阅读说明：本技术 一种盐酸氨柔比星中间体化合物i-4 (Aminorubicin hydrochloride intermediate compound I-4 ) 是由 张贵民 袁立华 徐冰 于 2019-03-04 设计创作，主要内容包括：本发明属于医药技术领域,具体涉及一种盐酸氨柔比星中间体化合物及其制备方法。本发明提供新的中间体及利用该中间体合成盐酸氨柔比星重要中间体,解决了现有技术中氨柔比星中间体需手性拆分造成的收率低的问题,本发明通过手性合成的新中间体化合物,产品收率高,操作简单,生产成本显著降低,适合工业化生产。(The invention belongs to the technical field of medicines, and particularly relates to an amrubicin hydrochloride intermediate compound and a preparation method thereof. The invention provides a new intermediate and an important intermediate for synthesizing amrubicin hydrochloride by using the intermediate, solves the problem of low yield caused by the chiral resolution of the amrubicin intermediate in the prior art, and the new intermediate compound synthesized by chirality has the advantages of high product yield, simple operation, obviously reduced production cost and suitability for industrial production.)

1. An amrubicin hydrochloride intermediate compound is shown as a formula I-4, and has the following structural formula:

2. a process for the chiral preparation of compound I-4 according to claim 1, comprising the steps of:

adding the compound I-3 and acid into a reaction solvent, and controlling the temperature until the hydrolysis reaction is finished to obtain a compound I-4; the reaction route is as follows:

3. the chiral preparation method of claim 2, wherein the acid is one or a combination of hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, formic acid, acetic acid and trifluoroacetic acid; the reaction solvent is one or the combination of methanol, ethanol, isopropanol, n-butanol, tetrahydrofuran, 1, 4-dioxane and diethyl ether.

4. The chiral preparation method according to claim 2, wherein the compound I-3 is prepared by: under the protection of inert gas, adding the compound I-2 and TMSCN into a dry solvent at room temperature, adding a catalyst at controlled temperature, and reacting to obtain a compound I-3 after the addition is finished; the reaction route is as follows:

5. the chiral preparation method of claim 4, wherein the reaction solvent is one or a combination of tetrahydrofuran, 1, 4-dioxane, dichloromethane, chloroform and toluene.

6. The chiral preparation method of claim 4, wherein the catalyst is one of tetraethyl titanate, tetraisopropyl titanate, tetrabutyl titanate, titanium tetrachloride, stannic chloride, ferric chloride and zinc chloride.

7. The chiral preparation method according to claim 4, wherein the compound I-2 is prepared by the following method: under the protection of inert gas, adding a compound I-1, (R) -tert-butyl sulfenamide and titanate into a dry solvent at room temperature, and controlling the temperature until the reaction is finished to obtain a compound I-2; the reaction route is as follows:

8. the chiral preparation method of claim 7, wherein the titanate is one of tetraethyl titanate, tetraisopropyl titanate, or tetrabutyl titanate; the reaction solvent is one or the combination of tetrahydrofuran, 1, 4-dioxane, dichloromethane, chloroform and toluene.

9. The use of compound I-4 according to claim 1 for the preparation of amrubicin.

10. The use of compound I-4 according to claim 1 for the preparation of (R) - (-) -2-amino-5, 8-dimethoxy-1, 2,3, 4-tetrahydro-2-naphthoic acid methyl ester, an important intermediate of amrubicin, represented by formula Z-3, the synthetic route of which is as follows:

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to an amrubicin hydrochloride intermediate compound and a preparation method thereof.

