CN110498770B - Method for preparing intermediate of oxaagolide - Google Patents
Method for preparing intermediate of oxaagolide Download PDFInfo
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- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
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Abstract
The invention relates to a method for preparing an intermediate of diragolide. Specifically, the invention discloses a preparation method for a key intermediate compound E8 of the diragolide, and compounds such as a compound C and the like for preparing the intermediate compound E8.
Description
Technical Field
The invention belongs to the field of drug synthesis, and particularly provides an intermediate and a method for preparing diragolide.
Background
The malagolide is a novel oral gonadotropin releasing hormone antagonist developed by Neurocrine Biosciences and AbbVie and used for treating endometriosis and uterine fibroids. Erbavil has filed new drug applications for the endometriosis of the moraxella in 2017 to the FDA.
The structural formula of the crystal is shown as follows:
the existing synthesis routes of the oxaagolide are mainly as follows:
1) Patent WO2005007165 reports that 2-fluoro-6- (trifluoromethyl) benzonitrile is used as raw material and is subjected to BH 3 Reducing, condensing with urea in hydrochloric acid water solution to obtain compound I-3, cyclizing with diketene to obtain pyrimidinedione cyclic compound I-4, bromizing at 5-position, reacting with N-tert-butoxy-D-phenylglycinol side chain to obtain compound I-6, suzuki coupling the compound I-6 with 2-fluoro-3-methoxyphenyl boric acid in a sealed tube, and performing column chromatography to obtain compound I-7. Removing Boc protection from I-7, substituting with 4-ethyl bromobutyrate, performing column chromatography to obtain a compound I-9, hydrolyzing the compound I-9 with sodium hydroxide, adjusting pH to 3 with citric acid, extracting, concentrating, and performing macroporous cation exchange column to obtain the Lagolide sodium salt. This route has some drawbacks: the preparation of I-6 by the Mitsunobu reaction is not suitable for industrial amplification and needs column chromatography purification, the preparation of I-7 needs special equipment for tube sealing, the danger is high, and the preparation of I-7 and I-9 both need column chromatography purification, and the yield is low.
2) Patent WO2009062087 uses o-fluoro anisole as a raw material, reacts with acetoacetic acid tert-butyl ester to obtain a compound II-3, and then the compound II-3 is subjected to reduction, mesylation and bromination to obtain II-6, the compound II-6 uses zinc as a catalyst, the compound II-7 reacts with acetonitrile to obtain enamine II-7 (Blies reaction), the compound II-8, II-8 and the compound II-10 are subjected to phenoxyl protection to obtain pyrimidinedione II-9, which is then cyclized with 2-fluoro-6- (trifluoromethyl) benzyl bromide and ethyl bromobutyrate to obtain I-9, and finally the compound I-9 is hydrolyzed to obtain the olagolide. The process has long steps and low yield. The first step requires a low temperature reaction, and the yield of the Brece reaction is relatively low.
3) Patent WO2009062087 also reports that carbamide I-3 is taken as a raw material, is cyclized with acetoacetic acid tert-butyl ester to obtain pyrimidinedione I-4, is subjected to iodination, is coupled with 2-fluoro-3-methoxyphenyl boric acid to obtain III-2, and is subjected to two-step substitution and one-step hydrolysis reaction to obtain the loragolide. The route uses virulent iodine chloride, is expensive and unsafe to operate, and is not suitable for industrial production.
Therefore, there is still a need in the art to develop a method for preparing loragolide suitable for large-scale industrial production.
Disclosure of Invention
The invention aims to provide a preparation method of the diragolide, which has mild reaction and simple and convenient operation and is suitable for large-scale industrial production.
The invention provides a preparation method of an intermediate compound E8, which comprises the following steps: reacting compound C with compound E7 in an inert solvent, thereby forming compound E8;
wherein R is 1 Is C1-C6 alkyl or benzyl.
In another preferred example, the reaction is carried out, and water removal treatment is required; preferably, water removal is performed with a water separator.
In another preferred example, the method comprises the steps of: reacting the compound C with the compound E7 in an inert solvent, adding a dehydrating agent to continue the reaction after the compound C is completely consumed, thereby forming a compound E8.
In another preferred example, the dehydrating agent is p-toluenesulfonic acid monohydrate.
In another preferred embodiment, the inert solvent is selected from the group consisting of: toluene, xylene, or combinations thereof.
