Preparation method of fatty diacid mono-tert-butyl ester and intermediate compound of fatty diacid mono-tert-butyl ester

Abstract

The invention belongs to the technical field of synthesis of medical intermediates, and particularly relates to a preparation method of fatty diacid mono-tert-butyl ester and an intermediate compound of the fatty diacid mono-tert-butyl ester. According to the preparation method, alkyl diacid monobenzyl ester is subjected to acyl halogenation, esterification and hydrogenation to prepare a target product. The target product obtained by the preparation method is high in yield (more than 75%) and high in purity (more than 99.3%), the reaction operation and post-treatment are simplified, the production safety is improved, the production cost is reduced, and the preparation method is more suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical intermediate synthesis, and particularly relates to a preparation method of fatty diacid mono-tert-butyl ester and an intermediate compound thereof. Background Art

[0002] Most long-chain alkyl diacid mono-tert-butyl esters are important intermediates in organic synthesis, especially in the pharmaceutical field as intermediates for the synthesis of important drugs. Among them, octadecane diacid mono-tert-butyl ester is used as an intermediate for the synthesis of semaglutide, which is an analog of glucagon-like peptide-1 (GLP-1). Semaglutide is the world's first and only oral glucagon-like peptide-1 receptor agonist drug. Semaglutide tablets have been approved by the US FDA to improve blood sugar control in adult patients with type 2 diabetes. It is a new type of hypoglycemic and weight-loss drug. Octadecanedioic acid mono-tert-butyl ester is the key raw material for the synthesis of the new hypoglycemic and weight-loss drug semaglutide, but octadecane diacid mono-tert-butyl ester is expensive and difficult to synthesize.

[0003] CN1829738A discloses using N,N-dimethylformamide di-tert-butyl acetal as a tert-butyl esterification reagent, separating the target product by recrystallization or column chromatography, with a yield of 33%; or using di-tert-butyl dicarbonate and N,N-dimethylaminopyridine as a tert-butyl esterification system, separating the target product by column chromatography, with a yield of 53%.

[0004] After the reaction, the product contains a large amount of raw materials and di-tert-butyl ester impurities, which is difficult to purify and has a low yield.

[0005]

[0006] CN117263796 discloses that octadecane dioic acid is subjected to a cyclization reaction to generate octadecane dioic anhydride; and then octadecane dioic anhydride is reacted with tert-butyl alcohol to generate octadecane dioic anhydride mono-tert-butyl ester. Although the synthesis route of this method is short, the yield is low, and the two-step yield is only 47%. In the second step post-treatment process, the pH needs to be adjusted to a strong acid. However, the tert-butyl group is extremely unstable under acidic conditions, so raw material impurities are easily generated, which brings difficulties to subsequent purification.

[0007]

[0008] CN111875495A discloses that 18-carbon dicarboxylic acid monomethyl ester is obtained by reflux esterification of sebacic acid and methanol, and then 18-carbon dicarboxylic acid monomethyl ester is reacted with isobutylene under the action of a composite catalyst, concentrated, and then the concentrated solution is alkalized, extracted, dried and filtered to obtain 18-carbon dicarboxylic acid monotert-butyl ester. This route has a total of 5 steps, with a total yield of 21%, poor reaction selectivity, and a yield of only 46% when the reduction reaction is performed in the second step. The selectivity is poor in the fourth and fifth steps, and disubstituted impurities are easily generated. Column chromatography is also required for purification during the reaction process, and the overall operation is complicated, which is not conducive to industrial production.

[0009] Summary of the invention

[0010] In order to overcome the defects of the existing preparation method of fatty diacid mono-tert-butyl ester, such as many reaction impurities, difficult purification, low yield, poor atom economy and unsuitability for industrial production, the present invention provides a preparation method of fatty diacid mono-tert-butyl ester and an intermediate compound thereof. The intermediate compound of the present invention can be used to prepare a target product with high purity and high yield, the reagents used are more economical, the preparation cost is low, and the post-processing is simple, which is suitable for industrial production.

