CN111925298B - 4-CNAB and preparation method thereof - Google Patents

4-CNAB and preparation method thereof Download PDF

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CN111925298B
CN111925298B CN202010910018.0A CN202010910018A CN111925298B CN 111925298 B CN111925298 B CN 111925298B CN 202010910018 A CN202010910018 A CN 202010910018A CN 111925298 B CN111925298 B CN 111925298B
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黄春
陆叶梦
王旭阳
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Wuxi Yeshan Pharmaceutical Co ltd
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    • 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
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Abstract

The invention discloses a 4-CNAB and a preparation method thereof, belonging to the field of medicine preparation, and the technical scheme is that the preparation method comprises the following steps of S1: adding 4-chlorosalicylic acid into dichloromethane, adding sodium bentonite and N, N-carbonyl diimidazole, then adding 4-aminobutyric acid ethyl ester hydrochloride, dropwise adding triethylamine, adding a dilute hydrochloric acid solution, adjusting the pH value to be 4.5-5, carrying out suction filtration, collecting filtrate, sequentially extracting with dilute ammonia water, pure water and saturated sodium chloride solution, and concentrating an organic phase to obtain an intermediate I; s2: dissolving the intermediate I by using a sodium hydroxide solution, dropwise adding a dilute hydrochloric acid solution, regulating the pH value to 4.5-5, separating out a product, carrying out suction filtration, and drying to obtain free acid; s3: dissolving the free acid in isopropanol, adding sodium hydroxide solution, reacting for 1h, adding isopropanol, reacting for 1-2h, filtering, and drying to obtain 4-CNAB. The method has the advantages of high yield of each step, good product purity and easy suction filtration of salified products.

Description

4-CNAB and preparation method thereof
Technical Field
The invention relates to the technical field of medicine preparation, in particular to 4-CNAB and a preparation method thereof.
Background
Sodium 4- (2-hydroxy-4-chlorobenzoylamino) butyrate (4-CNAB) is a novel pharmaceutical adjuvant, and the 4-CNAB in the present application is sodium 4- (2-hydroxy-4-chlorobenzoylamino) butyrate. 4-CNAB is an analogue of sodium 8- (2-hydroxybenzoamido) octoate (SNAC), which is a dicarboxphosphate compound absorption enhancer, for treating gastrointestinal diseases, especially gastrointestinal diseases caused by malabsorption of dicarboxphosphate compound.
Recently, the first oral GLP-1 hypoglycemic drug in the world, ma Lutai FDA, was marketed in bulk. Since cable Ma Lutai is a polypeptide drug, the challenge of degrading various peptidases in the intestinal tract is faced when the drug is taken orally and absorbed in the intestinal tract. Researchers have formed oral formulations by combining cord Ma Lutai with a small molecule absorption enhancer SNAC, which in combination with SNAC allows cord Ma Lutai to complete absorption in the stomach and partial dissolution of SNAC can create a relatively high pH environment locally in the stomach, thereby increasing the solubility of cord Ma Lutai and reducing degradation of the gastric peptidase. Therefore, novel pharmaceutical excipients such as SNAC, 4-CNAB and the like are very important for developing new dosage forms, and have very important market application prospects.
The preparation of 4-CNAB was reported in patent US2004048777A1, using the synthetic route shown below. The route is a common method for synthesizing similar polypeptide, wherein the carboxyl on one side is protected by ethyl ester, the synthesis of an amide bond is firstly carried out, then the ethyl ester is hydrolyzed, and finally the monosodium salt is formed.
The synthesis method described in this patent has the following problems:
(1) The overall yield is very low, and the yield of the free acid obtained by the previous two steps is only 37%;
(2) The purity of the product is not high, mainly because mono-hetero 4-chlorosalicylic acid in the free acid is difficult to remove, the content of 4-chloro salicylic acid in the free acid in the unpurified stage can reach about 5%, so the loss in the purification process is large, and the yield in the problem (1) is low;
(3) The final step of salification can obtain jelly-like products, and suction filtration can not be performed at all.