Background

Amrubicin hydrochloride (amrubicin hydrochloride), chemical name (+) - (7S,9S) -9-acetyl-9-amino-7- [ (2-deoxy- β -D-erythro-pentopyranosyl) oxy ] -7,8,9, 10-tetrahydro-6, 11-dihydroxy-5, 12-tetracene dione hydrochloride, having the following chemical structure:

amrubicin hydrochloride is a chemically fully synthesized novel anthracycline antitumor drug characterized by 9-amino group and sugar structure developed by Sumiotmo pharmaceutical corporation of Japan, registered and marketed in Japan in 2002 (trade name: Calsed). The traditional Chinese medicine composition is clinically used for treating non-small cell lung cancer (NSCLC) and Small Cell Lung Cancer (SCLC). As an anthracycline drug, the action mechanism of the anthracycline drug is slightly different from that of adriamycin, and amrubicin and its metabolite amrubicin alcohol (amrubicinol) mainly inhibit the activity of topoisomerase II (topoisomerase II, Topo II), and finally lead to the breakage of DNA to inhibit the proliferation of tumor cells. Amrubicin has little if any cardiotoxicity problems common with anthracycline drugs. In recent years, amrubicin has achieved better efficacy in SCLC second-line therapy, but its role in first-line chemotherapy is unclear and myelosuppression is evident.

The current synthetic method of amrubicin hydrochloride is mainly reported by the original patent US4673668 and the document j.org.chem.,1987,52,4477-4485 (the synthetic route is shown below). The method takes 5, 8-dimethoxy-2-tetralone (1) as a starting material, reacts with potassium cyanide/ammonia carbonate through Bucherer-Bergers, is hydrolyzed under the alkaline condition of barium hydroxide to generate 2-amino-5, 8-dimethoxy-1, 2,3, 4-tetrahydro-2-naphthoic acid (2), 2 and methanol are resolved by D- (-) -mandelic acid under the action of hydrogen chloride to obtain (R) - (-) -2-amino-5, 8-dimethoxy-1, 2,3, 4-tetrahydro-2-naphthoic acid methyl ester (Z-3), Z-3 is condensed with dimethyl sulfoxide under the action of sodium hydride to obtain 4, and NaOH 5 is reduced by Zn/3, 5, acylating with acetic anhydride to obtain (R) - (-) -2-acetyl-2-acetamido-5, 8-dimethoxy-1, 2,3, 4-tetrahydronaphthalene (6). 6 and phthalic anhydride are subjected to Friedel-Crafts acylation reaction to obtain (R) - (-) -9-acetyl-9-acetamido-6, 11-dihydroxy-7, 8,9, 10-tetrahydro-5, 12-naphtho naphthalene diketone (7), the 7 is subjected to reflux dehydration under the catalysis of p-toluenesulfonic acid, carbonyl is protected by ethylene glycol to form ketal derivatives 8 and 8, and the ketal derivatives are cyclized with 1, 3-dibromo-5, 5-dimethylhydantoin (DDH) under the action of light to generate 9, and the protecting groups are removed by hydrolysis under the acidic condition of sulfuric acid to obtain a key intermediate (+) -9-amino-4-demethoxy-9-deoxydaunorubicin (10). The 1,3, 4-tri-O-acetyl-2-deoxy-D-pyranoribose (11) is prepared into 12 by trimethyl bromosilane bromination, 12 is subjected to substitution reaction with a key intermediate 10 under the catalytic action of silver trifluoromethanesulfonate to generate glucoside, 13 is obtained by removing protecting groups under the alkaline condition of anhydrous potassium carbonate, and finally 13 is salified with hydrogen chloride by a conventional method to prepare a target product.

The synthesis steps of the route are longer, the yield of the product 13 is lower, and is about 9.14 percent (calculated as 1); the yield is low and is 33.0 percent when the chiral resolution is used for preparing Z-3; when the key intermediate 10 is prepared, the hydrolysis temperature is high (80 ℃), the reaction time is long (30h), partial products are racemized in the hydrolysis process, diastereoisomers of the compound 10 are generated, the yield is reduced, and the key intermediate 10 can be separated only by column chromatography due to similar properties, so that the operation is complicated; the consumption of the raw materials 12 for the nucleoside reaction is more (3 equivalents), and the used catalyst, namely silver trifluoromethanesulfonate, is expensive, so that the cost for producing the amrubicin is high; in the hydrolysis deprotection to prepare 13, the reaction time is 18h, and the operation period is also longer.