[0011] In a first aspect, the present invention provides a method for preparing a fatty diacid mono-tert-butyl ester represented by formula (I), comprising: a. subjecting a compound represented by formula (II) to an acyl halide reaction with an acyl halide reagent, and then subjecting the compound represented by formula (III) to an esterification reaction with tert-butyl alcohol to obtain a compound represented by formula (III); b. subjecting the compound represented by formula (III) to palladium-carbon catalytic hydrogenation debenzylation to obtain a compound represented by formula (I);

[0012]

[0013] Here, n is an integer from 8 to 18.

[0014] In some embodiments, the reaction temperature of the acyl halide reaction is 25-30° C., the reaction time is 2-4 h, and the reaction medium is a halogenated hydrocarbon or hydrocarbon solvent.

[0015] In some embodiments, the reaction temperature of the esterification reaction is 25 to 30° C., and the reaction time is 9 to 11 hours.

[0016] In some embodiments, the molar ratio of the compound represented by formula (II), the acyl halide reagent and tert-butyl alcohol is 1-1.1:1.2-1.5:2.0-3.0;

[0017] In some embodiments, the acyl halide reagent is selected from oxalyl chloride, thionyl chloride, phosphorus trichloride, or phosphorus trichloride.

[0018] In some embodiments, the reaction medium is dichloromethane or 1,2-dichloroethane.

[0019] In some embodiments, the reaction temperature of the catalytic hydrogenation is 20-30° C., the reaction time is 2-4 h, and the reaction medium is an ether, alcohol, halogenated hydrocarbon or nitrile solvent.

[0020] In some embodiments, the reaction medium is tetrahydrofuran, methanol, dichloromethane, acetonitrile, or 2-methyltetrahydrofuran.

[0021] In some embodiments, the process further includes removing the solvent from the esterification reaction product, adding water and ethyl acetate to extract the organic layer, washing the organic layer with a saturated sodium bicarbonate solution, and drying to obtain a crude compound of formula (III); adding petroleum ether to the crude product, stirring, filtering under an ice bath, concentrating the filtrate, and drying to obtain a pure compound of formula (III).

[0022] In some embodiments, the catalyst and solvent in the palladium-carbon catalyzed hydrogenation debenzylation reaction product are removed, n-heptane is added for recrystallization, and the filter cake is filtered under an ice bath and dried to obtain a pure product of the compound represented by formula (I).

[0023] In some embodiments, the preparation method of the compound represented by formula (II) comprises: firstly subjecting the compound represented by formula (IIa) to an esterification reaction with benzyl alcohol to obtain the compound represented by formula (IIb), and then hydrolyzing the compound represented by formula (IIb) under alkaline conditions to obtain the compound represented by formula (II). The preparation route is as follows:

[0024]

[0025] In some embodiments, the preparation method of the compound of formula (II) includes: mixing the compound of formula (IIa), benzyl alcohol, a hydrocarbon solvent and an esterification catalyst, reacting at 110-130°C for 1-3 hours to obtain the compound of formula (IIb); mixing the compound of formula (IIb) with an ether solvent and a lithium hydroxide aqueous solution, reacting at 25-35°C for 14-16 hours to obtain the compound of formula (II).

[0026] In some embodiments, the method for preparing the compound of formula (II) further comprises: adding saturated sodium bicarbonate solution to the esterification reaction product, stirring, adding water and ethyl acetate for extraction, washing the organic phase with water and concentrating and drying to obtain the compound of formula (IIb).

[0027] In some embodiments, the preparation method of the compound shown in formula (II) further includes: filtering the hydrolysis product, adding water and ethyl acetate to the filter cake for extraction, washing the organic phase with water, concentrating and drying, and slurrying with isopropanol to obtain the compound shown in formula (II).

