阅读说明：本技术 瑞卢戈利中间体及其制备方法 (Rugoside intermediate and preparation method thereof ) 是由 汪仙阳 赖中柳 刘广振 唐超 王婷婷 应述欢 于 2021-07-27 设计创作，主要内容包括：本发明公开了瑞卢戈利中间体及其制备方法。本发明提供了一种化合物D的制备方法,其包括以下步骤：以有机溶剂和/或水为溶剂,碱作用下,将化合物C进行水解反应,得到所述的化合物D。本发明的制备方法操作简单安全、后处理步骤简单、环境友好、总收率高、以本发明的中间体制得的瑞卢戈利产品纯度高、重金属元素含量低、达到原料药标准、生产成本低、适合于工业化生产。(The invention discloses a Ruugeli intermediate and a preparation method thereof. The invention provides a preparation method of a compound D, which comprises the following steps: and (2) taking an organic solvent and/or water as a solvent, and carrying out hydrolysis reaction on the compound C under the action of alkali to obtain the compound D. The preparation method provided by the invention is simple and safe to operate, simple in post-treatment steps, environment-friendly and high in total yield, and the Ruogeli product prepared from the intermediate provided by the invention is high in purity, low in heavy metal element content, low in production cost and suitable for industrial production, and reaches the standards of raw material medicines.)

1. A process for the preparation of compound D, characterized by comprising the steps of: taking an organic solvent and/or water as a solvent, and carrying out hydrolysis reaction on the compound C under the action of alkali to obtain a compound D;

2. a process for the preparation of compound D according to claim 1, characterized in that:

in the method for preparing the compound D, the organic solvent is an alcohol solvent;

and/or the presence of a gas in the gas,

in the method for preparing the compound D, the volume-to-mass ratio of the solvent to the compound C is 1 mL/g-30 mL/g;

and/or the presence of a gas in the gas,

in the method for preparing the compound D, the base is an inorganic base;

and/or the presence of a gas in the gas,

in the method for preparing the compound D, the molar ratio of the alkali to the compound C is 1.0-10.0;

and/or the presence of a gas in the gas,

in the method for preparing the compound D, the temperature of the hydrolysis reaction is 30-80 ℃;

and/or the presence of a gas in the gas,

in the method for preparing the compound D, the hydrolysis reaction time is 1-20 hours;

and/or the presence of a gas in the gas,

a process for the preparation of compound D, using the following work-up steps: and after the reaction is finished, removing the solvent, reducing the temperature, adjusting the pH value to 6-7, stirring, filtering, washing and drying to obtain the compound D.

3. A process for the preparation of compound D according to claim 2, characterized in that:

in the method for preparing the compound D, the alcohol solvent is preferably one or more of methanol, ethanol and isopropanol;

and/or the presence of a gas in the gas,

in the method for preparing the compound D, the volume-to-mass ratio of the solvent to the compound C is 2 mL/g-15 mL/g;

and/or the presence of a gas in the gas,

in the method for preparing the compound D, the inorganic base is sodium hydroxide and/or potassium hydroxide;

and/or the presence of a gas in the gas,

in the method for preparing the compound D, the molar ratio of the alkali to the compound C is 2.5-7.5;

and/or the presence of a gas in the gas,

in the method for preparing the compound D, the temperature of the hydrolysis reaction is 35-75 ℃;

and/or the presence of a gas in the gas,

in the method for preparing the compound D, the time of the hydrolysis reaction is 2 to 10 hours.

4. A process for the preparation of compound D according to claim 1, characterized in that: the preparation method of the compound D still further comprises the following steps: in an organic solvent, in the presence of a catalyst, carrying out a condensation reaction on the compound B and methoxyamine or methoxyamino phenyl formate to obtain a compound C;

5. a process for the preparation of compound D according to claim 4, characterized in that:

in the method for preparing the compound C, the organic solvent is a nitrile solvent;

and/or the presence of a gas in the gas,

in the method for preparing the compound C, the volume-mass ratio of the organic solvent to the compound B is 1 mL/g-10 mL/g;

and/or the presence of a gas in the gas,

in the method for preparing the compound C, the catalyst is 1,1' -carbonyl diimidazole or N, N-carbonyl diimidazole;

and/or the presence of a gas in the gas,

in the method for preparing the compound C, the molar ratio of the catalyst to the compound B is 1.0-3.0;

and/or the presence of a gas in the gas,

in the method for preparing the compound C, the base is an organic base;

and/or the presence of a gas in the gas,

in the method for preparing the compound C, the molar ratio of the alkali to the compound B is 0.1-2.0;

and/or the presence of a gas in the gas,

in the method for preparing the compound C, the molar ratio of the methoxyamine or the methoxy phenyl carbamate to the compound B is 1.0-5.0;

and/or the presence of a gas in the gas,

in the method for preparing the compound C, the condensation reaction temperature is 20-70 ℃;

and/or the presence of a gas in the gas,

in the method for preparing the compound C, the condensation reaction time is 1-10 hours;

and/or the presence of a gas in the gas,

the process for preparing compound C preferably employs the following reaction steps: adding methoxylamine hydrochloride into a mixture of an organic solvent, a catalyst and alkali, then adding a compound B, and carrying out condensation reaction to obtain the compound C.