In another preferred embodiment, the reaction is carried out at the reflux temperature of the solvent.
In another preferred embodiment, R 1 Is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl or benzyl.
In another preferred embodiment, the preparation method of compound C comprises the steps of: compound B and
reacting to form compound C;
wherein R is 1 The definition is the same as above.
In another preferred embodiment, the solvent is selected from the group consisting of: DMSO, DMF, or a combination thereof.
In another preferred embodiment, the ligand is selected from the group consisting of: trans-4-hydroxy-L-proline, 1, 3-benzoxazole, 1, 10-phenanthroline and L-proline.
In another preferred embodiment, the catalyst is selected from the group consisting of: cuprous bromide, cuprous iodide, cuprous chloride, or combinations thereof.
In another preferred embodiment, the reaction requires a base selected from the group consisting of: potassium carbonate, sodium hydroxide, cesium carbonate, potassium phosphate, triethylamine, diisopropylethylamine, or a combination thereof.
The invention also provides an intermediate compound C,
wherein R1 is C1-C6 alkyl or benzyl.
The invention also provides a preparation method of the intermediate compound C, which comprises the following steps: in a solvent, under the catalysis of a ligand and a catalyst, the compounds B and
the reaction is carried out, and the reaction solution is mixed,to form compound C;
wherein R is 1 The definition is the same as above.
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 repeated herein, depending on the space.
Detailed Description
The inventor finds a novel method for preparing the diragolide through extensive and intensive research, breaks through the existing technical barriers, reduces the reaction steps, has mild reaction conditions and simple and convenient operation, and is suitable for small-scale preparation in a laboratory and large-scale industrial production. The present invention has been completed on the basis of this finding.
Term(s)
As used herein, "inert solvent" refers to a solvent that does not react with the reaction starting materials in the reaction in which the solvent participates.
As used herein, "C1-C6 alkyl" refers to a straight or branched chain alkyl group having 1 to 6 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, or the like.
Intermediate product
The invention provides an intermediate compound with a novel structure for preparing the diragolide, which has the following structure:
wherein R1 is C1-C6 alkyl or benzyl.
Preparation method
The invention also provides a preparation method of a plurality of intermediate compounds for preparing the diragolide. For example,
the invention provides a preparation method for a key intermediate E8 of diragolide, which comprises the following steps: reacting compound C and compound E7 in an inert solvent, thereby forming compound E8;
wherein R is 1 Is C1-C6 alkyl or benzyl.
In another preferred example, the reaction is carried out, and water removal treatment is required; preferably, water removal is performed with a water separator.
Specifically, the method comprises the steps of: reacting the compound C with the compound E7 in an inert solvent, adding a dehydrating agent to continue the reaction after the compound C is completely consumed, thereby forming a compound E8.
In another preferred example, the dehydrating agent is p-toluenesulfonic acid monohydrate.
In another preferred embodiment, the inert solvent is selected from the group consisting of: toluene, xylene, or combinations thereof.
In another preferred embodiment, the reaction is carried out at the reflux temperature of the solvent.
In another preferred embodiment, the reaction time is within 4 to 8 hours; preferably, it is 6 hours.
In another preferred embodiment, the preparation method of compound C comprises the steps of: in a solvent, under the catalysis of a ligand and a catalyst, the compounds B and
reacting to form a compound C;
wherein R is 1 The definition is the same as above.
The reaction is carried out at 40-80 ℃.
The solvent is selected from the group consisting of: DMSO, DMF, or a combination thereof.
The ligand is selected from the group consisting of: trans-4-hydroxy-L-proline, 1, 3-benzoxazole, 1, 10-phenanthroline and L-proline.
The catalyst is selected from the group consisting of: cuprous bromide, cuprous iodide, cuprous chloride, or combinations thereof.
The reaction requires a base selected from the group consisting of: potassium carbonate, sodium hydroxide, cesium carbonate, potassium phosphate, triethylamine, diisopropylethylamine, or a combination thereof.
In another preferred embodiment, the preparation method of the compound B comprises the steps of: in a solvent, carrying out an iodination reaction on the compound A to form a compound B;
the invention also provides a preparation method of the oxaagolide, wherein the intermediate compound E8 is used as a raw material to prepare the oxaagolide, and the specific steps can refer to the steps from the compound III-2 to the preparation of the oxaagolide in the patent WO 2009062087.