[0028] In a second aspect, the present invention provides an intermediate compound for preparing a fatty diacid mono-tert-butyl ester of formula (I), which has a structural formula as shown in formula (III):

[0029]

[0030] Here, n is an integer from 8 to 18.

[0031] In a third aspect, the present invention provides a method for preparing the aforementioned intermediate compound, as described above.

[0032] In a fourth aspect, the present invention provides the use of the aforementioned intermediate compound in the preparation of mono-tert-butyl fatty diacid ester.

[0033] The beneficial effects of the present invention are:

[0034] The invention provides a novel preparation method of fatty diacid mono-tert-butyl ester, which avoids the problems of incomplete reaction or overreaction in the existing preparation method, has high yield (more than 75%) and high purity (more than 99.3%) of the target product, simplifies the operation and post-processing of the reaction, improves production safety, reduces production cost, and is more suitable for industrial production. DETAILED DESCRIPTION

[0035] In order to make the purpose, technical solution and advantages of the embodiments of the present invention clearer, the technical solution in the embodiments of the present invention is clearly and completely described below. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0036] Example 1 Preparation of tert-butyl octadecane dioate (n=16)

[0037] The preparation route is as follows:

[0038]

[0039] Step 1: Preparation of IM1

[0040] Take octadecane dioic acid (200.0 g, 0.63 mol) and add it to 2L toluene, add benzyl alcohol (172 g, 1.59 mmol), p-toluenesulfonic acid monohydrate (12.1 g, 0.06 mol), reflux at 120°C for 2h, monitor the reaction until it is complete by TLC, end the reaction, cool to room temperature, add saturated sodium bicarbonate solution and stir, add water and ethyl acetate and stir to separate the liquids, wash the organic phase with water and concentrate to obtain a crude white solid octadecane dioic acid dibenzyl ester (IM1). Purity: 94%. MS-ESI (m / z): 495.35 [M+H] +,517.33[M+Na] + , melting point: 67.8~67.9℃.

[0041] Step 2: Preparation of IM2

[0042] Take the crude product of octadecane dioic acid benzyl ester (30.0 g, 0.06 mol) and add 300 mL of ethylene glycol dimethyl ether to dissolve, then add lithium hydroxide (6.28 g, 0.16 mmol) aqueous solution, stir at 30 ° C for 15 h, monitor the reaction completely by TLC, filter, add 300 mL of EA and 150 mL of water to the filter cake, stir, add 100 mL of 2M HCl and stir until clear, separate the liquids, wash the organic phase with saturated brine, dry it with anhydrous sodium sulfate and concentrate it to obtain a white solid, and beat it with isopropanol to obtain octadecane dioic acid benzyl ester (IM2). Two-step yield: 80%, purity: 98%. 1 H NMR (400 MHz, DMSO-d 6 )δ11.95(s,1H),7.43-7.27(m,5H),5.08(s,2H),2.34(t,J=7.3Hz,2H),2.18(t,J=7.3H z,2H),1.51(dq,J=21.2,6.6Hz,4H),1.23(d,J=3.5Hz,24H).MS-ESI(m / z):405.30[M+H] + ,427.28[M+Na] + , melting point: 82.4~82.5℃.

[0043] Step 3: Preparation of IM3

[0044] Under nitrogen atmosphere, intermediate IM2 (15.80g, 39mmol) was dissolved in dichloromethane (150ml), and oxalyl chloride (6.41g, 51mmol) was slowly added dropwise to generate bubbles, and attention was paid to the material. After reacting for 3 hours, the reaction solution was spin-dried to obtain a yellow solid, and tert-butyl alcohol (8.5ml, 0.097mol) and DCM (75ml) were directly added to the solid, and stirring was waited until the reaction was completed after 10 hours. The reaction solution was spin-dried, ethyl acetate and water were added to stir, and the organic layer was washed once with a saturated sodium bicarbonate solution, and the organic layer was dried, filtered, and spin-dried to obtain a crude oil. Petroleum ether was added to the crude product, stirred, and a solid was precipitated under an ice bath, filtered, and the filtrate was spin-dried to obtain a colorless oil IM3 with a purity of 94%. 1 H NMR (400 MHz, DMSO-d 6)δ7.40-7.28(m,5H),5.08(s,2H),2.33(t,J=7.3Hz,2H),2.15(t,J=7.3Hz,2H),1.38(s,9H),1.23(d,J=3.6Hz,28H).