Disclosure of Invention
The invention aims to provide the 4-CNAB and the preparation method thereof, and the invention has the advantages of high yield of each step, good product purity and easy suction filtration of salified products.
The technical aim of the invention is realized by the following technical scheme:
a method for preparing 4-CNAB, comprising the following steps:
s1: adding 4-chlorosalicylic acid into dichloromethane, adding sodium bentonite, then adding N, N-carbonyl diimidazole, after the reaction is finished, adding 4-aminobutyric acid ethyl ester hydrochloride, and then dropwise adding triethylamine to prepare a reaction solution; adding a dilute hydrochloric acid solution into the reaction solution, adjusting the pH value of the reaction solution to 4.5-5, separating out a product, filtering to obtain a filter cake, and collecting a filtrate; sequentially extracting with dilute ammonia water, pure water and saturated sodium chloride solution, and concentrating the organic phase to obtain an intermediate I;
s2: dissolving the intermediate I by using a sodium hydroxide solution, dropwise adding a dilute hydrochloric acid solution, adjusting the pH to 4.5-5, separating out a product, performing suction filtration to obtain a filter cake, and drying the filter cake to obtain free acid;
s3: dissolving free acid in isopropanol, dropwise adding sodium hydroxide solution, reacting for 1h, adding isopropanol, continuing to react for 1-2h, filtering to obtain a filter cake, and drying the filter cake to obtain 4-CNAB;
the reaction route of the preparation process is as follows:
Figure BDA0002662925870000031
further, the ratio of the using amount of the methylene dichloride in the S1 to the raw material 4-chlorosalicylic acid is 4-5:1V/W; the ratio of the dosage of the sodium bentonite to the raw material 4-chlorsalicylic acid is 0.5-1:1W/W; the ratio of the N, N-carbonyl diimidazole to the raw material 4-chlorsalicylic acid is 1.00-1.10:1W/W, and the reaction is carried out for 1.5-2h after the addition is finished; the ratio of the dosage of the ethyl 4-aminobutyric acid hydrochloride to the raw material 4-chlorsalicylic acid is 1.00-1.10:1W/W; the ratio of the using amount of the triethylamine to the raw material 4-chlorsalicylic acid is 1.0-1.2:1V/W; the reaction temperature after the addition of the ethyl 4-aminobutyric acid hydrochloride and the triethylamine is 20-30 ℃ and the reaction time is 22-30h.
Further, an equal volume of dilute hydrochloric acid solution is added into the S1, and the solubility of the dilute hydrochloric acid solution is 1-2mol/L.
Further, the concentration of the sodium hydroxide solution in the S2 is 1-2mol/L, the temperature of the reaction solution is regulated to be below 10 ℃ after the intermediate I is dissolved by the sodium hydroxide solution, and 1-2mol/L of dilute hydrochloric acid solution is added dropwise.
Further, after suction filtration in the step S2, the filter cake is dried in vacuum at 45-55 ℃.
Further, the ratio of the amount of the isopropyl alcohol added for the first time in the step S3 to the free acid is 8-9:1V/W; the ratio of the sodium hydroxide solution to the free acid is 0.30-0.32:1W/W; the ratio of the amount of the added isopropanol to the free acid is 5-6:1V/W.
Further, when the isopropanol in the S3 dissolves the free acid, the temperature is raised to 40-50 ℃, the mixture is stirred until the free acid is completely dissolved, and the concentration of the dropwise added sodium hydroxide is 40-50wt%.
