WO2023202052A1 - 一种10-氧代十九烷二酸的制备方法 - Google Patents

一种10-氧代十九烷二酸的制备方法 Download PDF

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WO2023202052A1
WO2023202052A1 PCT/CN2022/131794 CN2022131794W WO2023202052A1 WO 2023202052 A1 WO2023202052 A1 WO 2023202052A1 CN 2022131794 W CN2022131794 W CN 2022131794W WO 2023202052 A1 WO2023202052 A1 WO 2023202052A1
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acid
compound
dimethylamino
binding agent
molar ratio
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PCT/CN2022/131794
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French (fr)
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陈永好
张再伟
陈明洪
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深圳深信生物科技有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/06—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid amides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/313—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of doubly bound oxygen containing functional groups, e.g. carboxyl groups

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  • the invention belongs to the field of biopharmaceuticals, and specifically relates to a preparation method of 10-oxononadecanedioic acid.
  • Gene drugs use artificial means to deliver genes with specific genetic information to target cells.
  • the expressed target proteins have the effect of regulating, treating or even curing diseases caused by congenital or acquired gene defects, or the gene series can interfere with or regulate related genes. expression to achieve clinical therapeutic effects.
  • WO2013086322A1 discloses a cationic lipid compound (Compound I) with low toxicity and suitable for delivering genes into cells. It is widely used in gene delivery. Its structural formula is as shown in formula (I):
  • WO2013086322A1 reports a method for preparing compound (I), which uses 10-oxononadecanedioic acid (English name: 10-Oxononadecanedioic Acid) with the structural formula (II) as the starting material. , through esterification, reduction steps, and finally condensation with 4-dimethylaminobutyric hydrochloride to prepare compound I.
  • 10-oxononadecanedioic Acid English name: 10-Oxononadecanedioic Acid
  • This method uses 8-bromooctanoic acid ethyl ester as a starting material, first reacts with 1,3 acetone dicarboxylic acid diethyl ester under the action of strong bases such as sodium ethoxide, and then hydrolyzes and decarboxylates to prepare 10-oxononadecanedioic acid. .
  • this method has the following shortcomings: first, ethyl 8-bromooctanoate is expensive, and at least two molecules of ethyl 8-bromooctanoate are needed to generate one molecule of product, resulting in high production costs; second, : There are many side reactions.
  • diethyl acetone dicarboxylate and the intermediate can undergo enol interconversion, making it difficult to monitor the reaction and control the reaction process.
  • two carboxyl groups need to be removed at the same time. , the reaction is complex, there are many side reactions, and the product purity is low. Therefore, this method is not an ideal preparation method.
  • This method uses monomethyl sebacic acid as a starting material, and uses Claisen condensation and then hydrolysis and decarboxylation to prepare 10-oxononadecanedioic acid.
  • this method first chlorides sebacic acid monomethyl ester, and then reacts with dimethylamine aqueous solution to obtain sebacic acid monomethyl ester amide, which has many side reactions and takes a long time to purify; and in the subsequent steps, metal sodium is dissolved in methanol and is newly prepared.
  • Sodium methoxide is used as a base, and the Claisen condensation of sebacic acid monomethyl ester amide is carried out by heating under vacuum conditions.
  • the reaction conditions are harsh, the safety is poor, the reaction time is long, the equipment requirements are high, and it is not conducive to industrial production. Therefore, this method Nor is it an ideal preparation method.
  • the object of the present invention is to provide a new preparation method of 10-oxononadecanedioic acid. This method has mild conditions, high conversion rate, easy operation, low cost, and is more suitable for industrial production.
  • the present invention provides a new method for preparing 10-oxononadecanedioic acid, which includes the following steps:
  • compound (VI) is treated with acid to obtain 10-oxononadecanedioic acid.
  • the acid is selected from one or more hydrohalic acids.
  • the condensing agent is titanium tetrachloride
  • the molar ratio of the sebacic acid monomethyl ester amide (compound (V)) to the condensing agent is 1:1.0-1:2.0; more preferably, the molar ratio of the compound (V) to the condensing agent is 1:1.2;
  • an acid-binding agent is added to the step; more preferably, the acid-binding agent is selected from the group consisting of pyridine, triethylamine, diethylamine, potassium carbonate, sodium carbonate, n-butylamine, potassium bicarbonate, and bicarbonate. Sodium; further preferably, the acid binding agent is triethylamine;
  • the molar ratio of the compound (V) to the acid-binding agent is 1:1.0-1:2.0; more preferably, the molar ratio of the compound (V) to the acid-binding agent is 1:1.4;
  • the reaction temperature of the step is -10°C to 20°C, preferably 0°C;
  • the steps usually include a post-treatment process.
  • a post-treatment process After the reaction, quench with water, separate the organic phase, extract the aqueous phase with the organic phase, combine the organic phases, wash with water, wash with brine, dry, and concentrate to obtain a crude product, which is passed Column chromatography prepared 12-(dimethylamino)-2-(8-(dimethylamino)-8-oxoctyl)-3,12-dioxododecanoic acid methyl ester (compound VI).
  • the condensing agent titanium tetrachloride is used to replace the metallic sodium used in the prior art. It is well known to those skilled in the art that the metallic sodium is highly chemically active, difficult to control, and has low safety. Therefore, Not conducive to industrial production. At the same time, it can be found from the foregoing that the above method of the present application does not involve steps that require high equipment and are difficult to operate, such as vacuum heating reactions. The reaction conditions are mild and easy to operate and control.
  • the present invention relates to a new method for preparing 10-oxonadecanedioic acid as described above, wherein the compound (V): 10-(dimethylamino)-10-oxodecanoic acid methyl ester
  • compound (IV) 10-(dimethylamino)-10-oxodecanoic acid methyl ester
  • the condensation agent is selected from one or more of DCC, DIC, and EDCI; more preferably, the condensation agent is EDCI;
  • the molar ratio of compound (IV) to dimethylamine hydrochloride is 1:1.0-1:1.6; more preferably, the molar ratio of compound (IV) (compound IV) to dimethylamine hydrochloride is 1:1.3;
  • a catalyst is added in the step; more preferably, the catalyst is DMAP;
  • the molar ratio of compound (IV) to catalyst is 1:0.05-1:0.3; more preferably, the molar ratio of compound (IV) to catalyst is 1:0.1;
  • an acid-binding agent is added to the step; more preferably, the acid-binding agent is selected from the group consisting of pyridine, N,N-diisopropylethylamine, triethylamine, cesium carbonate, potassium carbonate, sodium carbonate, n-butylamine, potassium bicarbonate, sodium bicarbonate; further preferably, the acid binding agent is pyridine;
  • the molar ratio of the compound (IV) to the acid-binding agent is 1:2.0-1:3.2; more preferably, the molar ratio of the compound (IV) to the acid-binding agent is 1:2.8;
  • the reaction temperature of the step is ambient temperature, preferably 20 to 30°C;
  • the present invention relates to a new method for preparing 10-oxononadecanedioic acid, which includes the following steps:
  • Step 1 Using dimethyl sebacate (compound (III)) as a starting material, in a solvent and under the action of a base, monomethyl sebacate (compound IV) is prepared.