6. A process for the preparation of compound D according to claim 5, characterized in that:

in the method for preparing the compound C, the nitrile solvent is acetonitrile;

and/or the presence of a gas in the gas,

in the method for preparing the compound C, the volume-mass ratio of the organic solvent to the compound B is 1 mL/g-5 mL/g;

and/or the presence of a gas in the gas,

in the method for preparing the compound C, the molar ratio of the catalyst to the compound B is 1.1-2.5;

and/or the presence of a gas in the gas,

in the method for preparing the compound C, the molar ratio of the methoxyamine or the methoxycarbamic acid phenyl ester to the compound B is 1.1-3.0;

and/or the presence of a gas in the gas,

in the method for preparing the compound C, the condensation reaction temperature is 25-60 ℃;

and/or the presence of a gas in the gas,

in the method for preparing the compound C, the condensation reaction time is 1.5 to 6.5 hours.

7. A process for the preparation of compound D according to claim 4, characterized in that: the preparation method of the compound D still further comprises the following steps: in an organic solvent, carrying out reduction reaction on the compound A and hydrogen under the catalysis of palladium carbon to obtain a compound B;

8. a process for the preparation of compound D according to claim 7, characterized in that:

in the method for preparing the compound B, the organic solvent is an alcohol solvent;

and/or the presence of a gas in the gas,

in the method for preparing the compound B, the volume-to-mass ratio of the organic solvent to the compound A is 1 mL/g-30 mL/g;

and/or the presence of a gas in the gas,

in the method for preparing the compound B, the mass ratio of the palladium-carbon to the compound A is 0.01-5.0;

and/or the presence of a gas in the gas,

in the method for preparing the compound B, the temperature of the reduction reaction is 0-50 ℃;

and/or the presence of a gas in the gas,

in the method for preparing the compound B, the time of the reduction reaction is 1 to 20 hours.

9. A process for the preparation of compound D according to claim 8, characterized in that:

in the method for preparing the compound B, the alcohol solvent is one or more of methanol, ethanol and isopropanol;

and/or the presence of a gas in the gas,

in the method for preparing the compound B, the volume-mass ratio of the organic solvent to the compound A is 2 mL/g-15 mL/g;

and/or the presence of a gas in the gas,

in the method for preparing the compound B, the mass ratio of the palladium-carbon to the compound A is 0.05-0.5;

and/or the presence of a gas in the gas,

in the method for preparing the compound B, the temperature of the reduction reaction is 10-40 ℃;

and/or the presence of a gas in the gas,

in the method for preparing the compound B, the time of the reduction reaction is 2 to 10 hours.

10. A process for the preparation of compound C, characterized by comprising the steps of: in an organic solvent, in the presence of a catalyst, carrying out a condensation reaction on the compound B and methoxyamine or methoxyamino phenyl formate to obtain a compound C;

wherein each reaction condition is as defined in any one of claims 4 to 9.

11. Compound B, compound C and compound D, the structures of which are shown below:

Technical Field

The invention relates to a Ruogeli intermediate and a preparation method thereof.

Background

Ruogeli (Relugolix), a small molecule gonadotropin releasing hormone (GnRH) receptor antagonist co-developed by Myovant and Wutian pharmaceuticals (Takeda). It is marketed in Japan in 2018, and can be used for treating hemorrhage and pain caused by hysteromyoma. Relugolix, when taken orally once a day, rapidly lowers estrogen and progestin levels in women. Wutian pharmacy compares the safety and effectiveness of Relugolix and leuprorelin in treating menorrhagia uterine fibrosis and the safety and effectiveness of the two drugs in treating pain symptoms associated with uterine fibrosis through a series of phase III clinical studies conducted in Japan, and finally confirms the safety and effectiveness of Relugolix for uterine fibroids. In addition, Wutian medicine was subjected to a phase II clinical study of relugolix endometriosis and prostate cancer, demonstrating that relugolix significantly reduces pain caused by endometriosis, as well as reduces serum testosterone to castration levels and significantly reduces Prostate Specific Antigen (PSA).

Ruogeli has CAS number 737789-87-6, and chemical name N- (4- (1- (2, 6-difluorobenzyl) -5- (dimethylamino) methyl) -3- (6-methoxy-3-pyridazinyl) -2, 4-dioxo-1, 2,3, 4-tetrahydrothieno [2,3-d ] pyrimidin-6-yl) phenyl) -N' -methoxyurea. There are many synthetic methods reported so far, for example, the synthetic route reported in patent CN104703992 is as follows:

the method adopts a mode of coupling first and then ring closing, has harsh reaction conditions, needs to react under the conditions of heating and pressurizing, and has higher requirements on equipment. Therefore, the preparation method of Ruugeli with low cost, high yield, mild reaction conditions, low equipment requirement and high product purity has great application value.