In summary, the invention has the following beneficial effects:
1. the yield of the product in S2 is improved. The yield of the previous two steps of reaction is only 33-37%, the yield reaches 64.2-73.7% and the product purity reaches more than 99.7% through optimization;
the molar ratio of three main reactants in S1 is close to 1:1:1, the first reaction step of the invention ensures that 4-chlorosalicylic acid in the first reaction stage preferentially forms carbonyl imidazole ester by adding sodium bentonite, and the reaction directly generates an amide bond along with the addition of ethyl aminobutyrate hydrochloride, so that the invention has no too many side reactions; in the original document, 2 equivalents of 4-chlorosalicylic acid only consume 1 equivalent of CDI due to intermolecular condensation of part of 4-chlorosalicylic acid to form ester, so that the CDI is excessive, and with the addition of ethyl aminobutyrate hydrochloride, the ethyl aminobutyrate is subjected to intermolecular condensation to form urea (the side reaction path is as follows);
Figure BDA0002662925870000041
3. the crude free acid of the method described in the prior patent has more impurities, so that 2 times of methanol/water recrystallization are needed to obtain a product with higher purity, but the operation is complicated and the yield is reduced. According to the invention, by designing a mode of washing with dilute ammonia water, part of unconverted 4-chlorosalicylic acid (main impurities) is removed, the recrystallization step of methanol/water in the original patent is reduced, a great amount of material loss generated by crystallization is avoided, the operation is simplified, the high-purity product in S2 is obtained, the yield reaches 64.2-73.7%, and the purity of the product reaches more than 99.7%;
and 4. The operation difficulty of the S3 step is reduced, the acetone used in the original patent can enable the final product to be in a jelly shape, the solvent can be dried by spin evaporation to obtain monosodium salt after practice, the operation is not suitable for large-scale production, and the uniformity of the product is poor. Through experimental attempts (including methanol, ethanol and isopropanol) of different hydrophilic solvents, only isopropanol is found to obtain a reaction solution which is easy to pump and filter. The process which is easy to amplify can be obtained by optimizing and selecting the mode of adding isopropanol once in the middle, and the solvent residue of the final product can meet the limit requirement of ICH.
Drawings
FIG. 1 is a schematic flow chart of a process for preparing 4-CNAB of the invention;
FIG. 2 is an HPLC chart of product 4-CNAB of example 1 of the present invention;
FIG. 3 is a free acid in S2 of example 1 of the present invention 1 HNMR profile;
FIGS. 4 and 5 are MS spectra (positive and negative ion modes) of the product 4-CNAB of example 1 of the present invention;
FIG. 6 is a sample of the 4-CNAB product of example 1 of the invention 1 HNMR profile;
FIG. 7 is a schematic diagram of the 4-CNAB product of example 1 of the present invention 13 C NMR spectrum.
Detailed Description
The present invention will be described in further detail with reference to the accompanying drawings.
The following description of the embodiments of the present invention will be made clearly and completely, and it is apparent that the described embodiments are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
It will be understood that terms, such as "having," "including," and "comprising," as used herein, do not preclude the presence or addition of one or more other elements or groups thereof.
Example 1:
as shown in fig. 1, a preparation method of 4-CNAB comprises the following steps:
s1: 5.0062g of 4-chlorosalicylic acid are weighed into a 100mL reaction flask, 20mL of dichloromethane is added, 2.5072g of sodium bentonite is added, 5.1772g of N, N-carbonyldiimidazole is slowly added under stirring, and a large amount of gas is generated. After the addition was completed, stirring was continued at room temperature for 1.5 hours. Adding 5.3507g of ethyl 4-aminobutyrate hydrochloride, dropwise adding 6ml of triethylamine, and stirring at 25 ℃ for reacting for 22 hours to obtain a reaction solution;
transferring the reaction liquid into a separating funnel, adding dilute hydrochloric acid with the same volume of 2mol/L into the reaction liquid, adjusting the pH value of the reaction liquid to 4.5-5, fully shaking, precipitating a large amount of solids, carrying out suction filtration (diatomite assisted filtration) to obtain a filter cake, and collecting filtrate; then the mixture was extracted with dilute ammonia water, pure water and saturated sodium chloride solution in this order, and the organic phase was concentrated to obtain 7.2g of intermediate I.