[0045] Step 4: Preparation of IM4

[0046] Take a round-bottom flask and add intermediate IM3 (5.00 g, 0.011 mol), add tetrahydrofuran (50 ml) and stir to dissolve, add palladium carbon (0.5 g, 10%), pass hydrogen, stir and react for about 3 hours, and the reaction is completed. Filter and recover palladium carbon, spin dry the filtrate to obtain a crude white solid. Add n-heptane (15 ml) to the solid for recrystallization, filter under ice bath to obtain a white solid IM4, with a two-step yield of 75% and a purity of 99.37% (CAD detection). 1 H NMR (400 MHz, DMSO-d 6 )δ11.96(s,1H),2.16(dt,J=8.4,7.3Hz,4H),1.52-1.43(m,4H),1.39(s,9H),1.23(s,24H).

[0047] Example 2 Preparation of Eicosanedioic Acid Mono-tert-Butyl Ester (n=18)

[0048] The preparation route is as follows:

[0049]

[0050] Step 1: Preparation of IM5

[0051] Take eicosanedioic acid (3.0 g, 0.008 mol) and add toluene (30 ml), add benzyl alcohol (2.36 g, 0.022 mol) and p-toluenesulfonic acid monohydrate (0.17 g, 0.8 mmol), reflux at 120 ° C for 2 h, monitor the reaction completion by TLC, terminate the reaction, cool to room temperature, add saturated sodium bicarbonate solution (15 ml) and stir, add water (15 ml) and ethyl acetate (30 ml) and stir to separate the liquids, wash the organic phase with water and concentrate to obtain a white solid eicosanedioic acid dibenzyl ester crude product (IM5). 1 H NMR (400 MHz, DMSO-d 6 )δ7.35(s,10H),5.08(s,4H),1.52(s,4H),1.23(d,J=4.8Hz,32H).

[0052] Step 2: Preparation of IM6

[0053] Take crude dibenzyl eicosanedioate (3.0 g, 0.006 mol) and add ethylene glycol dimethyl ether (30 ml) to dissolve, then add lithium hydroxide (0.35 g, 0.014 mol) aqueous solution, stir at 30 ° C for 15 h, monitor the reaction by TLC, filter, add 300 mL EA and 150 mL water to the filter cake and stir, add 100 mL 2M HCl and stir until clear, separate the liquid, wash the organic phase with saturated brine, dry it with anhydrous sodium sulfate and concentrate it to obtain a white solid, and beat it with isopropanol to obtain monobenzyl eicosanedioate (IM6). Two-step yield: 79%.

[0054] Step 3: Preparation of IM7

[0055] Under nitrogen atmosphere, intermediate IM6 (5g, 0.011mol) was dissolved in dichloromethane (50ml), and oxalyl chloride (1.90g, 0.015mol) was slowly added dropwise to generate bubbles, and attention was paid to the material. After 3 hours of reaction, the reaction solution was spin-dried to obtain a yellow solid, and tert-butyl alcohol (2.76ml, 0.028mol) and DCM (25ml) were directly added to the solid, and stirring was waited until the reaction was completed after 10 hours. The reaction solution was spin-dried, ethyl acetate (50ml) and water (25ml) were added to stir, and the liquid was separated. The organic layer was washed once with a saturated sodium bicarbonate solution (25ml), and the organic layer was dried, filtered, and spin-dried to obtain a crude oil. Petroleum ether (25ml) was added to the crude product, stirred, and then a solid was precipitated under an ice bath, filtered, and the filtrate was spin-dried to obtain a colorless oil IM7.