Disclosure of Invention

The invention aims to solve the technical problems that the preparation method of Rulugol in the prior art is harsh in reaction conditions, low in yield, low in purity of the prepared product, excessive in heavy metal elements, high in equipment requirement, not suitable for industrial production and the like, and provides a Rulugol intermediate completely different from the prior art and a preparation method thereof. The preparation method provided by the invention is simple and safe to operate, simple in post-treatment steps, environment-friendly and high in total yield, and the Ruogeli product prepared from the intermediate provided by the invention is high in purity, low in heavy metal element content, low in production cost and suitable for industrial production, and reaches the standards of raw material medicines.

The invention provides a compound B, a compound C, a compound D, a compound E, a compound F, a compound G, a compound H and a compound I, wherein the structures of the compounds are shown as follows:

wherein, X is chlorine, bromine or iodine.

The invention also provides a preparation method of the compound I, which comprises the following steps: performing nucleophilic substitution reaction on a compound H and dimethylamine in an organic solvent to obtain a compound I; wherein X is chlorine, bromine or iodine; r is an amino protecting group;

the process for preparing compound I may be a conventional process for such nucleophilic substitution reactions in the art, and the following reaction conditions are particularly preferred in the present invention:

the amino protecting group is preferably tert-butyloxycarbonyl (Boc).

In the method for preparing the compound I, the organic solvent is preferably a nitrile solvent, and the nitrile solvent is preferably acetonitrile.

In the method for preparing the compound I, the volume-to-mass ratio of the organic solvent to the compound H is preferably 1mL/g to 20mL/g, and more preferably 2mL/g to 10 mL/g.

In the method for preparing compound I, the molar ratio of dimethylamine to compound H is preferably 1.0 to 5.0, more preferably 1.1 to 3.0, such as 2.0. The dimethylamine can be used in the form of its hydrochloride salt. When the dimethylamine is used in the form of its hydrochloride, the reaction is carried out in the presence of a base, preferably an organic base, preferably triethylamine. The molar ratio of the base to the compound H is preferably 1 to 10, more preferably 2 to 8, for example 5.

In the process for producing compound I, the temperature of the nucleophilic substitution reaction is preferably 0 to 60 ℃, more preferably 5 to 60 ℃, for example, 15 to 25 ℃.

In the method for preparing the compound I, the time of the nucleophilic substitution reaction can be detected by a monitoring method (such as TLC, HPLC or NMR) which is conventional in the art, and is generally regarded as the end point of the reaction when the compound I disappears, and the time of the nucleophilic substitution reaction is preferably 0.5 hours to 10 hours, more preferably 1 hour to 5 hours, for example 1.5 hours.

The compound I prepared by the invention can be directly used for preparing Ruogeli without further purification.

In the invention, the preparation method of the compound I further comprises the following steps: in an organic solvent, in the presence of an initiator, carrying out nucleophilic substitution reaction on the compound G and a halogenated reagent to obtain a compound H; r is an amino protecting group;

the method for preparing the compound H may be a conventional method corresponding to such nucleophilic substitution methods in the art, and the following reaction conditions are particularly preferred in the present invention:

in the method for preparing the compound H, the organic solvent is preferably a nitrile solvent, and the nitrile solvent is preferably acetonitrile.

In the method for preparing the compound H, the volume-to-mass ratio of the organic solvent to the compound G is preferably 1mL/G to 20mL/G, more preferably 1mL/G to 10mL/G, for example 4 mL/G.

In the method for preparing the compound H, the initiator is preferably Azobisisobutyronitrile (AIBN).

In the method for preparing the compound H, the molar ratio of the initiator to the compound G is preferably 0.01 to 0.50, more preferably 0.05 to 0.20, for example 0.10.

In the method for preparing the compound H, the halogenating reagent can be N-chlorosuccinimide (NCS), N-bromosuccinimide (NBS) or N-iodosuccinimide (NIS).

In the method for preparing the compound H, the molar ratio of the halogenating agent to the compound G is preferably 1.0-3.0, more preferably 1.0-2.0, such as 1.5.

In the method for producing the compound H, the temperature of the nucleophilic substitution reaction is preferably from-5 ℃ to 20 ℃, more preferably from 0 ℃ to 10 ℃, for example, from 0 ℃ to 5 ℃.

In the method for preparing compound H, the time of the nucleophilic substitution reaction can be detected by a monitoring method (such as TLC, HPLC, or NMR) which is conventional in the art, and is generally the end point of the reaction when the compound G disappears, and the time of the nucleophilic substitution reaction is preferably 1 hour to 10 hours, more preferably 1 hour to 5 hours, for example 2 hours.

After the compound H is prepared, the compound H can be directly used for preparing the compound I without further purification.

In the invention, the preparation method of the compound I further comprises the following steps: in an organic solvent, in the presence of a catalyst, carrying out a condensation reaction on a compound F and an amino protection reagent to obtain a compound G; r is an amino protecting group;

the process for preparing compound G may be a conventional process for such condensation in the art, and the following reaction conditions are particularly preferred in the present invention:

in the method for preparing the compound G, the organic solvent is preferably a halogenated hydrocarbon solvent; the halogenated hydrocarbon solvent is preferably a chlorinated hydrocarbon solvent; the chlorinated hydrocarbon solvent is preferably Dichloromethane (DCM).