  • the process route is as follows:
  • the solvent is an organic solvent or water; more preferably, the solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, water, methanol, ethanol, acetone, dimethylformamide, One or more of methyl chloride, tetrahydrofuran, and acetonitrile; further preferably, the solvent is N,N-dimethylformamide;
  • the base is an inorganic base; more preferably, the base is selected from one of potassium hydroxide, sodium hydroxide, barium hydroxide, lithium hydroxide, cesium carbonate, potassium carbonate, sodium carbonate, ammonia water, or A variety of; further preferably, the base is potassium hydroxide;
  • the molar ratio of compound (III) to base is 1:1.0-1:1.3; preferably 1:1.1;
  • the mass volume ratio of compound (III) to solvent is 1:3-1:10; preferably 1:5;
  • the reaction temperature of the step is -20°C to 25°C; preferably -10°C;
  • the steps usually also include a treatment process.
  • a treatment process After the reaction is completed, add water to dilute the reactant, wash it with an organic solvent, acidify the aqueous phase, extract the product with an organic solvent, and finally obtain monomethyl sebacate ( Compound (IV));
  • Step 2 starts with monomethyl sebacate (compound (IV)), reacts with dimethylamine hydrochloride under the action of a condensing agent, and prepares 10-(dimethylamino)-10-oxodecanoic acid methyl ester.
  • Compound V the process route is as follows:
  • the condensation agent is selected from one or more of DCC, DIC, and EDCI; more preferably, the condensation agent is EDCI;
  • the molar ratio of compound (IV) to dimethylamine hydrochloride is 1:1.0-1:1.6; More preferably, the molar ratio of compound (IV) to dimethylamine hydrochloride is 1:1.3;
  • the molar ratio of the compound (IV) to the condensing agent is 1:1.0-1:2.0; more preferably, the molar ratio of the compound (IV) to the condensing agent is 1:1.5;
  • a catalyst is added in the step; more preferably, the catalyst is DMAP;
  • the molar ratio of compound (IV) to catalyst is 1:0.05-1:0.3; more preferably, the molar ratio of compound (IV) to catalyst is 1:0.1;
  • an acid-binding agent is added to the step; more preferably, the acid-binding agent is selected from the group consisting of pyridine, N,N-diisopropylethylamine, triethylamine, cesium carbonate, potassium carbonate, sodium carbonate, n-butylamine, potassium bicarbonate, sodium bicarbonate; further preferably, the acid binding agent is pyridine;
  • the molar ratio of the compound (IV) to the acid-binding agent is 1:2.0-1:3.2; more preferably, the molar ratio of the compound (IV) to the acid-binding agent is 1:2.8;
  • the reaction solvent of the step is an organic solvent; more preferably, the reaction solvent of the step is selected from dichloromethane, chloroform, 1,2-dichloroethane, acetone, N,N-dimethyl. One or more of methyl formamide, acetonitrile, and tetrahydrofuran; further preferably, the reaction solvent of the step is dichloromethane;
  • the steps usually include a treatment process. After the reaction, add water, acidify, extract with organic solvent, wash, dry, and concentrate to obtain 10-(dimethylamino)-10-oxodecanoic acid methyl ester (compound (V) )).
  • Step 3 Claisen condensation of 10-(dimethylamino)-10-oxodecanoic acid methyl ester (compound (V)) under the action of a condensing agent to prepare 12-(dimethylamino)-2- (8-(dimethylamino)-8-oxoctyl)-3,12-dioxododecanoic acid methyl ester (compound VI), the process route is as follows:
  • the condensing agent is titanium tetrachloride
  • the molar ratio of the sebacic acid monomethyl ester amide (compound (V)) to the catalyst is 1:1.0-1:2.0; more preferably, the molar ratio of the compound (V) to the catalyst is 1: 1.2;
  • the reaction solvent of the step is selected from one or more of dichloromethane, chloroform, 1,2-dichloroethane, acetone, N,N-dimethylformamide, acetonitrile, and tetrahydrofuran. ; Further preferably, the reaction solvent of the step is methylene chloride;
  • the mass-volume ratio of the compound (V) to the solvent is 1:3-1:10; more preferably, the mass-volume ratio of the compound (V) to the solvent is 1:5;
  • an acid-binding agent is added to the step; more preferably, the acid-binding agent is selected from the group consisting of pyridine, triethylamine, diethylamine, potassium carbonate, sodium carbonate, n-butylamine, potassium bicarbonate, and bicarbonate. Sodium; further preferably, the acid binding agent is triethylamine;
  • the molar ratio of the compound (V) to the acid-binding agent is 1:1.0-1:2.0; more preferably, the molar ratio of the compound (V) to the acid-binding agent is 1:1.4;
  • the steps usually include a post-treatment process.
  • a post-treatment process After the reaction, quench with water, separate the organic phase, extract the aqueous phase with the organic phase, combine the organic phases, wash with water, wash with brine, dry, and concentrate to obtain a crude product, which is passed Column chromatography prepared 12-(dimethylamino)-2-(8-(dimethylamino)-8-oxoctyl)-3,12-dioxododecanate methyl ester (compound (VI)) .
  • Step 4 Add 12-(dimethylamino)-2-(8-(dimethylamino)-8-oxoctyl)-3,12-dioxododecanate methyl ester (compound (VI)) in Through the action of acid, 10-oxononadecanedioic acid is prepared.
