CN110845348A - Preparation method of ARV-110 intermediate - Google Patents
Preparation method of ARV-110 intermediate Download PDFInfo
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- CN110845348A CN110845348A CN201911259532.6A CN201911259532A CN110845348A CN 110845348 A CN110845348 A CN 110845348A CN 201911259532 A CN201911259532 A CN 201911259532A CN 110845348 A CN110845348 A CN 110845348A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
Abstract
The invention provides a preparation method of an ARV-110 intermediate, wherein the ARV-110 intermediate is methyl 4- ((5- (2- (tert-butoxy) -2-oxoethoxy) pentyl) amino) benzoate, and the method comprises the following two steps: (1) compound p-aminobenzoic acid 2 and fatty aldehyde 3 at BH3To obtain a compound 4- ((5- (2- (tert-butoxy) -2-oxoethoxy) phenyl) pentylamino) benzoic acid 4; (2) esterification of compound 4- ((5- (2- (tert-butoxy) -2-oxoethoxy) phenyl) amino) benzoic acid 4 in a methyl halide/base system gave compound 4- ((5- (2- (tert-butoxy) -2-oxoethoxy) pentyl) amino) benzoic acid methyl ester 1. The reaction synthesis route is as follows:
Description
Technical Field
The invention relates to a preparation method of a medical intermediate, and particularly relates to a preparation method of 4- ((5- (2- (tert-butoxy) -2-oxoethoxy) pentyl) amino) methyl benzoate.
Background
ARV-110 is a novel anti-prostate cancer therapeutic drug developed by Arvinas, USA, based on the PROTAC protein degradation technology, and is currently in clinical research. The new drug has excellent degradation effect on AR in vitro and in vivo models, whether AR mutation or over-expression (both common reasons for failure of AR targeted therapy). ARV-110 qualifies for the fast channel granted by the U.S. FDA.
((5- (2- (tert-butoxy) -2-oxoethoxy) pentyl) amino) benzoic acid methyl ester (Compound 1) is an important intermediate for the preparation of ARV-110. The preparation of compound 1 is reported on page 169 of CN 201680014250.8: milligram-grade methyl 4-aminobenzoate and milligram-grade aliphatic aldehyde (compound 3) were reacted under the action of sodium triacetoxyborohydride, followed by silica gel chromatography purification to give milligram-grade target product in moderate yield (62%).
The present inventors have found, when repeating this reaction: the reaction has poor repeatability, low conversion rate of raw materials, more byproducts and more complex reaction, and although sodium triacetoxyborohydride is supplemented for many times, the reaction is not improved, the yield is low (< 20%), and the large-scale production is difficult. The reaction TLC plate (the developing solvent is petroleum ether/ethyl acetate-3/1) is shown in figure 1.
Therefore, the method for preparing the methyl 4- ((5- (2- (tert-butoxy) -2-oxoethoxy) pentyl) amino) benzoate by searching for a high reaction yield and few byproducts has important practical value.
Disclosure of Invention
Problems to be solved by the invention
In order to solve the technical problems, the invention provides a method for preparing methyl 4- ((5- (2- (tert-butoxy) -2-oxoethoxy) pentyl) amino) benzoate by large-scale production, high reaction yield, few byproducts, easy purification, simple reaction operation and mild conditions.
Means for solving the problems
In order to solve the above technical problem, the present invention provides a method for preparing methyl 4- ((5- (2- (tert-butoxy) -2-oxoethoxy) pentyl) amino) benzoate, which comprises the following two steps:
(1) compound p-aminobenzoic acid 2 and fatty aldehyde 3 at BH3To give 4- ((5- (2- (tert-butoxy) -2-oxoethoxy) pentyl) amino) benzoic acid 4;
(2) esterification of compound 4- ((5- (2- (tert-butoxy) -2-oxoethoxy) pentyl) amino) benzoic acid 4 in a methyl halide/base system to give compound 4- ((5- (2- (tert-butoxy) -2-oxoethoxy) pentyl) amino) benzoic acid methyl ester 1;
the reaction synthesis route is as follows:
preferably, in the step (1), the reaction solvent is an organic solvent, and preferably, the reaction solvent is one or more selected from tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, methanol, ethanol, acetonitrile, ethyl acetate, isopropyl acetate and methyl tert-butyl ether.
Preferably, in step (1), BH3The molar ratio of the compound to the compound 2 is 12:1, and the molar ratio of the compound 3 to the compound 2 is 1-3: 1.
Preferably, in step (1), the reaction temperature is 20 to 60 ℃, preferably room temperature.