In the method for preparing the compound G, the volume-to-mass ratio of the organic solvent to the compound F is preferably 1mL/G to 20mL/G, more preferably 5mL/G to 15mL/G, for example 10 mL/G.

In the method for preparing the compound G, the amino protecting reagent can be di-tert-butyl dicarbonate (Boc)₂O)。

In the method for preparing the compound G, the molar ratio of the amino protecting agent to the compound F is preferably 1.0 to 5.0, more preferably 1.5 to 3.0, such as 2.0.

In the process for preparing compound G, the catalyst is preferably 4-Dimethylaminopyridine (DMAP).

In the method for preparing the compound G, the molar ratio of the catalyst to the compound F is preferably 0.01 to 0.50, more preferably 0.05 to 0.20, for example 0.10.

In the method for producing the compound G, the condensation reaction temperature is preferably 0 to 50 ℃, more preferably 10 to 40 ℃, for example, 20 to 30 ℃.

In the method for preparing the compound G, the time of the condensation reaction can be detected by a monitoring method (e.g., TLC, HPLC, or NMR) which is conventional in the art, and is generally the end point of the reaction when the compound F disappears, and the time of the condensation reaction is preferably 1 hour to 30 hours, more preferably 2 hours to 25 hours, for example 12 hours.

The process for preparing compound G is preferably carried out under a protective gas, preferably nitrogen and/or argon.

The process for preparing compound G preferably employs the following work-up steps: after the reaction is finished, quenching the reaction, stirring, extracting, washing, drying and pulping to obtain the purified compound G.

The quenching is preferably carried out with water. The washing is preferably performed by washing with saturated brine, and the number of washing is preferably 1 to 3. The solvent adopted by the pulping is preferably alkane solvent, and the alkane solvent is preferably n-heptane.

In the invention, the preparation method of the compound I further comprises the following steps: taking an organic solvent and/or water as a solvent, and carrying out cyclization reaction on the compound E in the presence of alkali to obtain a compound F;

the process for preparing compound F may be a conventional process for such cyclization in the art, and the following reaction conditions are particularly preferred in the present invention:

in the method for preparing the compound F, the organic solvent is preferably an alcohol solvent, and the alcohol solvent is preferably one or more of methanol, ethanol and isopropanol.

In the method for preparing the compound F, the volume-to-mass ratio of the organic solvent to the compound E is preferably 1mL/g to 10mL/g, more preferably 1.1mL/g to 3.5mL/g, for example, 2.5 mL/g.

In the method for preparing the compound F, the base is preferably an organic base, and the organic base is preferably sodium methoxide.

In the method for preparing the compound F, the molar ratio of the base to the compound E is preferably 1.0 to 5.0, more preferably 1.1 to 3.5, for example 2.0.

In the process for producing the compound F, the temperature of the cyclization reaction is preferably 40 to 80 ℃, more preferably 50 to 70 ℃, for example 55 to 65 ℃.

In the process for preparing compound F, the cyclization reaction time can be detected by a monitoring method (e.g., TLC, HPLC, or NMR) which is conventional in the art, and is generally the end point of the reaction when compound E disappears, and the cyclization reaction time is preferably 5 hours to 30 hours, more preferably 10 hours to 25 hours, e.g., 18 hours.

The process for preparing compound F, preferably with the following work-up steps: and after the reaction is finished, cooling, adjusting the pH value to 6-7, stirring, filtering and drying to obtain the compound F. The temperature is preferably reduced to 20-30 ℃. The pH is preferably adjusted by using an inorganic acid, the inorganic acid is preferably hydrochloric acid, and the concentration of the inorganic acid is preferably 1mol/L to 3mol/L, for example 1 mol/L. The drying is preferably drying, and the drying temperature is preferably 40-80 ℃, for example 60 ℃. The drying time is preferably 1 hour to 30 hours, for example 20 hours.

In the present invention, the preparation method of the compound I further comprises the following steps: under the action of a condensing agent, carrying out condensation reaction on the compound D and p-3-amino-6-methoxypyridazine or salts thereof to obtain a compound E;

the process for preparing compound E may be a conventional process for such condensation in the art, and the following reaction conditions are particularly preferred in the present invention:

the process for preparing compound E can be carried out in an organic solvent. When the process for preparing compound E is carried out in an organic solvent, the organic solvent is preferably an amide-based solvent, and the amide-based solvent is preferably N, N-dimethylformamide and/or N, N-dimethylacetamide.

In the method for preparing the compound E, the volume-to-mass ratio of the organic solvent to the compound D is preferably 1mL/g to 30mL/g, more preferably 2mL/g to 15mL/g, for example 5.5 mL/g.

In the method for preparing the compound E, the condensing agent is preferably propyl phosphonic anhydride (T3P) ethyl acetate.

In the method for preparing the compound E, the molar ratio of the condensing agent to the compound D is preferably 1.0 to 3.0, more preferably 1.1 to 2.0, for example, 1.2.