S2: the intermediate I in S1 is placed in a concentration bottle, 144ml of 2mol/L sodium hydroxide solution is added, the temperature of the reaction solution is controlled to be 25 ℃, and the reaction is stirred until all solids are dissolved. The reaction solution is cooled to below 10 ℃,2mol/L of dilute hydrochloric acid is added dropwise, the pH is regulated to 5, a large amount of solids are separated out at the moment, a filter cake is obtained through suction filtration, and 4.8g of free acid is obtained through vacuum drying of the filter cake at 50 ℃.
The yield of the free acid produced in S1 and S2 was 64.2% and the purity was 99.60%. Of free acids 1 The H-NMR spectrum is shown in FIG. 3, which is resolved as follows, 1 H-NMR(500MHz,DMSO-d6)δ:12.98(1H,s,COOH),12.09(1H,s,OH),8.87(1H,s,NH),7.89(1H,d,Ar-H),6.95～6.99(2H,Ar-H),3.34(2H,m,CH 2 adjacent to NH),2.30(2H,m,CH 2 adjacent to COOH),1.80(2H,m,CH 2 betato COOH). Consistent with that described in US2004048777 A1.
S3: 4.0g of free acid is weighed and dissolved in 32mL of isopropanol, the temperature is raised to 50 ℃, the mixture is stirred until the free acid is completely dissolved, 1.2446g of 50% sodium hydroxide solution is added dropwise, the reaction is continued for 1h, 20mL of isopropanol is added, and the reaction is continued for 1.5h. And cooling the reaction solution to room temperature, carrying out suction filtration, washing a filter cake with a small amount of isopropanol, and drying the filter cake in a vacuum drying oven at 50 ℃ to obtain 4.1g of 4-CNAB finished product. The purity was 99.71%, the single impurity was less than 0.1%, and the HPLC profile was shown in FIG. 2.
The reaction route of the preparation process is as follows:
Figure BDA0002662925870000071
the MS spectra (positive and negative ion modes) of 4-CNAB in this example are shown in FIGS. 4 and 5, in which the mass-to-charge ratio m/z=258.0 [ M+H ]] + ,m/z＝280.0[M+Na] + ,m/z＝256.0[M-H] - It can be inferred that the molecular weight was 257, which was consistent with the target compound.
As shown in FIG. 6, the present example 4-CNAB 1 An H-NMR spectrum, wherein, 1 H-NMR(500MHz,DMSO-d6)δ:8～16(2H,br,NH and OH)，7.74(1H,d,Ar-H)，6.67(1H,s,Ar-H)，6.44(1H,d,Ar-H),3.27(2H,m,CH 2 adjacent to NH)，2.18(2H,m,CH 2 adjacent to COOH),1.73(2H,m,CH 2 betato COOH)。
as shown in FIG. 7, the present example 4-CNAB 13 C-NMR spectrum, wherein, 13 C-NMR(125MHz,DMSO-d6)δ:175.738,167.02,166.495,135.92,130.641,118.778,117.253,112.86,38.313,33.311,25.503。
example 2:
s1: 50g of 4-chlorosalicylic acid are weighed into a 1L reaction bottle, 250ml of dichloromethane is added, 50g of sodium bentonite is added, 50g of N, N-carbonyl diimidazole is slowly added under stirring, and a large amount of gas is generated. After the addition was completed, stirring was continued at room temperature for 2 hours. 50g of ethyl 4-aminobutyrate hydrochloride was added thereto, 50ml of triethylamine was then added dropwise thereto, and the mixture was stirred at 20℃for reaction for 30 hours to obtain a reaction solution.