  • the process route is as follows:
  • the acid is selected from one or more of hydrohalic acids; more preferably, the acid is selected from one or more of hydrochloric acid, hydrobromic acid; further preferably, the acid is hydrobromic acid;
  • the molar ratio of compound (VI) to acid is 1:3-1:10; more preferably, the molar ratio of compound (VI) to acid is 1:5;
  • the reaction temperature of the step is 80-130°C; more preferably, the reaction temperature is 120°C;
  • the step usually also includes a post-treatment process. After the reaction is completed, cool, add water, cool to precipitate solid, and filter to obtain a crude product;
  • the steps usually also include a recrystallization process
  • the recrystallization process includes mixing the crude product with an organic solvent, heating to completely dissolve the solid, cooling and crystallizing, and filtering to obtain 10-oxononadecanedioic acid;
  • the organic solvent used in the recrystallization process is selected from one or more of acetonitrile, acetone, ethyl acetate, toluene, 1,2 dichloroethane, and tetrahydrofuran; more preferably, the recrystallization process uses The organic solvent used was acetonitrile;
  • the heating temperature during the recrystallization process is 50°C-100°C; more preferably, the heating temperature during the recrystallization process is 80°C;
  • the cooling crystallization temperature during the recrystallization process is -20°C to 25°C; more preferably, the cooling crystallization temperature during the recrystallization process is -10°C.
  • the present invention relates to a new method for preparing 10-oxononadecanedioic acid, which includes the following steps:
  • the above-mentioned new method for preparing 10-oxononadecanedioic acid disclosed in the present invention at least includes unexpected beneficial effects as described below:
  • the preparation method of the present invention uses cheap and easily available dimethyl sebacate as the starting raw material.
  • the unreacted dimethyl sebacate can be recovered during post-processing.
  • the production cost is low and it is suitable for green chemistry. development requirements.
  • the preparation method of the present invention does not use substances that are highly chemically active, difficult to control, and have low safety, such as metallic sodium; at the same time, it does not involve steps that require high equipment and are difficult to operate, such as vacuum heating reactions, and the reaction conditions are mild. , easy to operate and control.
  • the preparation method of the present invention has a high conversion rate, few side reactions, a simple, compact and easy-to-control process, is suitable for industrial application, and has huge economic potential.
  • Figure 1 is 1 of 12-(dimethylamino)-2-(8-(dimethylamino)-8-oxoctyl)-3,12-dioxododecanate methyl ester (compound (VI)) H NMR spectrum
  • Figure 2 is 13 of 12-(dimethylamino)-2-(8-(dimethylamino)-8-oxoctyl)-3,12-dioxododecanoate methyl ester (compound (VI)) C NMR spectrum
  • Figure 3 is the 1 H NMR spectrum of 10-oxononadecanedioic acid.
  • Figure 4 is the 13 C NMR spectrum of 10-oxononadecanedioic acid.
  • Figure 5 is the NMR spectrum of the product of Comparative Example 1.
  • Step 3 Preparation of 12-(dimethylamino)-2-(8-(dimethylamino)-8-oxoctyl)-3,12-dioxododecanate methyl ester (compound VI)
  • Recrystallization purification add 25.4g of the obtained crude product into a 500mL flask, add 230mL of acetonitrile, heat to 80°C and reflux for half an hour to completely dissolve the solid, then cool to -10°C, separate out the product, filter and dry to obtain 10- 19.3g of oxynonadecanedioic acid (compound (II)), yield 95%, is an off-white solid, and the purity detected by HPLC normalization method is 99%.
  • the total yield of 10-oxononadecanedioic acid prepared from monomethyl sebacate (compound (IV)) as the initial raw material is About 52%, with few side reactions, simple process, easy control, high safety, low equipment requirements, and many advantages suitable for industrial application.
  • Comparative Example 1 Preparation of 10-oxononadecanedioic acid according to the preparation method reported in WO 2013/086322 A1
  • the raw material 8-bromooctanoic acid ethyl ester used in this scheme is expensive and has many side reactions compared with the starting raw material dimethyl sebacate used in the method of the present application, and the yield is significantly lower than that of the method of the present invention. ; And it can be seen from the nuclear magnetic resonance spectrum of the obtained product that the purity of the obtained product is significantly lower than that of the product obtained by the method of the present application.
  • 10-(dimethylamino)-10-oxodecanoic acid methyl ester can be prepared in only a single step reaction, and the product can be used in the following steps without further purification.
  • the reaction is complex and has many side reactions.
  • the product needs to be purified before it can be used in subsequent steps. , and the purity is not high. It can be seen that the method provided by this application has high conversion rate, few side reactions and is easy to control, which has obvious advantages.
  • step two must use metallic sodium and methanol to react to obtain sodium methoxide.
  • metallic sodium and methanol to react to obtain sodium methoxide.
  • the preparation of sodium methoxide in industrial production has high requirements and poor safety, and requires heating under reduced pressure and high equipment requirements. high.
  • the condensation agent titanium tetrachloride is used to replace the metallic sodium used in the prior art.
  • the reaction conditions are mild and easy to operate and control. Therefore it is very suitable for industrial production.
  • Recrystallization purification Put 600mg of the crude product in a 50mL flask, add 15mL of acetonitrile (25 times the volume), heat to 80°C and reflux for half an hour to completely dissolve the solid, then cool to 10°C, the product will precipitate, and 10- Oxynonadecanedioic acid 550 mg, yield 68%, is an off-white solid, and the purity detected by HPLC normalization method is 77%.
  • the preparation method for 10-oxonadecanedioic acid described in this application has a higher conversion rate, simpler steps, and fewer side reactions. Less, easy to control and highly safe.
  • the preparation method of 10-oxononadecanedioic acid described in the present application has a high conversion rate, few side reactions, and a simple process, and the products of step two and step three do not require further purification. It can be used in subsequent steps, is easy to control, has high safety, has low equipment requirements, is suitable for industrial application, and has huge economic potential.