In the method for preparing the compound E, the base is preferably an organic base, and the organic base is preferably ethyldiisopropylamine.

In the method for preparing the compound E, the molar ratio of the base to the compound D is preferably 1.0 to 10.0, more preferably 1.5 to 5.5, for example 3.0.

In the process for producing the compound E, the molar ratio of the 3-amino-6-methoxypyridazine or the salt thereof to the compound D is preferably 1.0 to 10.0, more preferably 1.5 to 5.5, for example, 3.0.

In the method for producing the compound E, the condensation reaction temperature is preferably 50 to 100 ℃, more preferably 60 to 90 ℃, for example, 70 to 80 ℃.

In the method for preparing the compound E, the time of the condensation reaction can be detected by a monitoring method (such as TLC, HPLC or NMR) which is conventional in the art, and is generally the end point of the reaction when the compound D disappears, and the time of the condensation reaction is preferably 5 hours to 30 hours, more preferably 10 hours to 25 hours, for example 20 hours.

The process for preparing compound E preferably employs the following steps: and (2) adding alkali into a mixture of the compound D, the 3-amino-6-methoxypyridazine or the salt thereof and the organic solvent, heating, then dropwise adding a condensing agent, and carrying out condensation reaction to obtain the compound E. The dropping speed is based on the maintenance of the temperature of the system not to exceed 80 ℃. The temperature rise is preferably to 50 ℃ to 60 ℃ (the internal temperature of the reaction system).

The process for preparing compound E preferably employs the following work-up steps: after the reaction is finished, cooling, adjusting the pH value to 7.5-8.5, stirring, filtering, pulping, filtering, washing and drying to obtain the compound E. The temperature is preferably reduced to 20-30 ℃. The pH is preferably adjusted by using an inorganic base, the inorganic base is preferably sodium hydroxide and/or potassium hydroxide, and the concentration of the inorganic base is preferably 1mol/L to 15mol/L, such as 8 mol/L. The preferable pulping and washing adopts an alcohol solvent, and the alcohol solvent is preferably methanol and/or ethanol. The number of washing may be 1 to 3. The drying is preferably drying, and the drying temperature is preferably 30-60 ℃, for example, 55 ℃. The drying time is preferably 1 hour to 30 hours, for example 20 hours.

In the present invention, the preparation method of the compound I further comprises the following steps: taking an organic solvent and/or water as a solvent, and carrying out hydrolysis reaction on the compound C under the action of alkali to obtain a compound D;

the method for preparing the compound D may be a conventional method corresponding to such hydrolysis methods in the art, and the following reaction conditions are particularly preferred in the present invention:

in the method for preparing the compound D, the organic solvent is preferably an alcohol solvent, and the alcohol solvent is preferably one or more of methanol, ethanol and isopropanol.

In the method for preparing the compound D, the volume-to-mass ratio of the solvent to the compound C is preferably 1mL/g to 30mL/g, more preferably 2mL/g to 15mL/g, for example 10 mL/g.

In the method for preparing the compound D, the base is preferably an inorganic base, and the inorganic base is preferably sodium hydroxide and/or potassium hydroxide. The inorganic base may be used in the form of an aqueous solution thereof, and the concentration of the aqueous solution of the inorganic base is preferably 1 to 5mol/L, for example 2 mol/L.

In the method for preparing the compound D, the molar ratio of the base to the compound C is preferably 1.0 to 10.0, more preferably 2.5 to 7.5, for example 5.0.

In the method for producing compound D, the temperature of the hydrolysis reaction is preferably 30 to 80 ℃, more preferably 35 to 75 ℃, still more preferably 55 to 65 ℃, for example, 60 ℃.

In the method for preparing the compound D, the time of the hydrolysis reaction can be detected by a monitoring method (e.g., TLC, HPLC, or NMR) which is conventional in the art, and is generally the end point of the reaction when the compound C disappears, and the time of the hydrolysis reaction is preferably 1 hour to 20 hours, more preferably 2 hours to 10 hours, for example 6 hours to 7 hours.

The process for the preparation of compound D preferably employs the following work-up steps: and after the reaction is finished, removing the solvent, reducing the temperature, adjusting the pH value to 6-7, stirring, filtering, washing and drying to obtain the compound D. The temperature is preferably reduced to 15-25 ℃. The pH is preferably adjusted by using an inorganic acid, the inorganic acid is preferably hydrochloric acid, and the concentration of the hydrochloric acid is preferably 1mol/L to 3mol/L, for example 1 mol/L. The washing is preferably carried out with water. The number of washing may be 1 to 3. The drying is preferably drying, and the drying temperature is preferably 30-60 ℃, for example 50 ℃. The drying time is preferably 1 hour to 5 hours, for example 2 hours.

In the present invention, the preparation method of the compound I further comprises the following steps: in an organic solvent, in the presence of a catalyst, carrying out a condensation reaction on the compound B and methoxyamine or methoxyamino phenyl formate to obtain a compound C;

the process for preparing compound C may employ methods conventional in the art for such condensation reactions, and the following reaction conditions are particularly preferred in the present invention:

in the method for preparing the compound C, the organic solvent is preferably a nitrile solvent, and the nitrile solvent is preferably acetonitrile.