Transferring the reaction liquid into a separating funnel, adding dilute hydrochloric acid with the same volume of 2mol/L into the reaction liquid, adjusting the pH value of the reaction liquid to 5, fully shaking and then separating out a large amount of solids, carrying out suction filtration (diatomite assisted filtration) to obtain a filter cake, and collecting filtrate; then the mixture was extracted with dilute ammonia water, pure water and saturated sodium chloride solution in this order, and the organic phase was concentrated to obtain 74.2g of intermediate I.
S2: placing the intermediate I in the S1 in a concentration bottle, adding 2mol/L sodium hydroxide solution 1.1L, controlling the temperature of the reaction solution to 20 ℃, and stirring to react until all solids are dissolved. The reaction solution is cooled to below 10 ℃,2mol/L of dilute hydrochloric acid is added dropwise, the pH is regulated to 5, a large amount of solids are separated out at the moment, a filter cake is obtained through suction filtration, and 55g of free acid is obtained through vacuum drying of the filter cake at 50 ℃. The yield of the free acid produced for S1 and S2 was 73.7% and the purity was 99.77%.
S3: 55g of free acid is weighed and dissolved in 495mL of isopropanol, the temperature is raised to 50 ℃, the mixture is stirred until the free acid is completely dissolved, 17.1g of 50% sodium hydroxide solution is added dropwise for continuous reaction for 1h, 275mL of isopropanol is added, and the reaction is continued for 1.5h. And cooling the reaction solution to room temperature, carrying out suction filtration, washing a filter cake with a small amount of isopropanol, and drying the filter cake in a vacuum drying oven at 50 ℃ to obtain 56.2g of 4-CNAB finished product with the purity of 99.80%.
Example 3:
s1: 200g of 4-chlorosalicylic acid are weighed into a 2L reaction bottle, 800ml of dichloromethane is added, 150g of sodium bentonite is added, 220g of N, N-carbonyl diimidazole is slowly added under stirring, and a large amount of gas is generated. After the addition was completed, the reaction flask was moved into an oil bath at 25℃and stirring was continued at room temperature for 2 hours. 220g of ethyl 4-aminobutyrate hydrochloride and 220ml of triethylamine are added dropwise, and the mixture is heated to 30 ℃ and stirred for reaction for 26 hours to prepare a reaction solution.
Transferring the reaction liquid into a separating funnel, adding dilute hydrochloric acid with the same volume of 2mol/L into the reaction liquid, adjusting the pH value of the reaction liquid to 5, fully shaking and then separating out a large amount of solids, carrying out suction filtration (diatomite assisted filtration) to obtain a filter cake, and collecting filtrate; then, the mixture was extracted with dilute ammonia water, pure water and saturated sodium chloride solution in this order, and 298g of intermediate I was obtained by concentrating the organic phase.
S2: to a 10L reactor was added 3L of 2mol/L sodium hydroxide solution, 298g of intermediate I was added to the reactor, the reaction solution temperature was controlled at 30℃and the reaction was stirred until all solids were dissolved. Cooling the reaction solution to below 10 ℃, dropwise adding 2mol/L of dilute hydrochloric acid, regulating the pH to 5, precipitating a large amount of solid at the moment, filtering to obtain a filter cake, and drying the filter cake in vacuum at 50 ℃ to obtain 197g of free acid. The yield of the free acid obtained in S1 and S2 was 66% and the purity was 99.73%.
S3: 1.6L of isopropanol was added to a 10L reactor, 197g of free acid was added, the temperature was raised to 50 ℃, stirring was carried out until complete dissolution, 61g of 50% sodium hydroxide solution was added dropwise, the reaction was continued for 1 hour, 1180mL of isopropanol was added, and the reaction was continued for 1.5 hours. And cooling the reaction liquid to room temperature, carrying out suction filtration, washing a filter cake with a small amount of isopropanol, and drying the filter cake in a vacuum drying oven at 50 ℃ to obtain 201g of 4-CNAB finished product with purity of 99.77%.