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Abstract

本申请涉及一种10-氧代十九烷二酸的制备方法。与现有技术中的相应合成方法相比，本申请所述制备方法转化率高、副反应少，工艺简单、易于控制，安全性高，对设备要求低，适合工业化运用，具有巨大的经济潜力。

Description

一种10-氧代十九烷二酸的制备方法 技术领域
本发明属于生物制药领域，具体涉及一种10-氧代十九烷二酸的制备方法。
背景技术
基因药物是通过人工手段将具有特定遗传信息的基因递送到靶细胞，表达的目标蛋白对先天或后天基因缺陷造成的病症具有调节、治疗甚至治愈的效果，或者基因系列能干扰或调控相关基因的表达，达到临床上的治疗效果。
WO2013086322A1公开了一种低毒性，适用于将基因递送到细胞内的阳离子脂质化合物(化合物I)，被广泛的应用于基因的递送，其结构式如式(I)所示：
Figure PCTCN2022131794-appb-000001
现有技术中，WO2013086322A1报道了化合物(I)的制备方法，该方法以结构式为式(II)所示的10-氧代十九烷二酸(英文名为10-Oxononadecanedioic Acid)为起始原料，先后经过酯化、还原步骤，最后与4-二甲基氨基丁酸盐酸盐缩合，制备得到化合物I。
Figure PCTCN2022131794-appb-000002
现有技术中，报道了多种10-氧代十九烷二酸的制备方法，如专利WO2013086322A1报道了一种以8-溴辛酸乙酯作为起始原料制备10-氧代十九烷二酸的制备方法，该方法工艺路线如下所示：
Figure PCTCN2022131794-appb-000003
该方法以8-溴辛酸乙酯作为起始原料，先在乙醇钠等强碱作用下与1，3丙酮二羧酸二乙酯反应，然后水解脱羧制备得到10-氧代十九烷二酸。但是在实际应用中发现，这种方法存在以下缺点：第一，8-溴辛酸乙酯的价格昂贵，并且每生成一分子产物至少需要两分子8-溴辛酸乙酯，生产成本高；第二：副反应多，加之1，3丙酮二羧酸二乙酯和中间体可以发生烯醇互变使得反应中控监测困难，反应过程难以控制；此外，在水解脱羧步骤，需要同时去除两个羧基，反应复杂，副反应多，产品纯度低，因此，该方法不是一种理想的制备方法。
文献《Claisen Condensation.A Method for the Synthesis of Long Chain Dicarboxylic Acids》Harry Cohen and Richard Shubart.J.Org.Chem.，Vol.88，No.7，1978，报道了一种以癸二酸单甲酯为起始原料制备10-氧代十九烷二酸的方法，该方法工艺路线如下所示：
Figure PCTCN2022131794-appb-000004
该方法以癸二酸单甲酯为起始原料，采用克莱森缩合再水解脱羧的方式制备得到10-氧代十九烷二酸。但该方法先将癸二酸单甲酯酰氯化，再与二甲胺水溶液反应，得到癸二酸单甲酯酰胺，副反应多，纯化耗时长；且后续步骤使用金属钠溶于甲醇中新制的甲醇钠做碱，在真空条件下加热进行癸二酸单甲酯酰胺自身克莱森缩合，反应条件苛刻，安全性差，反应时间长，对设备要求高，不利于工业生产，因此，该方法也不是一种理想的制备方法。
由此可见，开发一种反应条件温和、转化率高、易于操作的制备10-氧代十九烷二酸的方法，是本领域苛待解决的问题。
发明内容：
本发明的目的在于提供一种10-氧代十九烷二酸的新的制备方法。该方法条件温和、转化率高、易于操作、成本低廉，更适合工业化生产。
为了实现上述发明目的，本发明提供一种新的制备10-氧代十九烷二酸的方法，包括如下步骤：
使化合物(V)：10-(二甲氨基)-10-氧代癸酸甲酯在缩合剂的作用下进行克莱森缩合而得到化合物(VI)：12-(二甲氨基)-2-(8-(二甲氨基)-8-氧代辛基)-3，12-二氧代十二酸甲酯：
Figure PCTCN2022131794-appb-000005
然后，将化合物(VI)在酸的作用下而得到10-氧代十九烷二酸。所述酸选自氢卤酸中的一种或多种。
优选地，所述缩合剂为四氯化钛；
优选地，所述癸二酸单甲酯酰胺(化合物(V))与缩合剂的摩尔比为1∶1.0-1∶2.0；更优选地，所述化合物(V)与缩合剂的摩尔比为1∶1.2；
优选地，所述步骤还加入了缚酸剂；更优选地，所述缚酸剂选自吡啶、三乙胺、二乙胺、碳酸钾、碳酸钠、正丁胺、碳酸氢钾、碳酸氢钠；进一步优选地，所述缚酸剂为三乙胺；
优选地，所述化合物(V)与缚酸剂的摩尔比为1∶1.0-1∶2.0；更优选地，所述化合物(V)与缚酸剂的摩尔比为1∶1.4；
优选地，所述步骤的反应温度为-10℃～20℃，优选为0℃；
优选地，所述步骤通常还包括后处理过程，反应结束后，用水淬灭，分出有机相，水相用有机相萃取，合并有机相，水洗，盐水洗，干燥，浓缩得粗品，粗品通过柱层析制备得到12-(二甲氨基)-2-(8-(二甲氨基)-8-氧代辛基)-3，12-二氧代十二酸甲酯(化合物VI)。
本发明的上述方法中，采用了缩合剂四氯化钛替代现有技术中使用的金属钠，本领域技术人员公知的是，所述金属钠具有高度化学活性、不易控制且安全性低，因而不利于工业生产。同时，由前文所述 可发现，本申请的上述方法不涉及如真空加热反应等对设备要求高、不易操作的步骤，反应条件温和，易于操作和控制。
进一步地，本发明涉及如上文所述的新的制备10-氧代十九烷二酸的方法，其中所述化合物(V)：10-(二甲氨基)-10-氧代癸酸甲酯通过在缩合剂的作用下，使化合物(IV)与盐酸二甲胺反应而得到：
Figure PCTCN2022131794-appb-000006
优选地，所述缩合剂选自DCC、DIC、EDCI中的其中一种或多种；更优选地，所述缩合剂为EDCI；
优选地，化合物(IV)与盐酸二甲胺的摩尔比为1∶1.0-1∶1.6；更优选地，化合物(IV)(化合物IV)与盐酸二甲胺的摩尔比为1∶1.3；
优选地，所述步骤还加入了催化剂；更优选地，所述催化剂为DMAP；
