3 obtained in the step (1) under the action of a reducing agent to obtain a compound 4;

(3) hydrolyzing the compound 4 with acid to obtain a salt of the compound 1, and treating with alkali to obtain the compound 1; the reaction formula is shown as follows:

2. a method of preparing a GnRH receptor antagonist key intermediate as claimed in claim 1, wherein preferably, the condensing agent used in step (1) is selected from tetraethyl titanate and/or tetraisopropyl titanate.

3. The method for preparing a key intermediate of a GnRH receptor antagonist according to claim 1, wherein the molar ratio of compound 2 to (S) -tert-butylsulfinamide, condensing agent in step (1) is 1: 1-2: 1 to 3.

4. A process for the preparation of a key intermediate for a GnRH receptor antagonist according to claim 3, further characterized in that in step (1) the molar ratio of compound 2 to (S) -tert-butylsulfinamide, condensing agent is 1: 1-1.5: 1.1 to 3.

5. A process for the preparation of a key intermediate for a GnRH receptor antagonist according to claim 1, wherein the solvent used in step (1) comprises tetrahydrofuran, 2-methyltetrahydrofuran or toluene.

6. A process for the preparation of a GnRH receptor antagonist key intermediate as claimed in claim 1, wherein the reducing agent used in step (2) is sodium borohydride, potassium borohydride, lithium borohydride or diisobutylaluminum hydride.

7. The method for producing a key intermediate for a GnRH receptor antagonist according to claim 1, wherein the molar ratio of the imine compound 3 to the reducing agent in the step (2) is 1: 0.5 to 3.

8. A process for the preparation of a key intermediate for a GnRH receptor antagonist according to claim 1, wherein the acid used for the hydrolysis in the step (3) is selected from the group consisting of hydrochloric acid or trifluoroacetic acid; the molar ratio of compound 4 to acid was 1: 1 to 10.

9. A compound of formula 3:

10. a compound of formula 4:

Technical Field

The invention relates to the technical field of medicines, in particular to a GnRH receptor antagonist key intermediate and a preparation method thereof.

Background

Loragol (elagolix), a new drug for the treatment of endometriosis developed jointly by albivir (Abbive) and Neurocrine BioScienceS, was approved by the FDA in 23 japanese america in 7-month-2018. The product is a gonadotropin releasing hormone (GnRH) receptor antagonist, inhibits endogenous GnRH signaling by competitively binding with GnRH receptor in pituitary gland, and finally reduces the concentration of ovarian hormone, estradiol and progesterone in blood. The structural formula is as follows:

as shown in the following formula: compound 1 is a key intermediate of oxalagogrel

The synthesis of compound 1, which has been reported so far, is mainly a method of chiral source:

guo Zhijiajiang et al in WO2005007165A use 2-fluoro-6-trifluoromethyl benzonitrile as raw material, reduce cyano group with borane, then condense with urea under the action of hydrochloric acid to obtain 1- (2-fluoro-6-trifluoromethyl phenethyl) urea intermediate, then perform cyclization reaction with diketene to obtain intermediate 1- [ 2-fluoro-6- (trifluoromethyl) benzyl ] -6-methylpyrimidine-2, 4(1H,3H) -diketone, perform bromination, alkylation reaction of amine, then perform Suzuki coupling reaction with 2-fluoro-3-methoxy phenylboronic acid, and remove Boc protecting group to obtain target product.

The method 2 comprises the following steps: shivaji et al in WO2018198086 use 1- (2-fluoro-6-trifluoromethyl phenethyl) urea intermediate as raw material, undergo cyclization reaction with dimeric ketene to obtain intermediate 1- [ 2-fluoro-6- (trifluoromethyl) benzyl ] -6-methylpyrimidine-2, 4(1H,3H) -diketone, undergo bromination, undergo Suzuki coupling with 2-fluoro-3-methoxyphenylboronic acid, undergo nucleophilic substitution with chiral amine sulfonate, and undergo deprotection to obtain the product.

In both methods, L- (-) -phenylalaninol is used as a chiral source to carry out protection and derivatization, and then coupling is carried out by different methods, and finally deprotection is carried out to obtain the final product. However, the above methods all have significant disadvantages: the price of the raw material L- (-) -phenylalaninol is high, and the reaction reagent is special; the reaction steps are multiple, the reaction conditions are harsh, the MitSunobu reaction causes great pollution of three wastes, and the method is not favorable for industrial production.