Preferably, in the step (2), the methyl halide is methyl iodide, methyl bromide or methyl chloride, and the alkali is inorganic alkali.
Preferably, the inorganic base is selected from one or more of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, cesium carbonate, sodium hydroxide, potassium hydroxide or lithium hydroxide.
Preferably, in the step (2), the molar ratio of the halogenated methane to the compound 4 is 1-3: 1, and the molar ratio of the alkali to the compound 4 is 1-3: 1.
Preferably, in the step (2), the reaction solvent is one or more selected from the group consisting of N, N-dimethylformamide, N-dimethylacetamide and dimethylsulfoxide.
Preferably, in the step (2), the reaction temperature is 20-60 ℃.
Preferably, the reaction temperature is room temperature.
ADVANTAGEOUS EFFECTS OF INVENTION
According to the invention, a specific reaction substrate is adopted, the target product 4- ((5- (2- (tert-butoxy) -2-oxoethoxy) pentyl) amino) benzoic acid can be prepared with the total yield of up to 90% through two-step reaction, silica gel chromatography purification is not needed in both the two-step reaction, the post-treatment is simple, and the high-purity target product (HPLC: > 97%) is obtained through simple acid-base treatment.
The preparation method disclosed by the invention is mild in reaction conditions, does not need harsh reaction conditions such as high temperature and high pressure in the reaction process, only needs to react at room temperature, and is simple and safe to operate.
The preparation method can prepare target products of more than 200g, and can also prepare kilogram target products through simple amplification, so that the preparation method can be used for large-scale production and preparation. The preparation method has good repeatability, and target products can be obtained smoothly through repeated reaction of milligram level, gram level and more than 100 g.
The applicant has also surprisingly found that it is very important to use p-aminobenzoic acid in the starting material. When the reagent is replaced by methyl p-aminobenzoate, the reaction yield is drastically reduced (47%), and the target compound has a great amount of impurities, which makes purification extremely difficult.
Drawings
FIG. 1 schematic TLC plate of the reaction procedure
Description of reference numerals: 1 is raw material methyl p-aminobenzoate, 2 is target product compounds 1, 3 and 4 are impurities.
Detailed Description
The invention provides a preparation method of methyl 4- ((5- (2- (tert-butoxy) -2-oxoethoxy) pentyl) amino) benzoate, which comprises the following two steps:
(1) compound p-aminobenzoic acid 2 and fatty aldehyde 3 at BH3To obtain a compound 4- ((5- (2- (tert-butoxy) -2-oxoethoxy) phenyl) pentylamino) benzoic acid 4;
(2) esterification of compound 4- ((5- (2- (tert-butoxy) -2-oxoethoxy) phenyl) amino) benzoic acid 4 in a methyl halide/base system gave compound 4- ((5- (2- (tert-butoxy) -2-oxoethoxy) pentyl) amino) benzoic acid methyl ester 1.
The reaction synthesis route is as follows:
in a preferred embodiment, in step (1), the reaction solvent is an organic solvent commonly used in the art, and preferably, the reaction solvent is one or more selected from tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, methanol, ethanol, acetonitrile, ethyl acetate, isopropyl acetate, and methyl tert-butyl ether.
In a preferred embodiment, in step (1), the BH3Including BH3Organic solvent complexes of, e.g. BH3Complexes with tetrahydrofuran, or BH3A complex with dimethyl sulfide. BH3The mol ratio of the compound to the compound 2 is 1-2: 1, preferably 1.2 to 1:1, the molar ratio of the compound 3 to the compound 2 is 1 to 3:1, preferably 1 to 1.5: 1.
in a preferred embodiment, in step (1), the reaction temperature is from 20 to 60 ℃, preferably room temperature.
In a preferred embodiment, in step (2), the methyl halide is methyl iodide, methyl bromide or methyl chloride, and the base is an inorganic base commonly used in the art.
In a more preferred embodiment, the inorganic base is selected from one or more of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, or lithium hydroxide, and the like.
In a preferred embodiment, in the step (2), the molar ratio of the halogenated methane to the compound 4 is 1-3: 1, and the molar ratio of the base to the compound 4 is 1-3: 1.
In a preferred embodiment, in step (2), the reaction solvent is a solvent commonly used in the art, preferably a polar solvent, more preferably one or more selected from the group consisting of N, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, and the like.
In a preferred embodiment, in the step (2), the reaction temperature is 20 to 60 ℃, and the reaction temperature is room temperature.
The following examples are for illustrative purposes only and do not limit the scope of the claims provided herein.
