CN110759870A - Synthesis method of oxalagogri intermediate - Google Patents
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Abstract
The invention relates to a synthesis method of an oxalagogri intermediate. Specifically, the invention provides a synthesis method of an oxalagogrel intermediate compound X and an oxalagogrel intermediate compound I. According to the method, 2-fluoro-3-methoxy-phenylacetic acid is used as a raw material, and the intermediate compound X and the compound I of the oxa-rogue are obtained through the steps of cyclization, hydrolysis, amino protection, condensation, Mitsunobu reaction and the like in sequence. The method has the advantages of cheap and easily obtained reagents, high conversion rate, simple and convenient operation and low process cost, and is suitable for industrialization.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemicals, and particularly relates to a synthesis method of a novel oral GnRH antagonist oxadegril intermediate.
Background
Loragol (Elagolix), chemical name: (R) -4- [ [2- [5- (2-fluoro-3-methoxyphenyl) -3- [ 2-fluoro-6- (trifluoromethyl) benzyl ] -4-methyl-2, 6-dioxo-3, 6-dihydropyrimidin-1 (2H) -yl ] -1-phenylethyl ] amino ] butanoic acid, developed by Erberberine (Abbvie) in collaboration with neurosecretory Biosciences (Neurocrine Biosciences). Is an oral gonadotropin releasing hormone receptor antagonist, and finally reduces the level of the gonadotropin in the blood circulation by inhibiting pituitary gonadotropin releasing hormone receptors. Erbavia submitted the NDA of this drug in 2017, month 9, received FDA priority qualification after 1 month more, and approved by FDA in 2018, month 7 and 23, with the trade name Orilissa, for treating pain due to endometriosis, and became the first new oral drug for 10 years for this type of indication, with great market prospects, whose structure is shown below:
from compound structure analysis, the key points of synthesis of the loragol are efficient construction of 6-methylpyrimidine diketone and introduction of a side chain.
Patent WO2005007165 discloses a synthesis method of oxa-rogue and an intermediate thereof as follows:
the 6-methylpyrimidine diketone in the route is constructed into a second step and a third step, the total yield is 60 percent, and the yield is low. And the reagents used in the ring closing step are all 15 equivalent, so the atom economy is low. After the 6-methylpyrimidine diketone is constructed, heavy metal catalytic coupling reaction is needed for introducing the subsequent side chain, so that the cost is greatly improved. In addition, column chromatography separation means is required in the whole route, and the method is not suitable for industrial amplification.
Patent WO2005007165 also discloses a variation of the above mentioned methods of synthesis of oxalagril and intermediates. The method comprises the following specific steps:
this route only adjusts to the order and method of side chain introduction, but still suffers from the drawbacks of prior changes.
Patent WO2009062087a1 reports another synthesis method of oxalagoril and intermediates:
the method is optimized on the previous route, but still has the defects of low ring construction yield and high cost of metal catalytic coupling.
Patent WO2009062087a1 also reports another synthesis method of oxalagril and intermediates:
the route adopts 2-fluorobenzene methyl ether with relatively low price as a raw material, and zinc powder and acetonitrile are utilized to prepare a ring-closing precursor 3-aminocrotonic acid ethyl ester derivative, so that the construction of 6-methylpyrimidine diketone can be completed with a yield of 70%, and a metal catalytic coupling reaction is avoided. However, the prior bromination step needs column chromatography preparation, so that the industrial value of the route is not high.
From the existing synthesis route of the oxalagogrel, the compound I is a key intermediate for preparing the oxalagogrel. How to find a method for synthesizing the compound I with high efficiency and low cost has important significance for the industrial production amplification of the Oxagoli.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a series of synthesis methods of an oxalagril intermediate, which are efficient, low in cost and suitable for industrialization.