Therefore, finding a method which has mild conditions, simple operation, low cost, high product yield, high chemical purity and optical purity, can be successfully used for synthesis of the loragoid and is suitable for industrial production is a technical problem which needs to be solved in the field at present.

Disclosure of Invention

The technical problem to be solved by the invention is as follows: provides a preparation method of a GnRH receptor antagonist key intermediate with mild condition, simple operation, low cost and higher product yield.

The technical scheme for solving the technical problems is as follows:

a process for the preparation of a key intermediate of a GnRH receptor antagonist, characterized in that it comprises the steps of:

(1) carrying out condensation reaction on the compound 2 and chiral auxiliary agent (S) -tert-butyl sulfenamide under the action of a condensing agent to generate an imine compound 3;

(2) reducing the imine compound 3 obtained in the step (1) under the action of a reducing agent to obtain a compound 4;

(3) hydrolyzing the compound 4 with acid to obtain a salt of the compound 1, and treating with alkali to obtain the compound 1; the reaction formula is shown as follows:

preferably, the condensing agent used in step (1) is selected from tetraethyl titanate and/or tetraisopropyl titanate.

Preferably, the molar ratio of the compound 2 to the (S) -tert-butyl sulfinamide and the condensing agent in the step (1) is 1: 1-2: 1-3; further, the molar ratio of the compound 2 to the (S) -tert-butyl sulfinamide and the condensing agent in the step (1) is 1: 1-1.5: 1.1-3; further, the molar ratio of the compound 2 to the (S) -tert-butyl sulfinamide and the condensing agent in the step (1) is 1: 1.1-1.2: 1.5 to 3.

Preferably, the solvent used in step (1) includes tetrahydrofuran, 2-methyltetrahydrofuran or toluene.

Preferably, the reducing agent used in step (2) is sodium borohydride, potassium borohydride, lithium borohydride or diisobutylaluminum hydride.

Preferably, the solvent used in step (2) includes tetrahydrofuran, 2-methyltetrahydrofuran or toluene.

Preferably, the molar ratio of the imine compound 3 to the reducing agent in the step (2) is 1: 0.5 to 3; further, the molar ratio of the imine compound 3 to the reducing agent in the step (2) is 1: 1 to 2.

Preferably, the acid used for hydrolysis in step (3) is selected from hydrochloric acid or trifluoroacetic acid.

Preferably, the molar ratio of compound 4 to acid in step (3) is 1: 1-10; further, the molar ratio of the compound 4 to the acid in the step (3) is 1: 2 to 3.

Preferably, the solvent used in step (3) is an alcohol; the solvent used in the further step (3) is selected from methanol, ethanol, isopropanol or n-propanol.

Preferably, the base used in step (3) is selected from sodium carbonate, potassium bicarbonate or sodium bicarbonate; in a preferred embodiment of the invention, a saturated aqueous solution of the above-mentioned base is used.

Preferably, the temperature of the hydrolysis reaction in the step (3) is 5-35 ℃.

The reagents and starting materials used in the present invention are commercially available unless otherwise specified. The Chinese naming of the compound of the invention conflicts with the structural formula, and the structural formula is taken as the standard; except for obvious errors in the formula.

The positive progress effects of the invention provided by the invention are as follows: the method overcomes the defects of the existing chiral source method by introducing the chiral auxiliary agent to induce chirality, has simple operation, mild conditions, good yield and higher chemical purity and optical purity, and is suitable for industrial production.

In a second aspect, the present invention provides a key intermediate compound of a GnRH receptor antagonist, having a structural formula as shown in formula 3:

in a third aspect, the present invention provides another key intermediate compound of a GnRH receptor antagonist, which has a structural formula shown in formula 4:

drawings

FIG. 1 is a mass spectrum of Compound 3 of example 1;

FIG. 2 is a mass spectrum of Compound 4 of example 2;

FIG. 3 is a hydrogen spectrum of Compound 4 of example 2;

FIG. 4 is a hydrogen spectrum of Compound 1 of example 2.

Detailed Description

The invention is illustrated but not limited by the following examples. The technical solutions protected by the present invention are all the simple replacements or modifications made by the skilled person in the art.