Summary of the invention1H-NMR spectra Bruker-400 NMR spectrometer with chemical shifts in parts per million and internal standard tetramethylsilane. The coupling constant (J) is close to 0.1 Hz. The abbreviations used are as follows: s, single multiplet; d, doublet; t, triplet; q, quartet; qu, quintet; m, multiplet; br, broad peak. Mass Spectrometry A Quattro MicroTM API triple quadrupole mass spectrometer was used.
Example 1
Preparation of 4- ((5- (2- (tert-butoxy) -2-oxoethoxy) phenyl) amino) benzoic acid
P-aminobenzoic acid (100g,0.73moL, from Bikuai medicine) and BH3Tetrahydrofuran complex solution (800mL,1.0M,0.80moL, from Annaiji chemical) was added to tetrahydrofuran (2.5L). After the addition was complete, the mixture was stirred at room temperature for 30 minutes before the addition of the fatty aldehyde (174.0g,0.80moL, homemade according to the method provided on page 169 of CN 201680014250.8). Stirring at room temperature overnight, spotting the plate to detect the reaction is complete, and adding water to quench the reaction. The solvent was evaporated under reduced pressure, water (2.0L) was added to the residue, and the pH was adjusted to 12 with 4N NaOH solution. Ethyl acetate (500mL) was added and the mixture was separated. The aqueous phase was collected and the pH adjusted back to about 3 with concentrated HCl. Extracted with ethyl acetate (2X 1L), the organic phases were combined and back-washed with water (200 mL). The organic phase was dried over anhydrous magnesium sulfate, filtered, the solvent evaporated under reduced pressure and the residue dried under high vacuum to give 229.0g of a white solid with 93% yield. H-NMR (DMSO-d6,400mhz) δ 11.9(s,1H),7.66(d, J8.0 Hz,2H),6.40(dd, J)1＝8.0Hz,J2＝12.0Hz,2H),6.43-6.38(m,1H),3.94-3.92(m,2H),3.47-3.32(m,2H),3.08-3.02(m,2H),1.62-1.50(m,4H),1.41-1.37(m,11H).ESI-MS:338.4[M+H]+。
Example 2
Preparation of 4- ((5- (2- (tert-butoxy) -2-oxoethoxy) phenyl) amino) benzoic acid
Example 2 was conducted in the same manner as example 1 except that the reaction solvent was changed to tetrahydrofuran with 2-methyltetrahydrofuran, and the yield was 89%.
Example 3
Preparation of 4- ((5- (2- (tert-butoxy) -2-oxoethoxy) phenyl) amino) benzoic acid
The procedure of example 3 was the same as in example 1 except that dimethyl ether was used as a reaction solvent in place of tetrahydrofuran, and the yield was 89%.
Example 4
Preparation of methyl 4- ((5- (2- (tert-butoxy) -2-oxoethoxy) phenyl) amino) benzoate
Methyl 4- ((5- (2- (tert-butoxy) -2-oxoethoxy) phenyl) amino) benzoate (200g,0.59moL), sodium carbonate (94.4g,0.89moL) and iodomethane (55.0mL, 0.89moL) were added to N, N-dimethylformamide (1.5L, AR grade) and stirred at room temperature overnight. The reaction was completed by TLC, the solvent was distilled off under reduced pressure, and ethyl acetate (2.0L) was added to the residue, which was washed with water (2X 500 mL). The organic phase was dried over anhydrous magnesium sulfate, filtered, the solvent evaporated under reduced pressure and the residue dried under high vacuum to give 201g of a pale yellow oil in 97% yield.1H-NMR(DMSO-d6,400MHz)δ＝7.67(d,J＝8.0Hz,2H),6.55(d,J＝12.0Hz,2H),6.49(t,J＝4.0Hz,1H),3.92(s,2H),3.37(s,3H),3.43(t,J＝4.0Hz,2H),3.08-3.03(m,2H),1.59-1.50(m,4H),1.43-1.37(m,11H).ESI-MS:352.3[M+H]+ ,374.4[M+Na]+.HPLC:>97.0％。
Example 5
Preparation of methyl 4- ((5- (2- (tert-butoxy) -2-oxoethoxy) phenyl) amino) benzoate
Example 5 was performed as in example 4, except that potassium carbonate was used instead of sodium carbonate. The yield thereof was found to be 94%.
Example 6
Preparation of methyl 4- ((5- (2- (tert-butoxy) -2-oxoethoxy) phenyl) amino) benzoate
Example 6 was performed as in example 4 except that cesium carbonate was used instead of sodium carbonate, the yield was 95%.