In order to achieve the purpose, the invention provides the following technical scheme:
the invention provides a synthesis method of an oxalagogri intermediate compound X, which comprises the following steps:
(a) subjecting compound VI to a cyclization reaction with 1- [1- (dimethylamino) ethylene ] -2-methylthiourea salt in an inert solvent to form compound VII;
(b) subjecting compound VII to a hydrolysis reaction, thereby forming compound VIII;
(c) subjecting compound VIII to an amino-protecting reaction with an amino-protecting reagent in an inert solvent, thereby forming compound IX;
(d) firstly, carrying out condensation reaction on a compound IX and 2-trifluoromethyl-6-fluoro-benzyl bromide in an inert solvent in the presence of alkali; after the condensation reaction is finished, carrying out amino deprotection reaction on the mixture containing the condensation product under an acidic condition, thereby forming an oxagol intermediate compound X.
The invention provides a synthesis method of an oxalagogri intermediate compound I, which comprises the following steps:
(a) subjecting compound VI to a cyclization reaction with 1- [1- (dimethylamino) ethylene ] -2-methylthiourea salt in an inert solvent to form compound VII;
(b) subjecting compound VII to a hydrolysis reaction, thereby forming compound VIII;
(c) subjecting compound VIII to an amino-protecting reaction with an amino-protecting reagent in an inert solvent, thereby forming compound IX;
(d) firstly, carrying out condensation reaction on a compound IX and 2-trifluoromethyl-6-fluoro-benzyl bromide in an inert solvent in the presence of alkali; after the condensation reaction is finished, carrying out amino deprotection reaction on the mixture containing the condensation product under an acidic condition to form a compound X;
(e) firstly, carrying out Mitsunobu reaction on a compound X and N (Boc) -D-2-phenylethanolamine in an inert solvent; after the Mitsunobu reaction is finished, carrying out amino deprotection reaction on the reaction mixture under an acidic condition to form an oxalagoni intermediate compound I.
In another preferred example, the step (a) includes the steps of: firstly, carrying out acylation reaction on a compound VI (2-fluoro-3-methoxy-phenylacetic acid) in an inert solvent in the presence of an acylation reagent, and removing the redundant acylation reagent after the acylation reaction is finished; the mixture obtained after removing the excess acylating agent is then subjected to a cyclization reaction with 1- [1- (dimethylamino) ethylene ] -2-methylthiouronium salt in an inert solvent in the presence of an acid-binding agent to form compound VII.
In another preferred embodiment, in step (a), the acylating agent is selected from the group consisting of: thionyl chloride, oxalyl chloride, or combinations thereof.
In another preferred embodiment, in step (a), the acid scavenger is selected from the group consisting of: potassium carbonate, sodium carbonate, triethylamine, N-diisopropylethylamine, or a combination thereof.
In another preferred embodiment, in step (a), after the acylation reaction is completed, the mixture obtained by removing the excess acylating agent is a mixture containing the acylation product 2-fluoro-3-methoxy-phenylacetyl chloride.
In another preferred embodiment, in step (a), after the end of the ring-closure reaction, the reaction is quenched with water, and the organic phase is collected and concentrated to give compound VII.
In another preferred embodiment, in step (a), after the ring-closure reaction is finished, the reaction is quenched with water, and the organic phase is collected and concentrated; the concentrate is purified (e.g. by ethyl acetate) to give compound VII.
In another preferred embodiment, in step (a), the 1- [1- (dimethylamino) ethylene ] -2-methylthiourea salt is 1- [1- (dimethylamino) ethylene ] -2-methylthiourea hydrogen iodide.
In another preferred embodiment, in step (a), the inert solvent is selected from the group consisting of: dichloromethane, chloroform, toluene, xylene, or combinations thereof.
In another preferred embodiment, in the step (a), the temperature of the cyclization reaction is 0 to 100 ℃, preferably 10 to 70 ℃, and more preferably 15 to 50 ℃.
In another preferred embodiment, in step (b), the hydrolysis reaction is carried out under acidic conditions. Preferably, the acidic conditions refer to the presence of an acid selected from the group consisting of: sulfuric acid, hydrochloric acid. The acidic conditions comprise water in addition to the presence of an acid.
In another preferred embodiment, in the step (b), the temperature of the hydrolysis reaction is 15 ℃ to 200 ℃, preferably 20 ℃ to 100 ℃, and more preferably 50 ℃ to 100 ℃.