The (R) - (-) -2-amino-5, 8-dimethoxy-1, 2,3, 4-tetrahydro-2-naphthoic acid can be used as an intermediate for synthesizing amrubicin hydrochloride, directly influences the production, market supply and quality problems of the medicine, and has the following structural formula:

at present, no literature is available on the synthesis method of (R) - (-) -2-amino-5, 8-dimethoxy-1, 2,3, 4-tetrahydro-2-naphthoic acid, but the original patent U.S. Pat. No. 4673668 and J.org.chem.,1987,52,4477-4485 report the synthesis method of its racemate, but the relevant chiral isomer is obtained by chiral resolution in the downstream intermediate. However, this route has a long reaction time for the preparation of intermediate 2, which prolongs the production cycle, and yields only 33% when intermediate Z-3 is prepared by chiral resolution of D-mandelic acid. The intermediate Z-3 was synthesized by the following route starting from Compound 1 in an overall yield of only 28.24%. As can be seen, the resolution preparation process of the intermediate Z-3 seriously influences the industrialization process of the amrubicin hydrochloride. The intermediate Z-3(R) - (-) -2-amino-5, 8-dimethoxy-1, 2,3, 4-tetrahydro-2-methyl naphthoate becomes a key intermediate in the preparation process of amrubicin hydrochloride. The synthetic route is as follows:

therefore, it is still a problem to be solved at present to explore a process route for (R) - (-) -2-amino-5, 8-dimethoxy-1, 2,3, 4-tetrahydro-2-naphthoic acid methyl ester, which is simple and convenient to operate, short in production period, high in yield and more suitable for industrial production.

Disclosure of Invention

Aiming at the problems of longer production period and low conversion rate caused by the fact that raceme needs to be obtained by chiral resolution in the preparation process of the (R) - (-) -2-amino-5, 8-dimethoxy-1, 2,3, 4-tetrahydro-2-methyl naphthoate (Z-3) which is an important intermediate of amrubicin at present; the invention provides a novel compound shown as I-4; and provides a synthetic route for further preparing an important intermediate (R) - (-) -2-amino-5, 8-dimethoxy-1, 2,3, 4-tetrahydro-2-naphthoic acid methyl ester (Z-3) of amrubicin by utilizing the chiral preparation (R) - (-) -2-amino-5, 8-dimethoxy-1, 2,3, 4-tetrahydro-2-naphthoic acid (I) of the compound; the synthetic route has the advantages of simple operation, mild reaction conditions, short production period, high yield and suitability for industrial production.

The specific technical scheme of the invention is as follows:

an amrubicin hydrochloride intermediate compound is shown as a formula I-4, and the compound has the following structural formula:

the chiral preparation method of the compound I-4 comprises the following steps:

adding the compound I-3 and acid into a reaction solvent, and controlling the temperature until the hydrolysis reaction is finished to obtain a compound I-4; the reaction route is as follows:

in a preferable scheme, the feeding molar ratio of the compound I-3 to the acid is 1: 1.2 to 3.0, wherein a ratio of 1: 1.8.

in a preferred embodiment, the acid is one or a combination of hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, and trifluoroacetic acid, and hydrochloric acid is particularly preferred. The acid may be first combined with the reaction solvent to form a solution and then the reaction substrate may be added.

In a preferable scheme, the reaction solvent is one or a combination of methanol, ethanol, isopropanol, n-butanol, tetrahydrofuran, 1, 4-dioxane and diethyl ether.

In a preferable scheme, the reaction temperature is 0-30 ℃, and particularly preferably 20-25 ℃.

In the preferable scheme, the detection reaction is completed, and the reaction time is 1-5 h.

In a preferable scheme, the post-treatment operation is carried out, after the reaction is finished, the filtration is carried out, a filter cake is added into a saturated sodium carbonate solution, an extracting agent is used for extraction, an organic phase is combined, anhydrous sodium sulfate is used for drying, the filtration is carried out, and the filtrate is decompressed and concentrated to be dry, so that the compound I-4 is obtained; the extractant is one or the combination of dichloromethane, chloroform, ethyl acetate and methyl tert-butyl ether.