In the method for preparing the compound C, the volume-to-mass ratio of the organic solvent to the compound B is preferably 1mL/g to 10mL/g, more preferably 1mL/g to 5mL/g, for example 3 mL/g.

In the process for preparing compound C, the catalyst is preferably 1,1' -carbonyldiimidazole or N, N-Carbonyldiimidazole (CDI).

In the method for preparing the compound C, the molar ratio of the catalyst to the compound B is preferably 1.0 to 3.0, more preferably 1.1 to 2.5, for example 1.7.

In the method for preparing the compound C, the molar ratio of the methoxyamine or the phenyl methoxycarbamate to the compound B is preferably 1.0 to 5.0, more preferably 1.1 to 3.0, for example 1.9. The methoxyamine may be used in the form of its hydrochloride. When the methoxyamine is used in the form of its hydrochloride, the reaction is carried out in the presence of a base, preferably an organic base, preferably triethylamine. The molar ratio of the base to the compound B is preferably 0.1 to 2.0, more preferably 0.5 to 1.5, for example, 0.85.

In the method for producing the compound C, the condensation reaction temperature is preferably 20 to 70 ℃, more preferably 25 to 60 ℃, for example, 45 to 55 ℃.

In the method for preparing the compound C, the time of the condensation reaction can be detected by a monitoring method (e.g., TLC, HPLC, or NMR) which is conventional in the art, and is generally the end point of the reaction when the compound B disappears, and the time of the condensation reaction is preferably 1 hour to 10 hours, more preferably 1.5 hours to 6.5 hours, for example 2 hours to 3 hours.

The process for preparing compound C preferably employs the following reaction steps: adding methoxylamine hydrochloride or methoxylamine formate into a mixture of an organic solvent, a catalyst and alkali, then adding a compound B, and carrying out condensation reaction to obtain the compound C. The addition mode is preferably dropwise, and the dropwise adding speed is based on the condition that the temperature of the reaction system is not more than 30 ℃.

In the present invention, the preparation method of the compound I further comprises the following steps: in an organic solvent, carrying out reduction reaction on the compound A and hydrogen under the catalysis of palladium carbon (Pd/C) to obtain a compound B;

the process for preparing compound B may be a conventional process for such reduction in the art, and the following reaction conditions are particularly preferred in the present invention:

in the method for preparing the compound B, the organic solvent is preferably an alcohol solvent, and the alcohol solvent is preferably one or more of methanol, ethanol and isopropanol.

In the method for preparing the compound B, the volume-to-mass ratio of the organic solvent to the compound A is preferably 1mL/g to 30mL/g, more preferably 2mL/g to 15mL/g, for example 8 mL/g.

In the method for preparing the compound B, the mass ratio of the palladium on carbon to the compound a is preferably 0.01 to 5.0, more preferably 0.05 to 0.5, for example, 0.1.

In the method for producing the compound B, the temperature of the reduction reaction is preferably 0 to 50 ℃, more preferably 10 to 40 ℃, for example, 20 to 30 ℃.

In the method for preparing the compound B, the time of the reduction reaction can be detected by a monitoring method (e.g., TLC, HPLC, or NMR) which is conventional in the art, and is generally the end point of the reaction when the compound a disappears, and the time of the reduction reaction is preferably 1 hour to 20 hours, more preferably 2 hours to 10 hours, for example 4 hours to 6 hours.

In the present invention, the following synthetic route is preferably adopted for the preparation method of the compound I:

the invention also provides a preparation method of the compound H, which comprises the following steps: in an organic solvent, in the presence of an initiator, carrying out nucleophilic substitution reaction on the compound G and a halogenated reagent to obtain a compound H; r is an amino protecting group;

the reaction conditions and procedures were as described above.

The preparation method of the compound H in the invention preferably adopts the following synthetic route:

the invention also provides a preparation method of the Ruogeli intermediate G, which comprises the following steps: in an organic solvent, in the presence of a catalyst, carrying out a condensation reaction on a compound F and an amino protection reagent to obtain a compound G; r is an amino protecting group;

the reaction conditions and procedures were as described above.

The preparation method of the Ruugeli intermediate G preferably adopts the following route:

the invention also provides a preparation method of the Ruogeli intermediate F, which comprises the following steps: taking an organic solvent and/or water as a solvent, and carrying out cyclization reaction on the compound E in the presence of alkali to obtain a compound F;

the reaction conditions and procedures were as described above.

The preparation method of the Ruugeli intermediate F preferably adopts the following route:

the invention also provides a preparation method of the Ruugeli intermediate E, which comprises the following steps: under the action of a condensing agent, carrying out condensation reaction on the compound D and p-3-amino-6-methoxypyridazine or salts thereof to obtain a compound E;

the reaction conditions and procedures were as described above.