优选地，所述化合物(IV)与催化剂的摩尔比为1∶0.05-1∶0.3；更优选地，所述化合物(IV)与催化剂的摩尔比为1∶0.1；
优选地，所述步骤还加入了缚酸剂；更优选地，所述缚酸剂选自吡啶、N，N-二异丙基乙胺、三乙胺、碳酸铯、碳酸钾、碳酸钠、正丁胺、碳酸氢钾、碳酸氢钠；进一步优选地，所述缚酸剂为吡啶；
优选地，所述化合物(IV)与缚酸剂的摩尔比为1∶2.0-1∶3.2；更优选地，所述化合物(IV)与缚酸剂的摩尔比为1∶2.8；
优选地，所述步骤的反应温度为环境温度，优选为20～30℃；
本发明中的上述步骤中，以单个步骤得到10-(二甲氨基)-10-氧代癸酸甲酯(化合物(V))，与现有技术中使用的相应制备方法相比转化率高、副反应少且易于控制，具有明显的优势。
在另一方面，本发明涉及一种新的制备10-氧代十九烷二酸的方法，其包括如下的步骤：
步骤一，以癸二酸二甲酯(化合物(III))为起始原料，在溶剂中，在碱的作用下，制备得到癸二酸单甲酯(化合物IV)，工艺路线如下所示：
Figure PCTCN2022131794-appb-000007
优选地，所述溶剂为有机溶剂或者水；更优选地，所述溶剂选自N，N-二甲基甲酰胺、N，N-二甲基乙酰胺、水、甲醇、乙醇、丙酮、二氯甲烷、四氢呋喃、乙腈中的一种或者多种；进一步优选地，所述溶剂为N，N-二甲基甲酰胺；
优选地，所述碱为无机碱；更优选地，所述碱选自氢氧化钾、氢氧化钠、氢氧化钡、氢氧化锂、碳酸铯、碳酸钾、碳酸钠、氨水中的一种或多种；进一步优选地，所述碱为氢氧化钾；
优选地，所述化合物(III)与碱的摩尔比为1∶1.0-1∶1.3；优选为1∶1.1；
优选地，所述化合物(III)与溶剂的质量体积比为1∶3-1∶10；优选为1∶5；
优选地，所述步骤的反应温度为-20℃～25℃；优选为-10℃；
优选地，所述步骤通常还包括处理过程，反应结束后，加水稀释反应物，用有机溶剂洗涤，水相酸化后，用有机溶剂萃取产物，最后通过柱层析获得癸二酸单甲酯(化合物(IV))；
优选地，所述柱层析纯化过程使用乙酸乙酯与正己烷为洗脱剂，硅胶为填料；进一步优选地，使用乙酸乙酯∶正己烷＝1∶5(V/V)为洗脱剂。
步骤二，由癸二酸单甲酯(化合物(IV))开始，在缩合剂的作用下，与盐酸二甲胺反应，制备得到10-(二甲氨基)-10-氧代癸酸甲酯(化合物V)，工艺路线如下所示：
Figure PCTCN2022131794-appb-000008
优选地，所述缩合剂选自DCC、DIC、EDCI中的其中一种或多种；更优选地，所述缩合剂为EDCI；
优选地，所述化合物(IV)与盐酸二甲胺的摩尔比为1∶1.0-1∶1.6； 更优选地，所述化合物(IV)与盐酸二甲胺的摩尔比为1∶1.3；
优选地，所述化合物(IV)与缩合剂的摩尔比为1∶1.0-1∶2.0；更优选地，所述化合物(IV)与缩合剂的摩尔比为1∶1.5；
优选地，所述步骤还加入了催化剂；更优选地，所述催化剂为DMAP；
优选地，所述化合物(IV)与催化剂的摩尔比为1∶0.05-1∶0.3；更优选地，所述化合物(IV)与催化剂的摩尔比为1∶0.1；
优选地，所述步骤还加入了缚酸剂；更优选地，所述缚酸剂选自吡啶、N，N-二异丙基乙胺、三乙胺、碳酸铯、碳酸钾、碳酸钠、正丁胺、碳酸氢钾、碳酸氢钠；进一步优选地，所述缚酸剂为吡啶；
优选地，所述化合物(IV)与缚酸剂的摩尔比为1∶2.0-1∶3.2；更优选地，所述化合物(IV)与缚酸剂的摩尔比为1∶2.8；
优选地，所述步骤的反应溶剂为有机溶剂；更优选地，所述步骤的反应溶剂选自二氯甲烷、三氯甲烷、1，2-二氯乙烷、丙酮、N，N-二甲基甲酰胺、乙腈、四氢呋喃中的一种或多种；进一步优选地，所述步骤的反应溶剂为二氯甲烷；
优选地，所述步骤通常还包括处理过程，反应结束后，加水，酸化，有机溶剂萃取，洗涤，干燥，浓缩得10-(二甲氨基)-10-氧代癸酸甲酯(化合物(V))。
步骤三，将10-(二甲氨基)-10-氧代癸酸甲酯(化合物(V))在缩合剂的作用下进行克莱森缩合，制备得到12-(二甲氨基)-2-(8-(二甲氨基)-8-氧代辛基)-3，12-二氧代十二酸甲酯(化合物VI)，工艺路线如下所示：
Figure PCTCN2022131794-appb-000009
优选地，所述缩合剂为四氯化钛；
优选地，所述癸二酸单甲酯酰胺(化合物(V))与催化剂的摩尔比为1∶1.0-1∶2.0；更优选地，所述化合物(V)与催化剂的摩尔比为1∶1.2；
优选地，所述步骤的反应溶剂选自二氯甲烷、三氯甲烷、1，2-二氯乙烷、丙酮、N，N-二甲基甲酰胺、乙腈、四氢呋喃中的一种或多种；进一步优选地，所述步骤的反应溶剂为二氯甲烷；
优选地，所述化合物(V)与溶剂的质量体积比为1∶3-1∶10；更优选地，所述化合物(V)与溶剂的质量体积比为1∶5；
优选地，所述步骤还加入了缚酸剂；更优选地，所述缚酸剂选自吡啶、三乙胺、二乙胺、碳酸钾、碳酸钠、正丁胺、碳酸氢钾、碳酸氢钠；进一步优选地，所述缚酸剂为三乙胺；
优选地，所述化合物(V)与缚酸剂的摩尔比为1∶1.0-1∶2.0；更优选地，所述化合物(V)与缚酸剂的摩尔比为1∶1.4；
优选地，所述步骤通常还包括后处理过程，反应结束后，用水淬灭，分出有机相，水相用有机相萃取，合并有机相，水洗，盐水洗，干燥，浓缩得粗品，粗品通过柱层析制备得到12-(二甲氨基)-2-(8-(二甲氨基)-8-氧代辛基)-3，12-二氧代十二酸甲酯(化合物(VI))。
步骤四，将12-(二甲氨基)-2-(8-(二甲氨基)-8-氧代辛基)-3，12-二氧代十二酸甲酯(化合物(VI))在酸的作用，制备得到10-氧代十九烷二酸，工艺路线如下所示：
Figure PCTCN2022131794-appb-000010
优选地，所述酸选自氢卤酸中的一种或多种；更优选地，所述酸选自盐酸、氢溴酸、中的一种或多种；进一步优选地，所述酸为氢溴酸；
优选地，所述化合物(VI)与酸的摩尔比为1∶3-1∶10；更优选地，所述化合物(VI)与酸的摩尔比为1∶5；
优选地，所述步骤的反应温度为80-130℃；更优选地，所述反应温度为120℃；