[0056] Step 4: Preparation of IM8

[0057] Take a round-bottom flask and add intermediate IM7 (3g, 0.006mol), add tetrahydrofuran (30ml) and stir to dissolve, add palladium carbon (0.3g, 10%), pass hydrogen, stir and react for about 3h, and the reaction is complete. Filter and recover palladium carbon, spin dry the filtrate to obtain a crude white solid. Add n-heptane to the solid for recrystallization, filter under ice bath to obtain a white solid IM8. Two-step yield: 77%.

[0058] Example 3 Preparation of mono-tert-butyl dodecanedioate (n=10)

[0059] The preparation route is as follows:

[0060]

[0061] Step 1: Preparation of IM9

[0062] Take dodecanedioic acid (20.0 g, 0.087 mol) and add it to 2L toluene, add benzyl alcohol (172 g, 0.217 mol) and p-toluenesulfonic acid monohydrate (12.1 g, 0.08 mol), reflux at 120°C for 2h, monitor the reaction until it is complete by TLC, terminate the reaction, cool to room temperature, add saturated sodium bicarbonate solution and stir, add water and ethyl acetate and stir to separate the liquids, wash the organic phase with water and concentrate to obtain a white solid crude product of dibenzyl dodecanedioate (IM9). 1 H NMR (400 MHz, DMSO-d 6 )δ7.42-7.26(m,10H),5.07(s,4H),2.33(t,J=7.3Hz,4H),1.51(q,J=7.1Hz,4H),1.25-1.18(m,12H).

[0063] Step 2: Preparation of IM10

[0064] Take crude product of dibenzyl dodecanedioate (30.0 g, 0.073 mol) and add 300 mL of ethylene glycol dimethyl ether to dissolve, then add lithium hydroxide (4.37 g, 0.183 mmol) aqueous solution, monitor the reaction completely by TLC, filter, add 300 mL of EA and 150 mL of water to the filter cake and stir, add 100 mL of 2M HCl and stir until clear, separate the liquids, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate and concentrate to obtain a white solid, and beat with isopropanol to obtain monobenzyl dodecanedioate (IM10). Two-step yield: 83%, purity: 99%. 1 H NMR (400 MHz, DMSO-d 6 )δ11.95(s,1H),7.43-7.20(m,5H),5.08(s,2H),2.34(t,J=7.3Hz,2H),2.18(t,J=7.4Hz ,2H),1.50(dp,J=21.4,6.7Hz,4H),1.23(d,J=4.6Hz,12H).MS-ESI(m / z):343.20[M+Na] + , melting point: 135.1-136.0℃.

[0065] Step 3: Preparation of IM11

[0066] Under nitrogen atmosphere, intermediate IM10 (5.0g, 0.016mol) was dissolved in dichloromethane (50ml), and oxalyl chloride (2.6g, 0.02mol) was slowly added dropwise to generate bubbles. After 3 hours of reaction, the reaction solution was spin-dried to obtain a yellow solid, and tert-butyl alcohol (3.5ml, 0.04mol) and DCM (25ml) were directly added to the solid, and stirring was waited until the reaction was 10 hours, and the plate was completed. The reaction solution was spin-dried, ethyl acetate (50ml) and water (25ml) were added to stir, and the liquid was separated. The organic layer was washed once with a saturated sodium bicarbonate solution (25ml), and the organic layer was dried, filtered, and spin-dried to obtain a crude oil. Petroleum ether (15ml) was added to the crude product, stirred, and then a solid was precipitated under an ice bath, filtered, and the filtrate was spin-dried to obtain a colorless oil IM11. 1 H NMR (400 MHz, DMSO-d 6 )δ7.43-7.29(m,5H),5.08(s,2H),2.33(t,J=7.4Hz,2H),2.15(t,J=7.3Hz,2 H),1.50(ddd,J=25.2,8.3,4.8Hz,4H),1.39(s,9H),1.23(d,J=4.9Hz,12H).