In another preferred embodiment, in step (b), after the hydrolysis reaction is finished, the reaction mixture is filtered, and the solid is collected, washed with water and dried, so as to obtain the compound VIII.
In another preferred embodiment, in step (c), the amino protecting reagent is Boc anhydride.
In another preferred embodiment, in step (c), said Boc anhydride is added in portions.
In another preferred embodiment, in step (c), said Boc anhydride is used in an amount of more than 5 equivalents.
In another preferred embodiment, in step (c), said Boc anhydride is used in an amount of 5 to 6 equivalents.
In another preferred embodiment, in step (c), the amino protection reaction is carried out in the presence of a base. Preferably, the base is selected from the group consisting of: pyridine, lutidine, DMAP, triethylamine, diisopropylethylamine, or a combination thereof.
In another preferred embodiment, in step (c), the inert solvent is selected from the group consisting of: tetrahydrofuran, dichloromethane, chloroform, acetonitrile, or combinations thereof.
In another preferred embodiment, in step (c), after the amino protection reaction is completed, an organic phase (e.g., tert-butyl methyl ether) and an aqueous phase are separated, and the organic phase is collected and concentrated to obtain compound IX.
In another preferred embodiment, in step (d), the acidic conditions are in the presence of a solution containing hydrogen chloride.
In another preferred example, the solution containing hydrogen chloride is a solution containing hydrogen chloride, such as ethyl acetate, ethanol, tetrahydrofuran, and dichloromethane.
In another preferred embodiment, in step (d), the base is selected from the group consisting of: potassium carbonate, sodium hydrogen, or combinations thereof.
In another preferred embodiment, in step (d), the inert solvent is selected from the group consisting of: n, N-dimethylformamide, tetrahydrofuran, acetonitrile, or a combination thereof.
In another preferred embodiment, in step (d), after the condensation reaction is completed, the reaction is quenched with water, and then extracted with an organic phase (e.g., ethyl acetate, dichloromethane, etc.), and the organic phase is collected, thereby obtaining a mixture containing the condensation product.
In another preferred example, in the step (d), after the amino deprotection reaction is finished, the reaction mixture is washed with water, and the organic phase is collected and concentrated, thereby obtaining the oxarogril intermediate compound X.
In another preferred embodiment, in step (e), the acidic condition is in the presence of concentrated hydrochloric acid.
In another preferred example, in the step (e), after the Mitsunobu reaction is completed, the reaction mixture is directly subjected to an amino deprotection reaction under an acidic condition without any treatment.
In another preferred embodiment, in the step (e), after the amino deprotection reaction is finished, the reaction mixture is concentrated; then, isopropyl acetate and an aqueous sodium hydroxide solution were added for liquid separation, and the organic phase was collected and concentrated to obtain compound I.
In another preferred embodiment, in step (e), the inert solvent is selected from the group consisting of: dichloromethane, toluene, 1, 4-dioxane, tetrahydrofuran, or combinations thereof.
In another preferred example, step (5) is further included before step (a): subjecting compound V to a hydrolysis reaction in an inert solvent under basic conditions to form compound VI;
in another preferred example, step (5) is preceded by step (4): in an inert solvent, in the presence of an acid-binding agent, carrying out a cyanation reaction on the compound IV and a cyanation reagent to form a compound V;
in another preferred example, step (3) is further included before step (4): in an inert solvent, carrying out esterification reaction on a compound III and methanesulfonyl chloride in the presence of an acid-binding agent to form a compound IV;
in another preferred example, step (3) is preceded by step (2): subjecting compound II to a reduction reaction in an inert solvent in the presence of a reducing agent, thereby forming compound III;
in another preferred example, the step (2) is preceded by a step (1): in an inert solvent, under the action of alkali, carrying out condensation reaction on 2-fluorobenzyl ether and N, N-dimethylformamide to form a compound II;
the main beneficial effects of the invention include:
the invention provides a novel synthesis method of an intermediate compound X and a compound I of oxa-golli. The synthesis method has the advantages of cheap and easily-obtained raw materials and high atom economic utilization degree, avoids using noble metal catalysts, avoids complex separation and purification operations, reduces the process cost, and is suitable for industrial amplification.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.