Example 7
Preparation of methyl 4- ((5- (2- (tert-butoxy) -2-oxoethoxy) phenyl) amino) benzoate
Example 7 was conducted in the same manner as example 4 except that N, N-dimethylacetamide was used instead of N, N-dimethylformamide, whereby the yield was 98%.
Example 8
Preparation of methyl 4- ((5- (2- (tert-butoxy) -2-oxoethoxy) phenyl) amino) benzoate
The procedure of example 8 was the same as in example 4 except that dimethyl sulfoxide was used instead of N, N-dimethylformamide, and the yield was 92%.
Example 9
Preparation of methyl 4- ((5- (2- (tert-butoxy) -2-oxoethoxy) phenyl) amino) benzoate
Example 9 was performed as in example 1, except that methyl p-aminobenzoate was used instead of p-aminobenzoic acid, and the target product was obtained by flash column chromatography. The yield thereof was found to be 47%. Meanwhile, a large amount of impurities are mixed in the target product, and the purification is difficult.
The foregoing description of specific embodiments of the present invention has been presented. It is to be understood that the present invention is not limited to the specific embodiments or specific substituents described above, and that various changes, modifications and substitutions may be made by those skilled in the art within the scope of the claims without departing from the spirit of the present invention.
Claims (10)
1. A process for the preparation of methyl 4- ((5- (2- (tert-butoxy) -2-oxoethoxy) pentyl) amino) benzoate, characterized in that it comprises the following two steps:
(1) compound p-aminobenzoic acid 2 and fatty aldehyde 3 at BH3To give 4- ((5- (2- (tert-butoxy) -2-oxoethoxy) pentyl) amino) benzoic acid 4;
(2) esterification of compound 4- ((5- (2- (tert-butoxy) -2-oxoethoxy) pentyl) amino) benzoic acid 4 in a methyl halide/base system to give compound 4- ((5- (2- (tert-butoxy) -2-oxoethoxy) pentyl) amino) benzoic acid methyl ester 1;
the reaction synthesis route is as follows:
2. the method according to claim 1, wherein the reaction solvent in step (1) is an organic solvent, preferably the reaction solvent is one or more selected from tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, methanol, ethanol, acetonitrile, ethyl acetate, isopropyl acetate, and methyl tert-butyl ether.
3. The process according to claim 1, wherein in step (1), BH is performed in a process for the preparation of methyl 4- ((5- (2- (tert-butoxy) -2-oxoethoxy) phenyl) pentylamino) benzoate3The molar ratio of the compound to the compound 2 is 1-2: 1, and the molar ratio of the compound 3 to the compound 2 is 1-3: 1.
4. The process according to claim 1, wherein in step (1), the reaction temperature is 20-60 ℃, preferably room temperature.
5. The method according to claim 1, wherein in step (2), the methyl halide is methyl iodide, methyl bromide or methyl chloride, and the base is an inorganic base.
6. The process of claim 5, wherein the inorganic base is selected from one or more of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, or lithium hydroxide.
7. The method for preparing methyl 4- ((5- (2- (tert-butoxy) -2-oxoethoxy) phenyl) pentylamino) benzoate according to claim 5, wherein in step (2), the molar ratio of methyl halide to compound 4 is 1-3: 1, and the molar ratio of base to compound 4 is 1-3: 1.
8. The process according to claim 1, wherein the reaction solvent in step (2) is one or more selected from the group consisting of N, N-dimethylformamide, N-dimethylacetamide and dimethylsulfoxide.
9. The method for preparing methyl 4- ((5- (2- (tert-butoxy) -2-oxoethoxy) phenyl) pentylamino) benzoate according to claim 1, wherein in the step (2), the reaction temperature is 20-60 ℃.
10. The process according to claim 9, wherein the reaction temperature is room temperature, and the reaction temperature is about 5- ((5- (2- (tert-butoxy) -2-oxoethoxy) phenyl) pentylamino) benzoic acid methyl ester.
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| WO2019191502A1 (en) * | 2018-03-29 | 2019-10-03 | Elex Biotech, Inc. | Compounds for treatment of cardiac arrhythmias and heart failure |
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2019
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| CN1288457A (en) * | 1998-01-20 | 2001-03-21 | 田边制药株式会社 | Inhibitors of & alpha, 4 mediated cell adhesion |
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| CN107428734A (en) * | 2015-01-20 | 2017-12-01 | 阿尔维纳斯股份有限公司 | Compounds and methods for for the targeting degraded of androgen receptor |
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