[0067] Step 4: Preparation of IM12

[0068] Take a round-bottom flask and add intermediate IM11 (5.0 g, 0.013 mol), add tetrahydrofuran (50 ml) and stir to dissolve, add palladium carbon (0.5 g, 10%), pass hydrogen, stir and react for about 3 hours, and the reaction is complete. Filter and recover palladium carbon, spin dry the filtrate to obtain a crude white solid. Add n-heptane to the solid for recrystallization, filter under ice bath to obtain a white solid IM8. Two-step yield: 78%, purity 99.4%.

[0069] The preferred embodiments of the present invention are described in detail above. However, the present invention is not limited to the specific details in the above embodiments. Within the technical concept of the present invention, a variety of simple modifications can be made to the technical solution of the present invention, and these simple modifications all belong to the protection scope of the present invention.

Claims

1. A method for preparing a fatty diacid mono-tert-butyl ester represented by formula (I), characterized in that: The preparation method comprises: a. first subjecting the compound represented by formula (II) to an acyl halide reaction with an acyl halide reagent, and then subjecting the compound represented by formula (III) to an esterification reaction with tert-butyl alcohol; b. Debenzylating the compound represented by formula (III) by palladium-carbon catalytic hydrogenation to obtain the compound represented by formula (I); Here, n is an integer from 8 to 18.

2. The preparation method according to claim 1, characterized in that: The reaction temperature of the acyl halide reaction is 25-30°C, the reaction time is 2-4h, and the reaction medium is a halogenated hydrocarbon or hydrocarbon solvent; And / or, the reaction temperature of the esterification reaction is 25-30° C., and the reaction time is 9-11 h; and / or, the molar ratio of the compound represented by formula (II), the acyl halide reagent and tert-butyl alcohol is 1-1.1:1.2-1.5:2.0-3.0; And / or, the acyl halide reagent is selected from oxalyl chloride, thionyl chloride, phosphorus trichloride or phosphorus trichloride.

3. The preparation method according to claim 2, characterized in that: The reaction medium is dichloromethane or 1,2-dichloroethane.

4. The preparation method according to claim 1, characterized in that: The reaction temperature of the catalytic hydrogenation is 20-30° C., the reaction time is 2-4 hours, and the reaction medium is an ether, alcohol, halogenated hydrocarbon or nitrile solvent.

5. The preparation method according to claim 4, characterized in that: The reaction medium is tetrahydrofuran, methanol, dichloromethane, acetonitrile or 2-methyltetrahydrofuran.

6. An intermediate compound for preparing mono-tert-butyl fatty diacid ester represented by formula (I), characterized in that: It has a structural formula as shown in formula (III): Here, n is an integer from 8 to 18.

7. The method for preparing the intermediate compound according to claim 6, characterized in that: The preparation method comprises: firstly subjecting the compound represented by formula (II) to an acyl halide reaction with an acyl halide reagent, and then subjecting the compound represented by formula (III) to an esterification reaction with tert-butyl alcohol; 8. The preparation method according to claim 7, characterized in that: The reaction temperature of the acyl halide reaction is 25-30°C, the reaction time is 2-4h, and the reaction medium is a halogenated hydrocarbon or hydrocarbon solvent; And / or, the reaction temperature of the esterification reaction is 25-30° C., and the reaction time is 9-11 h; and / or, the molar ratio of the compound represented by formula (II), the acyl halide reagent and tert-butyl alcohol is 1-1.1:1.2-1.5:2.0-3.0; And / or, the acyl halide reagent is selected from oxalyl chloride, thionyl chloride, phosphorus trichloride or phosphorus trichloride.

9. The preparation method according to claim 8, characterized in that: The reaction medium is dichloromethane or 1,2-dichloroethane.

10. Use of the intermediate compound according to claim 6 in the preparation of fatty diacid mono-tert-butyl ester.

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