Detailed Description
Through intensive research, the inventor designs a brand-new synthesis method of the intermediate of the oxalagrange, which is suitable for industrial production. The synthesis method provided by the invention takes a compound VI with a known structure as a raw material, and obtains the intermediate compound I of the oxagoril through the steps of cyclization reaction, hydrolysis, amino protection, condensation, Mitsunobu reaction and the like in sequence, so that a new choice is provided for synthesizing the intermediate compound of the oxagoril and the oxagoril in the field.
The invention provides a synthesis method of an oxagoril intermediate compound X, which comprises the following steps:
(a) subjecting compound VI to a cyclization reaction with 1- [1- (dimethylamino) ethylene ] -2-methylthiourea salt in an inert solvent to form compound VII;
(b) subjecting compound VII to a hydrolysis reaction, thereby forming compound VIII;
(c) subjecting compound VIII to an amino-protecting reaction with an amino-protecting reagent in an inert solvent, thereby forming compound IX;
(d) firstly, carrying out condensation reaction on a compound IX and 2-trifluoromethyl-6-fluoro-benzyl bromide in an inert solvent in the presence of alkali; after the condensation reaction is finished, carrying out amino deprotection reaction on the mixture containing the condensation product under an acidic condition, thereby forming an oxagol intermediate compound X.
The invention provides a synthesis method of an oxagoril intermediate compound I, which comprises the following steps:
(a) subjecting compound VI to a cyclization reaction with 1- [1- (dimethylamino) ethylene ] -2-methylthiourea salt in an inert solvent to form compound VII;
(b) subjecting compound VII to a hydrolysis reaction, thereby forming compound VIII;
(c) subjecting compound VIII to an amino-protecting reaction with an amino-protecting reagent in an inert solvent, thereby forming compound IX;
(d) firstly, carrying out condensation reaction on a compound IX and 2-trifluoromethyl-6-fluoro-benzyl bromide in an inert solvent in the presence of alkali; after the condensation reaction is finished, carrying out amino deprotection reaction on the mixture containing the condensation product under an acidic condition to form a compound X;
(e) firstly, carrying out Mitsunobu reaction on a compound X and N (Boc) -D-2-phenylethanolamine in an inert solvent; after the Mitsunobu reaction is finished, carrying out amino deprotection reaction on the reaction mixture under an acidic condition to form an oxalagoni intermediate compound I.
Preferably, in any of the above methods, the conditions of step (a) to step (e) are as described above.
Preferably, in any one of the above methods, the step (a) further comprises, before step (5): compound V is subjected to a hydrolysis reaction in an inert solvent under basic conditions to form compound VI.
Preferably, in step (5), the basic conditions are carried out in the presence of a base selected from the group consisting of: sodium hydroxide, potassium carbonate and sodium carbonate.
Preferably, in step (5), the inert solvent is a combination of ethanol and water or a combination of methanol and water. Preferably, in the combination, the volume ratio of the ethanol or the methanol to the water is 1: 1-1: 10, preferably 1: 1-1: 5, and more preferably 1: 1-1: 3.
Preferably, in the step (5), the temperature of the hydrolysis reaction is 40 to 100 ℃.
Preferably, in any of the above methods, the step (5) further comprises, before step (4): and (2) carrying out a cyanation reaction on the compound IV and a cyanation reagent in an inert solvent in the presence of an acid-binding agent to form a compound V.
Preferably, in step (4), the cyanating reagent is selected from the group consisting of: trimethylsilyl cyanide, sodium cyanide and potassium cyanide.
Preferably, in the step (4), the acid scavenger is selected from the group consisting of: potassium carbonate, sodium carbonate, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, triethylamine, and N, N-diisopropylethylamine.
Preferably, in step (4), the inert solvent is acetonitrile.