优选地，所述步骤通常还包括后处理过程，反应结束后，冷却，加入水，冷却析出固体，过滤得粗品；
优选地，所述步骤通常还包括重结晶过程；
优选地，所述重结晶过程包括将粗品与有机溶剂混合，加热使固体完全溶解，冷却析晶，过滤得10-氧代十九烷二酸；
优选地，所述重结晶过程使用的有机溶剂选自乙腈、丙酮、乙酸乙酯、甲苯、1，2二氯乙烷、四氢呋喃中的一种或多种；更优选地，所述重结晶过程使用的有机溶剂为乙腈；
优选地，所述重结晶过程中加热温度为50℃-100℃；更优选地，所述重结晶过程中加热温度为80℃；
优选地，所述重结晶过程中的冷却析晶温度为-20℃～25℃；更优选地，所述重结晶过程中的冷却析晶温度为-10℃。
在另一方面，本发明涉及一种新的制备10-氧代十九烷二酸的方法，其包括如下的步骤：
Figure PCTCN2022131794-appb-000011
与现有技术相比，本发明中公开的上述新的制备10-氧代十九烷二酸的方法至少包括如下文所述的不可预期有益效果：
1)本发明所述的制备方法使用便宜易得的癸二酸二甲酯为起始原料，未反应的癸二酸二甲酯可在后处理过程中回收，生产成本低，并且契合绿色化学发展的要求。
2)本发明所述的制备方法不使用如金属钠等具有高度化学活性，不易控制，安全性低的物质；同时不涉及如真空加热反应等对设备要求高、不易操作的步骤，反应条件温和，易于操作和控制。
3)本发明所述的制备方法转化率高、副反应少，工艺简单、紧凑、易于控制，适合工业化运用，具有巨大的经济潜力。
附图说明
图1为12-(二甲氨基)-2-(8-(二甲氨基)-8-氧代辛基)-3，12-二氧代十二酸甲酯(化合物(VI))的 1H NMR图谱
图2为12-(二甲氨基)-2-(8-(二甲氨基)-8-氧代辛基)-3，12-二氧代十二酸甲酯(化合物(VI))的 13C NMR图谱
图3为10-氧代十九烷二酸的 1H NMR图谱
图4为10-氧代十九烷二酸的 13C NMR图谱
图5为对比例1产物的核磁图谱。
具体实施方式
以下参照具体的实施例来说明本发明。本领域技术人员能够理解，这些实施例仅用于说明本发明，其不以任何方式限制本发明的范围。除非另有说明，否则本发明中涉及的术语都具有本领域所通用的含义，且为本领域技术人员所理解。
下述实施例中的实验方法，如无特殊说明，均为常规方法。下述实施例中所用的原料、辅料、试剂材料等，均为市售购买产品。
实施例
步骤一：癸二酸单甲酯(化合物(IV))的制备
Figure PCTCN2022131794-appb-000012
实施例1
在2000mL圆底烧瓶中称取癸二酸二甲酯(化合物(III))(1.0当量，170g，738.2mmol)，溶于N，N-二甲基甲酰胺(850mL，5倍体积)，冷却至-10℃，加入氢氧化钾粉末(1.1当量)，并在-10℃使反应过夜，溶液由澄清逐渐变白色浑浊。反应结束后加2L水稀释，用乙酸乙酯500mL萃取三次，回收未转化的原料癸二酸二甲酯。水相用稀盐酸调至PH＝3后用乙酸乙酯500mL萃取三次，旋转蒸发除去溶剂得到粗品，采用硅胶柱层析(乙酸乙酯∶正己烷＝1∶5，V/V)纯化，得到癸二酸单甲酯(化合物(IV))121g，收率76％，为白色固体，HPLC归一化法检测纯度为99％。
LC-MS(ESI)：计算值(M-H)：215.13，实测值：215.4。
步骤二：10-(二甲氨基)-10-氧代癸酸甲酯(化合物V)的制备
Figure PCTCN2022131794-appb-000013
实施例2
在500mL圆底烧瓶中称取癸二酸单甲酯(化合物(IV))(1.0当量，5.1g，23.57mmol)、盐酸二甲胺(1.3当量，2.5g，30.64mmol)、EDCI(1.5当量，6.78g，35.36mmol)、DMAP(0.1当量，288mg，2.36mmol)，溶于50mL二氯甲烷，最后加入吡啶(2.8当量，5.22g，66mmol)，室温下搅拌过夜。反应结束后加入50mL水稀释，用稀盐酸调至PH＝3，分出有机相，水相用二氯甲烷70mL萃取两次，合并有机相，水洗，饱和氯化钠溶液洗，经无水硫酸钠干燥，浓缩得到10-(二甲氨基)-10-氧代癸酸甲酯(化合物(V))4.8g，收率84％，为棕黄色油状物，无需进一步纯化即可直接用于下一步。
LC-MS(ESI)：计算值(M+H)：244.19，实测值：244.5。
步骤三：12-(二甲氨基)-2-(8-(二甲氨基)-8-氧代辛基)-3，12-二氧代十二酸甲酯(化合物VI)的制备
Figure PCTCN2022131794-appb-000014
实施例3
在配备两个100mL恒压滴液漏斗和三通氮气球的250mL三颈瓶中，称取10-(二甲氨基)-10-氧代癸酸甲酯(化合物(V))(1.0当量，10g，41.09mmol)，溶于50mL二氯甲烷中，抽换氮气保护，将装置冷却到0℃，称取四氯化钛(1.2当量，9.35g，49.31mmol)并用注射器注入恒压滴液漏斗以滴加进反应液中，滴加完成后保温5分钟，此时溶液呈橙色，再称取三乙胺(1.4当量，5.82g，57.53mmol)并用注射器注入恒压滴液漏斗以滴加进反应液中，反应液变黑色伴有白烟产生，滴加完成后使反应保温1小时。反应结束后，在0℃加等体积水淬灭，分出有机相，水相用二氯甲烷50mL萃取两次，合并的有机相用水、饱和氯 化钠溶液洗涤，经无水硫酸钠干燥，旋转蒸发除去溶剂而得到粗品，经柱层析(乙酸乙酯∶正己烷＝2∶1和二氯甲烷∶甲醇＝50∶1，V/V，洗脱)得到12-(二甲氨基)-2-(8-(二甲氨基)-8-氧代辛基)-3，12-二氧代十二酸甲酯(化合物(VI))黄色油状物8g，收率86％，无需进一步纯化即可直接用于下一步。
1H NMR(600MHZ，CDCl 3)δ3.70-3.69(m，3H)，3.42-3.39(m，1H)，2.98(s，6H)，2.92(s，6H)，2.54-2.41(m，2H)，2.29-2.26(m，4H)，1.83-1.77(m，2H)，1.59-1.53(m，6H)，1.28-1.26(m，16H).