The present embodiment is only for explanation of the present invention and is not to be construed as limiting the present invention, and modifications to the present embodiment, which may not creatively contribute to the present invention as required by those skilled in the art after reading the present specification, are all protected by patent laws within the scope of claims of the present invention.

Claims (7)

1. A method for preparing 4-CNAB, comprising the steps of:
s1: adding 4-chlorosalicylic acid into dichloromethane, adding sodium bentonite, then adding N, N-carbonyl diimidazole, after the reaction is finished, adding 4-aminobutyric acid ethyl ester hydrochloride, and then dropwise adding triethylamine to prepare a reaction solution; adding a dilute hydrochloric acid solution into the reaction solution, adjusting the pH value of the reaction solution to 4.5-5, separating out a product, filtering to obtain a filter cake, and collecting a filtrate; sequentially extracting the filtrate with dilute ammonia water, pure water and saturated sodium chloride solution, and concentrating the organic phase to obtain an intermediate I;
s2: dissolving the intermediate I by using a sodium hydroxide solution, dropwise adding a dilute hydrochloric acid solution, adjusting the pH to 4.5-5, separating out a product, performing suction filtration to obtain a filter cake, and drying the filter cake to obtain free acid;
s3: dissolving free acid in isopropanol, dropwise adding sodium hydroxide solution, reacting for 1h, adding isopropanol, continuing to react for 1-2h, filtering to obtain a filter cake, and drying the filter cake to obtain 4-CNAB;
the reaction route of the preparation process is as follows:
Figure FDA0003892471240000011
2. the process for the preparation of 4-CNAB as defined in claim 1, wherein: the ratio of the using amount of the methylene dichloride in the S1 to the raw material 4-chlorosalicylic acid is 4-5:1V/W; the ratio of the dosage of the sodium bentonite to the raw material 4-chlorsalicylic acid is 0.5-1:1W/W; the ratio of the N, N-carbonyl diimidazole to the raw material 4-chlorsalicylic acid is 1.00-1.10:1W/W, and the reaction is carried out for 1.5-2h after the addition is finished; the ratio of the dosage of the ethyl 4-aminobutyric acid hydrochloride to the raw material 4-chlorsalicylic acid is 1.00-1.10:1W/W; the ratio of the using amount of the triethylamine to the raw material 4-chlorsalicylic acid is 1.0-1.2:1V/W; the reaction temperature after the addition of the ethyl 4-aminobutyric acid hydrochloride and the triethylamine is 20-30 ℃ and the reaction time is 22-30h.
3. The method for preparing 4-CNAB according to claim 1, wherein: and adding an equal volume of dilute hydrochloric acid solution into the S1, wherein the solubility of the dilute hydrochloric acid solution is 1-2mol/L.
4. The method for preparing 4-CNAB according to claim 1, wherein: the concentration of the sodium hydroxide solution in the S2 is 1-2mol/L, after the intermediate I is dissolved by the sodium hydroxide solution, the temperature of the reaction solution is regulated to be below 10 ℃, and 1-2mol/L of dilute hydrochloric acid solution is added dropwise.
5. The method for preparing 4-CNAB according to claim 1, wherein: and (3) after suction filtration in the step S2, vacuum drying the filter cake at 45-55 ℃.
6. The method for preparing 4-CNAB according to claim 1, wherein: the ratio of the dosage of the isopropanol added for the first time in the S3 to the free acid is 8-9:1V/W; the ratio of the sodium hydroxide solution to the free acid is 0.30-0.32:1W/W; the ratio of the amount of the added isopropanol to the free acid is 5-6:1V/W.
7. The method for preparing 4-CNAB according to claim 1, wherein: and when the isopropanol in the S3 dissolves the free acid, heating to 40-50 ℃, stirring until the isopropanol is completely dissolved, and dropwise adding sodium hydroxide with the concentration of 40-50wt%.
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