In addition, the preparation of compound E7 can refer to the field technicians familiar with the method, can also be used in the application of the disclosed experimental steps.
The main advantages of the invention are:
the invention provides a novel method for preparing the diragolide.
The method simplifies the preparation steps, and has mild conditions, no need of special equipment and no need of highly toxic and harmful reagents, thereby having simpler and safer operation and lower cost.
The method is suitable for small-scale preparation in a laboratory and is also suitable for large-scale industrial production.
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 by weight.
The test materials and reagents used in the following examples are commercially available without specific reference.
Preparation of oxaagolide
EXAMPLE 1 preparation of 2-fluoro-3-methoxyiodobenzene B
Adding 15.56g of pentamethyl-di- (ethylene) triamine and 200ml of THF into a 500ml three-neck flask, dropwise adding 35.2ml of n-BuLi at-78 ℃, stirring for 40min, dropwise adding 10g of 2-fluorophenylmethyl ether, stirring for 1h at-78 ℃, and dropwise adding I 2 22.84g THF solution 100ml, 78 degrees after stirring for 2 hours, the reaction liquid to room temperature, with 400ml saturated ammonium chloride solution quenching, liquid separation, organic phase layer rotary evaporation to remove solvent, residual liquid with ethyl acetate 200ml, using sodium sulfite saturated solution, saturated saline water washing, organic phase with anhydrous sodium sulfate drying, filtration, filtrate concentration, yellow liquid 18.16g (yield 90.89%).
1 H NMR(CDCl 3 )δ3.88(s,3H),6.83-6.85(m,1H),6.90-6.92(m,1H),7.28-7.30(m,1H)；MS(ESI)m/z 253.12(MH + )。
EXAMPLE 2 preparation of tert-butyl 2- (2-fluoro-3-methoxyphenyl) -3-oxo-butyrate (R1 is tert-butyl) C-1
A250 ml reaction flask was charged with B15 g, t-butyl acetoacetate 19g, cuprous iodide 4.6g, trans-4-hydroxy-L-proline 6.3g, cesium carbonate 78g and DMSO 150ml, and the mixture was heated with stirring and reacted at 60 ℃ for four days. Then the reaction solution was cooled to room temperature, the solid was removed by filtration, the mother liquor was diluted with water, extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a black oily substance, which was subjected to column chromatography to give 5.37g (yield 32%) of a yellow oily liquid.
1 H NMR(CDCl 3 )δ1.38(s,9H),1.83(s,1.4H),2.21(s,1.6H),3.88(s,3H),4.96(s,0.53H),6.67(t,0.44H),6.69-7.09(m，2.51H)，13.33(s,0.47H)；MS(ESI)m/z 283.31(MH + )。
EXAMPLE 3 preparation of 2- (2-fluoro-3-methoxyphenyl) -3-oxo-butyric acid ethyl ester (R1 is ethyl) C-2
A250 ml reaction flask was charged with B15 g, ethyl acetoacetate 18g, cuprous iodide 4.6g, trans-4-hydroxy-L-proline 6.3g, cesium carbonate 78g and DMSO 150ml, and the mixture was heated with stirring and reacted at 60 ℃ for four days. Then the reaction solution was cooled to room temperature, the solid was filtered off, the mother liquor was diluted with water, extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered under suction, and the filtrate was concentrated to give a black oily substance, which was subjected to column chromatography to give 4.38g (yield 29%) of a yellow oily liquid.
1 H NMR(CDCl 3 )δ1.28(t,3H),1.86(s,1.8H),2.23(s,1.2H),3.89(s,3H),4.15(m,2H)；5.05(s,0.4H),6.72(t,0.6H),6.90-7.10(m，2.4H)，13.2(s,0.63H)；MS(ESI)m/z 255.10(MH + )。
Example 4 preparation of benzyl 2- (2-fluoro-3-methoxyphenyl) -3-oxo-butyrate (R1 is benzyl) C-3
A250 ml reaction flask was charged with 15g of B, 20.2g of benzyl acetoacetate, 4.6g of cuprous iodide, 6.2g of trans-4-hydroxy-L-proline, 78g of cesium carbonate and 150ml of DMSO, and the mixture was heated with stirring and reacted at 60 ℃ for four days. Then the reaction solution was cooled to room temperature, the solid was filtered off, the mother liquor was diluted with water, extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a black oily substance, which was subjected to column chromatography to give 5.65g (yield 30%) of a yellow oily liquid.