The compound I-3 can be prepared by the following preparation method, comprising the following steps:

under the protection of inert gas, adding the compound I-2, Trimethylsilylcyanane (TMSCN) into a dry solvent at room temperature, adding a catalyst at controlled temperature, and reacting to obtain a compound I-3 after the addition is finished; the reaction route is as follows:

in a preferable scheme, the feeding molar ratio of the compound I-2 to the Trimethylsilane (TMSCN) is 1: 1.1 to 3.5, wherein 1: 2.3; the feeding molar ratio of the I-2 to the catalyst is 1: 0.6 to 1.5.

In a preferable scheme, the catalyst is one of tetraethyl titanate, tetraisopropyl titanate, tetrabutyl titanate, titanium tetrachloride, stannic chloride, ferric trichloride and zinc chloride.

Preferably, the reaction solvent is one or a combination of tetrahydrofuran, 1, 4-dioxane, dichloromethane, chloroform and toluene.

In the preferable scheme, the temperature of the reaction solution is controlled to be-5-10 ℃ when the catalyst is added; the reaction temperature is 0-40 ℃, and particularly preferably 20-25 ℃; and (3) detecting the reaction for 2-6 h until the reaction is completed.

In a preferable scheme, post-treatment, after the reaction is finished, pouring the reaction solution into a saturated sodium carbonate aqueous solution, filtering, extracting a filtrate with an extracting agent, drying the organic phase, filtering, and concentrating the filtrate under reduced pressure to obtain a compound I-3; the extractant is one or the combination of dichloromethane, chloroform, ethyl acetate and methyl tert-butyl ether.

The compound I-2 can be prepared by the following preparation method, comprising the following steps:

under the protection of inert gas, adding a compound I-1, (R) -tert-butyl sulfenamide and titanate into a dry solvent at room temperature, and controlling the temperature until the reaction is finished to obtain a compound I-2; the reaction route is as follows:

in a preferable scheme, the feeding molar ratio of the compound I-1 to the (R) -tert-butyl sulfinamide and the titanate is 1: 1.1-2.2: 1.2 to 2.3.

Preferably, the titanate is one of tetraethyl titanate, tetraisopropyl titanate and tetrabutyl titanate.

Preferably, the reaction solvent is one or a combination of tetrahydrofuran, 1, 4-dioxane, dichloromethane, chloroform and toluene.

In the preferable scheme, the reaction temperature is 15-80 ℃, and preferably 40-45 ℃. And (5) detecting the reaction for 1-6 h until the reaction is completed.

In a preferable scheme, the post-treatment operation is carried out, after the reaction is finished, the reaction solution is poured into a saturated sodium carbonate aqueous solution, after an extracting agent is extracted, the mixture is filtered, the organic phase is dried, the filter liquor is filtered, and the filtrate is decompressed and concentrated to be dried to obtain a compound I-2; the extractant is one or the combination of dichloromethane, chloroform, ethyl acetate and methyl tert-butyl ether.

The compound I-4 is used for preparing amrubicin.

The compound I-4 is used for preparing an important amrubicin intermediate (R) - (-) -2-amino-5, 8-dimethoxy-1, 2,3, 4-tetrahydro-2-methyl naphthoate, the intermediate is shown as a formula Z-3, and the synthetic route is as follows:

preferably, the preparation steps of the above-mentioned intermediate (Z-3) are described in further detail in the following sections:

preparation of compound I:

adding the compound I-4 and acid into a reaction solvent, controlling the temperature until the reaction is finished, filtering, adding a filter cake into an alkaline aqueous solution, washing with an extractant, adjusting the pH value of the aqueous phase with acid, filtering, and drying the filter cake in vacuum to obtain a target product I; the synthetic route is as follows:

in a preferred embodiment, the acid for reacting and adjusting the pH is one or a combination of hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, and trifluoroacetic acid, and particularly preferred is sulfuric acid.

Preferably, the reaction solvent is one or a combination of methanol, ethanol, isopropanol, n-butanol, tetrahydrofuran, 1, 4-dioxane, purified water and dimethyl sulfoxide, wherein the purified water is particularly preferred.

In a preferred embodiment, the mass-to-volume ratio of the compound I-4 to the acid is 1: 0.8 to 1.3 g/mL.

In the preferable scheme, the reaction temperature is 60-120 ℃, and particularly preferably 90-95 ℃.

In the preferable scheme, the detection reaction is completed, and the reaction time is 2-8 h.