Preferably, in step (4), the temperature of the cyanation reaction is 20 to 100 ℃, preferably 50 to 90 ℃, and more preferably 60 to 80 ℃.
Preferably, in any of the above methods, the step (4) further comprises, before step (3): in an inert solvent, carrying out esterification reaction on the compound III and methanesulfonyl chloride in the presence of an acid-binding agent to form a compound IV.
Preferably, in the step (3), the acid scavenger is selected from the group consisting of: potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, triethylamine and N, N-diisopropylethylamine.
Preferably, in step (3), the inert solvent is selected from the group consisting of: tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane and dichloromethane.
Preferably, in the step (3), the temperature of the esterification reaction is from-10 ℃ to 25 ℃.
Preferably, in any of the above methods, the step (3) further comprises, before step (2): compound II is subjected to a reduction reaction in an inert solvent in the presence of a reducing agent to form compound III.
Preferably, in step (2), the reducing agent is selected from the group consisting of: sodium borohydride, potassium borohydride, borane.
Preferably, in step (2), the inert solvent is selected from the group consisting of: ethanol, methanol, diethyl ether, ethylene glycol dimethyl ether, 1, 4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran and dichloromethane.
Preferably, in the step (2), the temperature of the reduction reaction is 0 to 100 ℃.
Preferably, in any of the above methods, the step (2) further comprises, before step (1): in an inert solvent, under the action of alkali, 2-fluorobenzyl ether and N, N-dimethylformamide are subjected to condensation reaction, so that a compound II is formed.
Preferably, in step (1), the inert solvent is selected from the group consisting of: n, N-dimethylformamide, N-methylpyrrolidone, tetrahydrofuran, 2-methyltetrahydrofuran and 1, 4-dioxane.
Preferably, in step (1), the base is selected from the group consisting of: n-butyllithium, t-butyllithium, sec-butyllithium, and potassium tert-butoxide.
Preferably, in step (1), the condensation reaction is carried out at a temperature of-78 ℃ to-50 ℃, preferably-78 ℃ to-65 ℃.
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are percentages and parts by weight. The test materials and reagents used in the following examples are commercially available without specific reference.
Unless otherwise defined, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs, and it is to be noted that the terms used herein are merely for describing particular embodiments and are not intended to limit example embodiments of the present application.
Example 1
Adding 2-fluorophenylmethyl ether (85.0g, 0.67mol), tetrahydrofuran (3540mL), tetramethylethylenediamine (78.3g, 0.67mol) into a three-neck flask at room temperature, replacing with nitrogen for three times, starting stirring, cooling to-50-78 ℃, dripping sec-butyl lithium solution (870mL, 1.3M), keeping the temperature and stirring for 2-3 hours after dripping is finished, dropwise adding N, N-dimethylformamide (67.5g, 0.92mol), keeping the temperature and stirring for 1 hour, dropwise adding 13% acetic acid aqueous solution (1464g) at the temperature of between 50 ℃ below zero and 78 ℃ below zero after the reaction is finished, separating liquid, extracting an aqueous phase by using ethyl acetate (350mL by 3), combining organic phases, washing by using 1N hydrochloric acid after washing by using water (500mL), concentrating the organic phase until no liquid drop exists to obtain a light yellow mixture, crystallizing by using methyl tert-butyl ether (150mL) to obtain a white solid, and drying to obtain a compound II (57.7g, 57.3%).1HNMR-(300MHz，CDCl3)δ，10.38(s，1H)，7.39-7.43(m，1H)，7.17-7.21(m，2H)，3.93(s，3H)。LCMS(ESI)m/z：155.3(MH+)。