13C NMR(CDCl 3)δ205.6，173.3，173.3，170.5，59.0，52.4，42.0，37.4，35.4，33.4，33.4，29.5，29.4，29.3，29.3，29.2，29.0，28.3，27.5，25.2，25.2，23.5.
LC-MS(ESI)：计算值(M+H)：455.35，实测值：455.6。
步骤四：10-氧代十九烷二酸的制备
Figure PCTCN2022131794-appb-000015
实施例4
在500mL烧瓶中称取12-(二甲氨基)-2-(8-(二甲氨基)-8-氧代辛基)-3，12-二氧代十二酸甲酯(化合物(VI))(1.0当量，27g，59.34mmol)、氢溴酸(48％水溶液，135mL)，在120℃回流20小时。反应结束后冷却至室温，加入135mL水，冷却至-10℃并搅拌10分钟以使产物充分析出，经抽滤得固体粗品25.4g。
重结晶纯化：在500mL烧瓶中加入所得的粗品25.4g，加入乙腈230mL，加热至80℃并回流半小时使固体完全溶解，然后冷却至-10℃，析出产品，经抽滤并干燥得到10-氧代十九烷二酸(化合物(II))19.3g，收率95％，为类白色固体，HPLC归一化法检测纯度为99％。
1H NMR(DMSO-d6)δ11.94(brs，1H)，2.37(t，J＝7.3，4H)，2.18(t，J＝7.5，4H)，1.50-11.41(m，8H)，1.24-1.19(m，16H).
13C NMR(DMSO-d6)δ210.6，174.5，41.8，33.7，28.8，28.7，28.6，28.5，24.5，23.3.
LC-MS(ESI)：计算值(M-1)：341.23，实测值：341.4。
如上述实施例中所示出的，按照本发明所述的制备方法，以癸二酸单甲酯(化合物(IV))为初始原料制备10-氧代十九烷二酸的总收率为约52％，且副反应少、工艺简单、易于控制、安全性高，对设备要求低，具有适合工业化运用的很多优点。
由下文提供的对比实施例，进一步说明本发明方法的优点及益处：
对比例1：按照WO 2013/086322 A1报道的制备方法制备10-氧代十九烷二酸
Figure PCTCN2022131794-appb-000016
取500mL烧瓶称取1，3-丙酮二羧酸二乙酯(1.0当量，27.19g，134.46mmol)，将乙醇钠(1.0当量，9.15g，134.47mmol)溶于70mL乙醇，加入反应液。装置加热至80℃回流，缓慢加入8-溴辛酸乙酯(1.0当量，33.77g，134.47mol)，滴加完成后保温反应2h，再称取乙醇钠(1.0当量，9.15g，134.47mmol)溶于70mL乙醇，加入反应液，保温反应半小时后滴加8-溴辛酸乙酯(1.0当量，33.77g，134.47mol)，滴加完成后回流过夜。TLC中控困难，极性接近，副反应多，旋蒸除去溶剂，加水用乙酸乙酯萃取，旋蒸得74.2g浑浊油。加入135mL浓盐酸，67.5mL冰醋酸120℃回流过夜。反应结束冷却至室温，旋蒸除去溶剂，加水，体系呈粘稠糊状，加入丙酮打浆，抽滤得粘稠固体49g。TLC监测，溴甲酚绿染色至少有三个组分，取49g粗品，加125mL丙酮，加热至60℃回流溶解，冷却至-10℃析出固体，抽滤得蜡状湿粘固体5.8g，产率13％，核磁图谱如图5所示，显示有较多杂质，纯度低。
如前文所述，该方案采用的原料8-溴辛酸乙酯与本申请方法中所用的起始原料癸二酸二甲酯相比，价格昂贵且副反应多，产率明显低于本发明方法；且由其所得产品的核磁共振图谱可看出所得产品的纯度明显低于由本申请的方法所得的产品。
对比例2：按照文献《Claisen Condensation.A Method for the Synthesis of Long Chain Dicarboxylic Acids》报道的方法制备10-氧代十九烷二酸
Figure PCTCN2022131794-appb-000017
步骤一：
在500mL烧瓶中称取癸二酸单甲酯(1.0当量，12.47g，57.63mmol)，并加入二氯甲烷(100mL)和二甲亚砜(2.0当量，13.71g，115.26mmol)，将反应混合物在室温搅拌2小时，旋转蒸发除去溶剂和二甲亚砜后，将残余物溶于50mL四氢呋喃，冷却至5℃，并滴加二甲胺水溶液(10.0当量，65mL，576.3mmol)，将反应混合物在室温搅拌过夜。最后向所得反应混合物加入水100ml，经二氯甲烷萃取并蒸干溶剂得到6g黄色油状物，经柱层析(乙酸乙酯∶正己烷＝2∶1，V/V)得到10-(二甲氨基)-10-氧代癸酸甲酯4.92g，产率35％，为黄色油状物，HPLC归一化法检测纯度为71％。
相比之下，在本发明相应步骤二中，仅以单步反应即可制备得到10-(二甲氨基)-10-氧代癸酸甲酯，且产品无需进一步的纯化，即可用于下一步；而在本步骤中，原料癸二酸单甲酯需经氯化、再与二甲胺缩合两步反应才能制备得到产品，反应复杂，副反应多，产品需要纯化后才能用于后续步骤，且纯度不高。可以看出，本申请提供的方法转化率高、副反应少且易于控制，具有明显的优势。
步骤二：