The preparation method of the Ruugeli intermediate E preferably adopts the following route:

the invention also provides a preparation method of the Ruugeli intermediate D, which comprises the following steps: taking an organic solvent and/or water as a solvent, and carrying out hydrolysis reaction on the compound C under the action of alkali to obtain a compound D;

the reaction conditions and procedures were as described above.

The preparation method of the Ruugeli intermediate D preferably adopts the following route:

the invention also provides a preparation method of the Ruogeli intermediate C, which comprises the following steps: in an organic solvent, in the presence of a catalyst, carrying out a condensation reaction on the compound B and methoxyamine or methoxyamino phenyl formate to obtain a compound C;

the reaction conditions and procedures were as described above.

The preparation method of the Ruugeli intermediate C preferably adopts the following route:

the invention also provides a preparation method of Ruogeli, which comprises the following steps: after the compound I is prepared according to the preparation method, carrying out a reaction of removing an amino protecting group on the compound I to obtain Ruugeli;

the method for preparing Ruugeli can be a conventional method for removing amino protecting group in the field, and the following reaction conditions are particularly preferred in the invention:

the process for preparing relogelide can be carried out in an organic solvent, preferably an ester solvent, preferably ethyl acetate, or under solvent-free conditions. The volume-mass ratio of the organic solvent to the compound I is preferably 1 mL/g-20 mL/g.

The process for preparing relogelide may be carried out in the presence of an acid, preferably hydrochloric acid; the hydrochloric acid can be a conventional and commercially available hydrochloric acid reagent; the concentration of the hydrochloric acid may be 1mol/L to 12mol/L, for example 6 mol/L. The molar ratio of the acid to the compound I is preferably 1-10, and more preferably 2-5.

In the method for producing Ruogeli, the reaction temperature for removing the amino protecting group is preferably 0 to 40 ℃, more preferably 5 to 35 ℃, for example 10 to 20 ℃.

In the method for preparing relogelide, the reaction time for removing the amino protecting group can be detected by a monitoring method (such as TLC, HPLC or NMR) which is conventional in the art, and is generally the end point of the reaction when the compound I disappears, and the time for the nucleophilic substitution reaction is preferably 1 hour to 20 hours, more preferably 2 hours to 15 hours, such as 2 hours to 10 hours.

The process for preparing Ruogeli may employ the following post-treatment steps: and after the reaction is finished, adjusting the pH value to 7-8, filtering, washing and drying to obtain the Ruogeli. The pH is preferably adjusted by using an inorganic base, and the inorganic base can be sodium bicarbonate. The washing is preferably carried out using an alcohol solvent and/or water. The alcohol solvent is preferably ethanol. The drying is preferably carried out under reduced pressure. The drying temperature is preferably 45-55 ℃. The drying pressure is preferably-0.085 MPa to 0.1 MPa.

In the invention, the preparation method of Ruugeli preferably adopts the following preparation route:

the above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.

The reagents and starting materials used in the present invention are commercially available.

In the invention, the room temperature refers to the ambient temperature and is 10-35 ℃.

The positive progress effects of the invention are as follows: the preparation method provided by the invention is simple and safe to operate, simple in post-treatment steps, environment-friendly and high in total yield, and the Ruugeli product prepared from the intermediate provided by the invention is high in purity, low in production cost and suitable for industrial production, and heavy metal residues reach the standard of raw material medicines.

The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.

Detailed Description

EXAMPLE 1 Synthesis of Compound B

Compound A (80.0g) was added to methanol (640mL) under a nitrogen atmosphere, 10% Pd-C (8.0g, the percentages refer to the mass of palladium as a percentage of the total mass of palladium on carbon) was added thereto, and the mixture was stirred under a hydrogen balloon pressure at 25. + -. 5 ℃ for 4-6 hours. The activated carbon and catalyst were filtered and washed with methanol (160 mL). Concentration at 45 + -5 deg.C under reduced pressure until the weight was constant gave compound B as a yellow-brown oil in 99.0% yield and 98.0% HPLC purity.

EXAMPLE 2 Synthesis of Compound C

Acetonitrile (30mL) and 1,1' -carbonyldiimidazole or (CDI, 5.01g, 1.7eq) were added to the reactor, and the mixture was stirred. Triethylamine (1.56g, 0.85eq) was added with stirring and cooled to an internal temperature of 10 ± 5 ℃. Methoxyamine hydrochloride (2.90g, 1.91eq) was added thereto portion by portion under stirring at an internal temperature of 30 ℃ or lower, and the container used for the reagents was washed with acetonitrile (5 mL). After stirring the mixture at an internal temperature of 25 ± 5 ℃ and confirming that the mixture is dissolved, the solution is stirred for another 10 minutes or more. Then, compound B (10.00g) was added thereto with stirring, and the container used for the reagent was washed with acetonitrile (5 mL). The reaction mixture was warmed to an internal temperature of 50 + -5 deg.C and stirred at the same temperature for 2-3 hours, cooled to an internal temperature of 25 + -5 deg.C, dichloromethane (DCM, 100ml) and water (40ml) were added, stirred for 30min, the liquid was separated, and the organic phase was washed once with saturated sodium chloride solution (40 ml). The organic phase was concentrated at 50 ℃ to give a pale yellow solid in 92.0% yield and 97.0% HPLC purity.