Example 2
Adding the compound II (104.8g, 0.68mol) and sodium borohydride (13.0g, 0.34mol) into a three-neck flask at room temperature, adding methanol (1000mL), and stirring and reacting at 15-50 ℃ for 0.5-1.5 hours. After the reaction, a 5% diluted hydrochloric acid aqueous solution was dropped into the system, followed by extraction with ethyl acetate, liquid separation, washing of the organic phase with saturated brine, and concentration of the organic phase until no liquid was dropped and distillation were carried out to obtain Compound III (107.0g, 100%).1HNMR-(300MHz，CDCl3)δ：7.05-7.07(m，1H)，6.99-7.01(s，1H)，6.92-6.94(m，1H)，4.76(s，2H)，3.89(s，3H)。
Example 3
Adding a compound III (107g, 0.68mol) and tetrahydrofuran (1000mL) into a three-neck flask at room temperature, stirring, cooling to 0-10 ℃, dropwise adding triethylamine (90.1g, 0.89mol) and methanesulfonyl chloride (95.2g, 0.83mol), and reacting for 2-4 hours under heat preservation. After the reaction, water (500mL) was added to the system, 5% diluted hydrochloric acid (150mL) was added, ethyl acetate was added for extraction (300mL × 3), the organic phases were combined, washed with saturated brine, concentrated and purified with methyl tert-ether to obtain compound IV (134.0g, 83.5%).1HNMR(300MHz，CDCl3)δ：7.09-7.13(m，1H)，6.99-7.02(m，2H)，5.30(s，3H)，3.90(s，3H)，2.99(s，3H)。
Example 4
Adding the compound IV (190.6g, 0.81mol) and acetonitrile (2300mL), potassium carbonate (168.69g, 1.22mol) and trimethylsilyl cyanide (121.08g, 1.22mol) into a three-neck flask at room temperature, and heating to 60-80 ℃ for reacting for 4-6 hours until the reaction is finished. Cooling to normal temperature, adding saturated sodium bicarbonate aqueous solution (1000mL), separating, extracting the aqueous phase with ethyl acetate (350mL × 3), combining the organic phases, washing with 4% ferrous sulfate solution, washing with saturated brine, concentrating the organic phase until a solid is precipitated, filtering and drying to obtain a brown yellow solid which is compound V (132.0g, 98.2%).1HNMR(300MHz，CDCl3)δ：7.08-7.13(m，1H)，6.94-7.02(m，2H)，3.89(s，3H)，3.77(s，2H)。
Example 5
At room temperature, a three-neck flask is added with a compound V (40.2g, 0.24mmol), ethanol (200mL) and water (200mL), added with sodium hydroxide (29.2g, 0.73mol) and heated to 40-100 ℃ until the reaction is completed. Concentrating ethanol, adding methyl tert-butyl ether for washing, cooling to 0-10 ℃, adjusting the pH to 3-4 with dilute hydrochloric acid, filtering and drying to obtain a light brown solid which is a compound VI (43.2g, 96.4%).1HNMR(300MHz，CDCl3)δ：7.03-7.05(m，1H)，6.84-6.92(m，1H)，6.80-6.82(m，1H)，3.87(s，3H)，3.71(s，2H)。LCMS(ESI)m/z：183.3(MH-)。
Example 6
Compound VI (9.7g, 52.7mmol) and methylene chloride (80mL) were added to a three-necked flask at room temperature, and after stirring to dissolve it, sulfoxide chloride (18.6g, 156.3mmol) was added dropwise thereto, followed by stirring at room temperature until the reaction was completed. The thionyl chloride was evaporated and dichloromethane (50mL) was added to dissolve the supernatant. Dropping 1- [1- (dimethylamino) ethylene]A mixture of-2-methylthiourea hydrogen iodide (15.1g, 52.7mmol) and triethylamine (26.6g, 0.26mol) was stirred until the reaction was complete, water (100mL) was added, the layers were separated, the organic phase was washed with saturated brine, the concentrate was purified with ethyl acetate and filtered to dryness to give compound VII as a white solid (10.9g, 73.8%).1HNMR(300MHz，DMSO)δ：7.08-7.16(m，2H)，6.77-6.79(m，1H)，3.88(s，3H)，2.59(s，3H)，2.10(s，3H)。LCMS(ESI)m/z：281.7(MH+)。