In a preferred embodiment, the alkali is one or a combination of sodium hydroxide, potassium hydroxide, barium hydroxide, sodium carbonate and potassium carbonate, wherein sodium hydroxide is particularly preferred.

Preferably, the extractant is one or a combination of dichloromethane, chloroform, ethyl acetate and methyl tert-butyl ether.

In a preferable scheme, the pH value is adjusted to be 5.0-6.5.

The preparation method of the important intermediate (R) - (-) -2-amino-5, 8-dimethoxy-1, 2,3, 4-tetrahydro-2-naphthoic acid methyl ester (Z-3) of amrubicin can refer to the preparation scheme of the prior art or to the following preparation method:

the preparation method of the intermediate (Z-3) comprises the following steps:

the compound I and methanol are subjected to methyl esterification under the action of hydrogen chloride to obtain (R) - (-) -2-amino-5, 8-dimethoxy-1, 2,3, 4-tetrahydro-2-methyl naphthoate (Z-3), and the reaction route is as follows:

in the present invention, nitrogen and argon are generally selected as the inert gas, and argon is particularly preferred.

The dry solvent is obtained by means of molecular sieve water removal or rectification and the like, and the water or water does not influence the reaction.

Compared with the prior art, the invention has the following technical effects:

1. the method adopts a Trimethylsilylcyanide (TMSCN) reagent to introduce the cyano group, and has the advantages of high space selectivity, low toxicity, mild use conditions and high conversion rate compared with the traditional cyaniding reagents of sodium cyanide and hydrogen cyanide;

2. the (R) - (-) -2-amino-5, 8-dimethoxy-1, 2,3, 4-tetrahydro-2-methyl naphthoate is prepared by an asymmetric synthesis method, the yield is more than 60%, the production efficiency and the product quality are greatly improved, process units such as optical isomer resolution, racemization and the like are reduced, and the production cost is reduced.

Detailed Description

The invention is further illustrated by the following examples, which should be properly understood: the examples of the present invention are merely illustrative and not restrictive, and therefore, the present invention may be modified in a simple manner without departing from the scope of the invention as claimed.

The structure of the compound obtained by the invention is confirmed:

compound I-2: high resolution mass spectrometry: ESI-HRMS (m/z): 310.1476[ M + H]⁺；¹H NMR(400MHz,CDCl₃)6.79～6.84(m,2H),4.12(s,2H),3.78(s,6H),2.77(t,J＝4.0Hz,2H),2.55(t,J＝4.0Hz,2H),1.39(s,9H).

Compound I-3: high resolution mass spectrometry: ESI-HRMS (m/z): 317.1864[ M + H]⁺；¹H NMR(400MHz,CDCl₃)8.20(s,1H),6.54(s,2H),3.79(s,6H),3.05～3.61(m,4H),2.16～2.22(s,1H),1.29(s,9H).

Compound I-4: high resolution mass spectrometry: ESI-HRMS (m/z): 233.1291[ M +H]⁺；¹H NMR(400MHz,CDCl₃)6.56(s,2H),3.77(s,6H),2.80～3.25(m,4H),2.55(s,1H),2.47(s,1H),2.26～2.39(m,1H),1.83～2.12(m,1H).

A compound I: high resolution mass spectrum of (R) - (-) -2-amino-5, 8-dimethoxy-1, 2,3, 4-tetrahydro-2-naphthoic acid: ESI-HRMS (m/z): 252.1235[ M + H]⁺；¹H NMR(400MHz,CDCl₃)；¹H NMR(400MHz,CDCl₃)6.58(s,2H),3.77(s,6H),2.85～3.29(m,4H),2.55(s,1H),2.47(s,1H),2.31～2.37(s,1H),1.87～2.03(s,1H).

Compound Z-3: high resolution mass spectrometry: ESI-HRMS (m/z): 265.1312[ M + H]⁺；¹H NMR(400MHz,CDCl₃)6.55(s,2H),3.77(s,6H),3.73(s,3H),2.60～3.23(m,4H),1.73～3.27(m,2H),1.62(s,2H)。

Synthesis of intermediate Compound I-2