EXAMPLE 3 Synthesis of Compound D

Compound C (10.0g) was dissolved in ethanol (100mL), 2N NaOH (45.7mL, 5.0eq) was added thereto, and the mixture was stirred at 60 ℃ for about 6 hours at ambient temperature. The reaction was concentrated to remove ethanol, cooled to 20. + -. 5 ℃ and the pH was slowly adjusted to about neutral with 1N HCl (5.0 eq). And stirred at room temperature for more than 2 hours, filtered to give a yellow solid, which was rinsed with water (20 ml). After drying the material in a wet product air-blast oven at 50 ℃ for 2 hours, the temperature is raised to 60 ℃ and the material is dried overnight, and 7.7g of off-white solid which is the compound D is obtained with the yield of 81 percent.

EXAMPLE 4 Synthesis of Compound E

Compound D (10g) and 3-amino-6-methoxypyridazine (3.0eq) were added to N, N' -dimethylacetamide (DMAc, 55ml, 5.5v), followed by addition of ethyldiisopropylamine (3.0eq) thereto at 25. + -. 15 ℃. The mixture was warmed to an internal temperature of 55 ± 5 ℃ and stirred for 30 minutes. At an internal temperature of 60 ℃ or less, a 50.5% ethyl acetate solution (9.55g, 15.01mmol, 1.2eq) of propylphosphonic anhydride (T3P) was added dropwise thereto, and the mixture was stirred at an internal temperature of 75. + -. 5 ℃ for 20 hours. After cooling to 25. + -. 5 ℃ an 8N aqueous sodium hydroxide solution was added thereto with vigorous stirring, the pH of the mixture was adjusted to 7.5-8.5, and the mixture was stirred at 25. + -. 5 ℃ for 1 hour. Filtration, slurrying of the filter cake with methanol (25mL) for 2 hours, filtration, rinsing with methanol (10mL), and oven 55 ℃ for 20 hours gave a brown solid in 92.6% yield with an HPLC purity of 98.0%.

EXAMPLE 5 Synthesis of Compound F

Compound E (10g) was added to methanol (25mL) and sodium methoxide (2.0eq) and stirred at 60. + -. 5 ℃ for 18 h. The mixture was cooled to 25. + -. 5 ℃ and 1N dilute hydrochloric acid (2.0eq) was added dropwise thereto to adjust the pH6-7 and the mixture was stirred for 2 hours. Filtering, and drying in an oven for 20 hours at 60 ℃ to obtain yellow solid with the yield of 90.0 percent and the HPLC purity of 97.0 percent.

EXAMPLE 6 Synthesis of Compound G (R is Boc)

Compound F (10g) was added to DCM (100ml), DMAP (0.1eq) was added, stirring was carried out at 25. + -. 5 ℃ for 5min, and Boc was added₂O (2.0eq) was added dropwise to the reaction mixture, and the mixture was stirred overnight (about 12 hours) at 25. + -. 5 ℃ under nitrogen. Water (30ml) was added thereto, and after stirring at room temperature for 0.5 hour, the mixture was separated, and the organic phase was washed once with a saturated NaCl solution (30 ml). The organic phase is concentrated to dryness and slurried in n-heptane to give 11.1g of a bright yellow solid. (yield 94.8%, HPLC purity 95.0%).

EXAMPLE 7 Synthesis of Compound H (X is bromo and R is Boc)

The compound G (10G) was added to acetonitrile (40ml), the temperature was reduced to 0-5 ℃ after clearing, AIBN (240mg,0.1eq) and NBS (3.92G,1.5eq) were added to the reaction solution, and under nitrogen protection, stirring was carried out at 0-5 ℃ for 2 hours to obtain compound H (HPLC purity 94.0%, yield 97.8%), which was used directly in the next reaction.

EXAMPLE 8 Synthesis of Compound I (X is bromo and R is Boc)

Dimethylamine hydrochloride (2.4g,2eq) was suspended in acetonitrile (50ml), triethylamine (7.42g,5eq) was added thereto, and the mixture was stirred at 25 ± 5 ℃ for 30 minutes. The mixture was cooled to 5. + -. 5 ℃ and the reaction mixture of compound H was added and stirred at 15-25 ℃ for 1.5H and used directly in the next step. (HPLC purity: about 92.0%, yield 98.5%)

Example 9 Synthesis of Rulugol (R is Boc)

150ml of 6N HCl ethyl acetate solution was added to the reaction solution of the previous step. The reaction mixture was stirred at 15. + -. 5 ℃ for 2-10 hours. After the reaction is finished, the solvent is decompressed, concentrated and dried, sodium bicarbonate aqueous solution is added to adjust the pH value to 7-8, solid is separated out, the solid is filtered, a filter cake is washed by ethanol/tap water and decompressed and dried at 50 +/-5 ℃ (0.085 MPa-0.1 MPa), and off-white solid Ruugeli 7.6g is obtained (the yield is 85%, and the HPLC purity is 95.6%).