Example 7
Adding the compound VII (4.0g, 14.3mmol) and sulfuric acid (40mL, 2N) into a three-necked flask at room temperature, heating to 50-80 ℃, stirring until the reaction is complete, cooling to room temperature, filtering, washing with water, and drying to obtain a white solid which is the compound VIII (3.5g, 98.0%).1HNMR(300MHz，DMSO)δ：11.14(s，1H)，11.04(s，1H)，7.07-7.14(m，2H)，6.73-6.77(m，1H)，3.82(s，3H)，1.87(s，3H)。LCMS(ESI)m/z：251.6(MH+)。
Example 8
Adding a compound VI (58.8g, 0.32mol) and dichloromethane (580mL) into a three-neck flask at room temperature, stirring to dissolve, dropwise adding thionyl chloride (76.14g, 0.64mol), stirring at room temperature until the reaction is complete, evaporating the thionyl chloride, adding dichloromethane (1160mL), dissolving, dropwise adding a mixed solution of 1- [1- (dimethylamino) ethylene ] -2-methylthiourea hydrogen iodide (91.7g, 0.32mol) and triethylamine (96.9g, 0.96mol), stirring until the reaction is complete, adding water (600mL), separating, washing an organic phase with saturated saline, adding sulfuric acid (64mL, 2N) into a concentrate, adding water (600mL), heating to 50-80 ℃, stirring until the reaction is complete, cooling to room temperature, filtering, washing with water, and drying to obtain a white solid which is a compound VIII (75.0g, 83.8%).
Example 9
A three-necked flask was charged with dry tetrahydrofuran (50mL), pyridine (1.58g, 0.02mol), DMAP (0.244g, 0.002mol), Compound VIII (5g, 0.02mol), nitrogen-substituted three times, stirred while controlling the temperature at 20 ℃ and Boc anhydride (4.8g, 0.022mol) was slowly added dropwise. After the dropwise addition, the temperature was raised to 70 ℃ to react for 2 hours. The temperature was lowered to 20 ℃ and Boc anhydride (4.8g, 0.022mol) was slowly added dropwise, and after the addition, the temperature was raised to 70 ℃ for reaction for 2 hours. The above supplementing step was repeated four times. The reaction was stopped, concentrated, extracted with methyl tert-butyl ether and water, dried and concentrated to give compound IX (3.5g, 50%). 1HNMR- (400MHz, CDCl3) δ 9.93(s, 1H), 7.09-7.13(m, 1H), 6.96-7.00(m, 1H), 6.82-6.86(m, 1H), 3.89(s, 3H), 2.04-2.07(m, 3H), 1.58-1.62(m, 9H). m/z: 251.3(MH +).
Example 10
Into a three-necked flask was charged DMF (10mL), Compound IX (1.1g,3mmol), 2-trifluoromethyl-6-fluoro-benzyl bromide (0.8g,3mmol), potassium carbonate (0.87g, 6mmol), TBAI (0.011g, 0.03 mmol). The temperature is raised to 75 ℃, and the reaction is stirred for 3 hours. The reaction was stopped, extracted with ethyl acetate (20mL) and water (20mLx3), and dried over anhydrous magnesium sulfate. The resulting solution was added dropwise to 10mL (4.76mol/L) of a hydrogen chloride solution of ethyl acetate. After the dropwise addition, the reaction mixture was stirred at 30 ℃ for 16 hours to stop the reaction. Water was added for washing, and the organic phase was dried and concentrated to obtain Compound X (1.1g, 83.6%). 1HNMR (400MHz, DMSO) δ ═ 11.54(s, 1H), 7.54-7.63(m, 3H), 7.13-7.14(m, 2H), 6.71-6.72(m, 1H), 5.31(s, 2H), 3.83(s, 3H), 2.02(s, 3H). m/z: 427.3(MH +). HPLC: 93.6 percent.