MS(ESI)m/z 317.11(MH + )。
EXAMPLE 5 preparation of methyl 2- (2-fluoro-3-methoxyphenyl) -3-oxo-butanoate (R1 is methyl) C-4
A250 ml reaction flask was charged with B15 g, methyl acetoacetate 14g, cuprous iodide 4.6g, trans-4-hydroxy-L-proline 6.2g, cesium carbonate 78g and DMSO 150ml, and the mixture was heated with stirring and reacted at 60 ℃ for four days. Then the reaction solution was cooled to room temperature, the solid was filtered off, the mother liquor was diluted with water, extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a black oily substance, which was subjected to column chromatography to give 4.43g (yield 31%).
MS(ESI)m/z 241(MH + )。
EXAMPLE 6 preparation of 2-fluoro-6-trifluoromethylbenzylamine E6
In a 100ml three-necked flask, 5g of E, 2.17g of hydroxylamine hydrochloride and 50ml of absolute ethanol were added, and after stirring and reacting at room temperature for 1 hour, hydrochloric acid (6 mol/L,8.7 ml) was added dropwise at room temperature, 5.1g of zinc powder was added, and after stirring at 35 ℃ or lower for 0.5 hour, the mixture was filtered and concentrated to remove ethanol, water and ethyl acetate were added to the residue, liquid separation was performed, the pH of the aqueous phase was adjusted to 11 with sodium hydroxide, the aqueous phase was extracted 2 times with dichloromethane, the organic phase was washed with saturated brine, dried with anhydrous sodium sulfate, suction filtration and concentration of the filtrate were performed to obtain 2.39g of a yellow oily substance (yield 47.50%).
EXAMPLE 7 preparation of 2-fluoro-6-trifluoromethylbenzylamine E6
Adding 2.4g of hydroxylamine hydrochloride and 50ml of water into a 250ml three-neck flask, adjusting the water phase to be neutral by using 10% sodium hydroxide, then slowly dropwise adding an ethanol solution (5 g/20 ml) of E5, stirring for 1h after dropwise adding, adding 6g of zinc powder in batches, dropwise adding hydrochloric acid (6 mol/L,40 ml), reacting for 2h, filtering, and adding 50ml of ammonia water into the filtrate. The mixture was then adjusted to pH 11 with 6ml of 33% sodium hydroxide, extracted with dichloromethane, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered with suction, and the filtrate was concentrated to give 4.78g (yield 95%) of a yellow oil.
EXAMPLE 8 preparation of 1- [ 2-fluoro-6- (trifluoromethyl) benzyl ] urea E7
3.4g of E6, 20ml of water, 4.23g of urea and hydrochloric acid (12 mol/L,2 ml) are added into a 250ml three-neck bottle, reflux reaction is carried out for 3 hours, and then the reaction solution is cooled to 4 ℃ by using an ice water bath and filtered to obtain 3.78g of white solid (the yield is 91%).
1 H NMR(DMSO-d 6 )δ4.36(s,2H),5.47(s,2H),6.16(s,1H),7.49-7.61(m,3H)；MS(ESI)m/z 237.07(MH + )。
EXAMPLE 9 preparation of 5- (2-fluoro-3-methoxy-phenyl) -1- (2-fluoro-6- (trifluoromethyl) benzyl) -6-methylpyrimidine-2, 4 (1H, 3H) -dione E8
0.6g of ethyl 2- (2-fluoro-3-methoxyphenyl) -3-oxo-butyrate (C-2), 0.67g of E7 and 30ml of toluene are added into a 250ml three-necked flask, the flask is heated to reflux, a water separator divides water, and after refluxing for 4 hours, 0.67g of p-toluenesulfonic acid monohydrate is added, and the mixture is refluxed for 2 hours. The reaction was monitored by TLC and the reaction was allowed to cool to rt, concentrated under reduced pressure to remove toluene to give crude brown oil which was chromatographed to give product E8.31 g (31% yield).