氮气保护下在25mL烧瓶中称取单质钠(0.5当量，189mg，8.22mmol)，用注射器取5mL无水甲醇注入反应瓶，产生大量氢气，搅拌半小时使固体完全溶解。减压蒸去甲醇，瓶底有白色固体甲醇钠粉末。加入10-(二甲氨基)-10-氧代癸酸甲酯(1.0当量，4g，16.44mmol)，反应液变为棕色胶体，在50℃反应1.5小时，抽真空并在减压下于60℃过夜。反应结束后得到呈棕色干胶状的反应物，向其中加入10ml水，用稀盐酸调至PH＝4，用乙酸乙酯萃取，旋转蒸发溶剂，得到粗棕色油状物3g，薄层色谱显示有较多原料10-(二甲氨基)-10-氧代癸酸甲酯剩余，经过柱层析(二氯甲烷∶甲醇＝50∶1)得到12-(二甲氨基)-2-(8-(二 甲氨基)-8-氧代辛基)-3，12-二氧代十二酸甲酯1.0g，产率27％，为黄色油状物，HPLC归一化法检测纯度为72％。
上述步骤二必须采用金属钠与甲醇进行反应以得到甲醇钠，然而对本领域技术人员公知的是，工业生产中制备甲醇钠，要求高、安全性差，并且需要减压加热反应，对设备要求也很高。
相比之下，在本申请的相应步骤三中，，采用了缩合剂四氯化钛替代现有技术中使用的金属钠，同时，由前文所述可发现，本申请的上述方法不涉及如真空加热反应等对设备要求高、不易操作的步骤，反应条件温和，易于操作和控制。因而非常适合工业化生产。
步骤三：
在50mL烧瓶中称取12-(二甲氨基)-2-(8-(二甲氨基)-8-氧代辛基)-3，12-二氧代十二酸甲酯(1.0当量，1.0g，2.36mmol)、氢溴酸(48％水溶液，5mL)，在115℃加热至回流过夜。反应结束后冷却至室温，加入5mL水，搅拌30分钟使产物充分析出，经抽滤得10-氧代十九烷二酸固体粗品600mg。
重结晶纯化：在50mL烧瓶中放入所得粗品600mg，加入乙腈15mL(25倍体积)，加热至80℃回流半小时使固体完全溶解，后冷却至10℃，产品析出，经抽滤得10-氧代十九烷二酸550mg，收率68％，为灰白色固体，HPLC归一化法检测纯度为77％。
与上述对比例2中所述合成10-氧代十九烷二酸的方法相比，本申请所述的10-氧代十九烷二酸的制备方法转化率高、步骤更简单、副反应少，易于控制且安全性高。
综上所述，与现有技术相比，本申请所述10-氧代十九烷二酸的制备方法转化率高，副反应少，工艺简单，且步骤二和步骤三产品无需进一步纯化，即可用于后续步骤，易于控制，安全性高，对设备要求低，适合工业化运用，具有巨大的经济潜力。
对于本领域技术人员来说，很明显，本公开不局限于上述说明性的实施例，并且在不背离本公开实质特性的条件下，其可以通过其它具体形式来具体实施。因此，期望在各方面都认为这些实施例是说明性的和非限制性的，应参照的是附加的权利要求，而不是上述实施例，且由此在权利要求的等效含义和范围内的所有变化都被包括在其中。

Claims (11)

  1. 一种制备10-氧代十九烷二酸的方法，包括如下步骤：
    使化合物(V)：10-(二甲氨基)-10-氧代癸酸甲酯在缩合剂的作用下进行克莱森缩合而得到化合物(VI)：12-(二甲氨基)-2-(8-(二甲氨基)-8-氧代辛基)-3，12-二氧代十二酸甲酯：
    Figure PCTCN2022131794-appb-100001
    其中，所述缩合剂为四氯化钛；然后
    将化合物(VI)在酸的作用下而得到10-氧代十九烷二酸；
    所述酸选自氢卤酸中的一种或多种。
  2. 权利要求1所述的方法，其中所述化合物(V)与缩合剂的摩尔比为1∶1.0-1∶2.0；更优选为1∶1.2。
  3. 权利要求1所述的方法，其中还加入了缚酸剂，所述缚酸剂选自吡啶、三乙胺、二乙胺、碳酸钾、碳酸钠、正丁胺、碳酸氢钾、碳酸氢钠；优选地，所述缚酸剂为三乙胺。
  4. 权利要求3所述的方法，其中所述化合物(V)与缚酸剂的摩尔比为1∶1.0-1∶2.0；优选为1∶1.4。
  5. 权利要求1所述的方法，其中所述化合物(V)：10-(二甲氨基)-10-氧代癸酸甲酯通过在缩合剂的作用下，使化合物(IV)与盐酸二甲胺反应而得到：
    Figure PCTCN2022131794-appb-100002
    其中，所述缩合剂选自DCC、DIC、EDCI中的一种或多种。
  6. 权利要求5所述的方法，其中所用的缩合剂为EDCI。
  7. 权利要求5所述的方法，其中所述化合物(IV)与盐酸二甲胺的摩尔比为1∶1.0-1∶1.6；优选为1∶1.3。
  8. 权利要求5所述的方法，其中所述化合物(IV)与缩合剂的摩 尔比为1∶1.0-1∶2.0；优选为1∶1.5。
  9. 权利要求5所述的方法，其中还加入了催化剂，所述催化剂为DMAP。
  10. 权利要求5所述的方法，其中还加入了缚酸剂，所述缚酸剂选自吡啶、N，N-二异丙基乙胺、三乙胺、碳酸铯、碳酸钾、碳酸钠、正丁胺、碳酸氢钾、碳酸氢钠；优选地，所述缚酸剂为吡啶。
  11. 权利要求10所述的方法，其中所述化合物(IV)与缚酸剂的摩尔比为1∶2.0-1∶3.2；优选为1∶2.8。
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