Example 11
A three-necked flask was charged with compound X (1.0g,2.4mmol), N- (tert-butoxycarbonyl) -D-2-phenylethanolamine (0.67g,2.8mmol), triphenylphosphine (0.74g, 2.8mmol) and tetrahydrofuran (50 ml). Diisopropyl azodicarboxylate (0.71g, 3.5mmol) was added dropwise while controlling the temperature at 20-30 ℃. After completion of the reaction, concentrated hydrochloric acid (1mL) was added. Stirring at 50-60 ℃ to react completely, and concentrating to remove tetrahydrofuran. To the residue were added isopropyl acetate and an aqueous sodium hydroxide solution, followed by stirring and liquid separation. The organic phase is concentrated and separated by column chromatography (ethyl acetate: n-hexane 20% to 100%) to obtain compound I (0.5g, 39%). m/z: 546.2(MH +).
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.
Claims (10)
1. A synthetic method of an oxalagori intermediate compound X is characterized by comprising the following steps:
(a) subjecting compound VI to a cyclization reaction with 1- [1- (dimethylamino) ethylene ] -2-methylthiourea salt in an inert solvent to form compound VII;
(b) subjecting compound VII to a hydrolysis reaction, thereby forming compound VIII;
(c) subjecting compound VIII to an amino-protecting reaction with an amino-protecting reagent in an inert solvent, thereby forming compound IX;
(d) firstly, carrying out condensation reaction on a compound IX and 2-trifluoromethyl-6-fluoro-benzyl bromide in an inert solvent in the presence of alkali; after the condensation reaction is finished, carrying out amino deprotection reaction on the mixture containing the condensation product under an acidic condition, thereby forming an oxagol intermediate compound X.
2. A synthetic method of an oxalagori intermediate compound I is characterized by comprising the following steps:
(a) subjecting compound VI to a cyclization reaction with 1- [1- (dimethylamino) ethylene ] -2-methylthiourea salt in an inert solvent to form compound VII;
(b) subjecting compound VII to a hydrolysis reaction, thereby forming compound VIII;
(c) subjecting compound VIII to an amino-protecting reaction with an amino-protecting reagent in an inert solvent, thereby forming compound IX;
(d) firstly, carrying out condensation reaction on a compound IX and 2-trifluoromethyl-6-fluoro-benzyl bromide in an inert solvent in the presence of alkali; after the condensation reaction is finished, carrying out amino deprotection reaction on the mixture containing the condensation product under an acidic condition to form a compound X;
(e) firstly, carrying out Mitsunobu reaction on a compound X and N (Boc) -D-2-phenylethanolamine in an inert solvent; after the Mitsunobu reaction is finished, carrying out amino deprotection reaction on the reaction mixture under an acidic condition to form an oxalagoni intermediate compound I.
3. The method of synthesis of claim 1 or 2, wherein step (a) comprises the steps of: firstly, carrying out acylation reaction on a compound VI (2-fluoro-3-methoxy-phenylacetic acid) in an inert solvent in the presence of an acylation reagent, and removing the redundant acylation reagent after the acylation reaction is finished; the mixture obtained after removing the excess acylating agent is then subjected to a cyclization reaction with 1- [1- (dimethylamino) ethylene ] -2-methylthiouronium salt in an inert solvent in the presence of an acid-binding agent to form compound VII.
4. The synthetic method of claim 3 wherein in step (a), the acylating reagent is selected from the group consisting of: thionyl chloride, oxalyl chloride, or combinations thereof.
5. The synthetic method of claim 3 wherein in step (a), the acid scavenger is selected from the group consisting of: potassium carbonate, sodium carbonate, triethylamine, N-diisopropylethylamine, or a combination thereof.
6. The method of synthesis according to claim 1 or 2, wherein in step (b) the hydrolysis reaction is carried out under acidic conditions.
7. The method of claim 1 or 2, wherein in step (c) the amino protecting reagent is Boc anhydride.
8. The method of claim 7, wherein in step (c) said Boc anhydride is used in an amount greater than 5 equivalents.
9. The synthesis process according to claim 1 or 2, characterized in that in step (d), the acidic conditions are in the presence of a solution containing hydrogen chloride.
10. The method of claim 2, wherein in step (e), the acidic conditions are in the presence of concentrated hydrochloric acid.
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| CN113683572A (en) * | 2020-05-18 | 2021-11-23 | 陈晓雯 | Intermediate of oxadegril and preparation method and application thereof |
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