1 H NMR(CDCl 3 )δ2.04(s,3H),3.88(s,3H),5.47(s,2H),6.79(m,1H),6.95(m,1H),7.10(m,1H),7.26(m，1H)，7.39(m,1H)，7.55(m，1H),8.46(s,1H)；MS(ESI)m/z 427.23(MH + )。
EXAMPLE 10 preparation of 5- (2-fluoro-3-methoxy-phenyl) -1- (2-fluoro-6- (trifluoromethyl) benzyl) -6-methylpyrimidine-2, 4 (1H, 3H) -dione E8
0.6g of 2- (2-fluoro-3-methoxyphenyl) -3-oxo-tert-butyl butyrate (C-1), 0.6g of E7, and 30ml of toluene are added into a 250ml three-neck flask, heated to reflux, a water separator divides water, and after refluxing for 4h, 0.61g of p-toluenesulfonic acid monohydrate is added, and refluxing is carried out for 2h. TLC monitors the reaction is finished, the reaction liquid is cooled to room temperature, reduced pressure concentration is carried out to remove toluene, ethyl acetate is added into residual liquid, white solid is separated out, suction filtration is carried out, and the solid is washed by cold ethyl acetate, so that 0.65g of E8 (yield is 72%) is obtained.
EXAMPLE 11 preparation of 5- (2-fluoro-3-methoxy-phenyl) -1- (2-fluoro-6- (trifluoromethyl-) benzyl) -6-methylpyrimidine-2, 4 (1H, 3H) -dione E8
0.6g of benzyl 2- (2-fluoro-3-methoxyphenyl) -3-oxo-butyrate (C-3), 0.54g of E7 and 30ml of toluene are added into a 250ml three-necked bottle, the bottle is heated to reflux, a water separator divides water, and after refluxing for 4h, 0.54g of p-toluenesulfonic acid monohydrate is added, and the mixture is refluxed for 2h. TLC monitored the reaction completion, the reaction was cooled to room temperature and concentrated under reduced pressure to remove toluene to give crude brown oil which was chromatographed to give E8.29 g (36% yield).
Example 12 preparation of 5- (2-fluoro-3-methoxy-phenyl) -1- (2-fluoro-6- (trifluoromethyl-) benzyl) -6-methylpyrimidine-2, 4 (1H, 3H) -dione E8
0.6g of (2-fluoro-3-methoxyphenyl) -3-oxo-butyric acid methyl ester (C-4), 0.71g of E7 and 30ml of toluene were added to a 250ml three-necked flask, heated to reflux, the water separator was used for water separation, and after refluxing for 4 hours, 0.7 g of p-toluenesulfonic acid monohydrate was added, and the mixture was refluxed for 2 hours. TLC monitored the reaction completion, the reaction was cooled to room temperature and concentrated under reduced pressure to remove toluene to give crude brown oil which was chromatographed to give E8.40 g (38% yield).
EXAMPLE 13 preparation of (R) -3- (2-amino-2-phenylethyl) -5- (2-fluoro-3-methoxy-phenyl) -1- (2-fluoro-6-trifluoromethyl-benzyl) -6-methylpyrimidine-2, 4 (1H, 3H) -dione E9
Adding 1g of E8, 1.1g of methanesulfonic acid (R) -2-phenyl 2-tert-butoxycarbonylaminoethyl ester, 2g of potassium carbonate and 25ml of DMF into a 250ml three-neck flask, reacting at 100 ℃ for 7h, adding isopropyl acetate and water, separating, drying an organic phase, filtering, adding 0.5g of methanesulfonic acid into a filtrate, stirring at 60 ℃ for 2h, adding water, separating, adjusting the pH of an aqueous phase to be alkaline by using an aqueous solution of potassium carbonate, extracting by using isopropyl acetate, drying and concentrating the organic phase to obtain 1g of a crude product of E9 (the yield is 78.12%).
1 H NMR(CDCl 3 )δ2.07(s,3H),3.89(s,3H),4.12(m,1H),4.28(m,1H),4.41(dd,J＝4.5,10.2Hz,1H),5.49(s,2H),6.78-6.84(ddd，J＝1.5,6.0,7.8Hz,1H),6.95-6.98(dd,J＝1.5,8.1Hz,1H),7.11(m,1H),7.21-7.28(m,2H),7.33(t,J＝6.9Hz,2H),7.37-7.46(m,3H),7.55(d,J＝7.8Hz,1H)；MS(ESI)m/z 546.22(MH + )。
Example 14 preparation of 4- ((R) -2- [3- (2-amino-2-phenylethyl) -5- (2-fluoro-3-methoxy-phenyl) -3- (2-fluoro-6-trifluoromethyl-benzyl) -4-methyl-2, 6-dioxo-3, 6-dihydro-2H-1-yl ] -1-phenyl-ethylamino) butyric acid ethyl ester-pyrimidine-2, 4 (1H, 3H) -dione E10
Adding E9 1g, DMF 10ml, ethyl 4-bromobutyrate 0.54g and diisopropylethylamine 0.5g into a 250ml three-necked bottle, stirring at 60 ℃ for 2 hours, adding isopropyl acetate and water, adjusting the pH of an aqueous phase to 2 by using 85% phosphoric acid aqueous solution, separating, adjusting the pH of the aqueous phase to be alkaline by using potassium carbonate aqueous solution, extracting by using isopropyl acetate, and drying and concentrating an organic phase to obtain E10 g (the yield is 85%).
1 H NMR(CDCl 3 )δ1.28(t,3H),1.91(m,2H),2.20-2.40(m,2H),2.71(m,1H),2.95(m,1H),3.84(s,1H),4.13(q,2H),4.15(m,1H),4.38(m,0.5H),4.60-4.80(m,1.5H),5.24(d,J＝17.1Hz，1H),5.66(d,J＝17.1Hz，1H),6.81-7.00(m,2H),7.11(t,J＝5.8Hz，1H),7.18-7.31(m,2H),7.36-7.50(m，5H),7.52(d，J＝7.8Hz，1H)；MS(ESI)m/z 660.24(MH + )。
Example 15 preparation of pergolide E11
Adding E10 g and ethanol 15ml into a 250ml three-neck bottle, then dripping 2mol/L NaOH aqueous solution 1.2ml, reacting at 50 ℃ for 2h, cooling the reaction solution to 0-10 ℃, dripping 1mol/L hydrochloric acid to adjust the pH value to 6, stirring at room temperature for 3h, and filtering to obtain off-white solid 0.8g (yield 83.59%).
1 H NMR(CD 3 OD)δ1.72(m,2H),2.08(s,3H),2.16(t,J＝6.9Hz,2H),2.50(t,J＝6.9Hz,2H),3.84(s,3H),4.24(m,3H),5.40(d,J＝9.0Hz,1H),5.46(d,J＝9.0Hz,1H),6.62-6.78(m,1H),7.12(m,2H),7.34(m,5H),7.41(m，1H),7.56(m，1H),7.61(d,J＝8.0Hz,1H)；MS(ESI)m/z 632.21(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 or 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 appended claims of the present application.
Claims (4)
1. A process for the preparation of intermediate compound E8, comprising the steps of: reacting compound C and compound E7 in an inert solvent, thereby forming compound E8;
wherein R is 1 Is a tertiary butyl group;
the preparation method of the compound C comprises the following steps: in a solvent, under the catalysis of a ligand and a catalyst, the compound B reacts to form a compound C;
the ligand is trans-4-hydroxy-L-proline;
the catalyst is selected from the group consisting of: cuprous bromide, cuprous iodide, cuprous chloride, or combinations thereof.
2. The method of claim 1, wherein the method comprises the steps of: reacting the compound C with the compound E7 in an inert solvent, adding a dehydrating agent to continue the reaction after the compound C is completely consumed, thereby forming a compound E8.
3. The method of claim 1, wherein the inert solvent is selected from the group consisting of: toluene, xylene, or combinations thereof.
4. The method according to claim 2, wherein the dehydrating agent is p-toluenesulfonic acid monohydrate.
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| CN110669014B (en) * | 2019-11-14 | 2021-04-30 | 重庆医药高等专科学校 | Preparation method of oxalagogri intermediate |
| CN110759870B (en) * | 2019-12-06 | 2021-03-23 | 上海博璞诺科技发展有限公司 | Synthesis method of oxalagogri intermediate |
| CN111333548B (en) * | 2020-04-10 | 2022-04-26 | 江苏海悦康医药科技有限公司 | Preparation method of 1- (2-fluoro-6- (trifluoromethyl) benzyl) urea |
| CN112679442B (en) * | 2021-01-08 | 2022-09-06 | 浙江乐普药业股份有限公司 | Preparation method of oxaagolide sodium |
| CN115232077A (en) * | 2021-04-22 | 2022-10-25 | 成都倍特药业股份有限公司 | Oxagolide sodium related substance and preparation method thereof |
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