CN106083759B - Brand-new synthesis process of lutofopa - Google Patents
Brand-new synthesis process of lutofopa Download PDFInfo
- Publication number
- CN106083759B CN106083759B CN201610415303.9A CN201610415303A CN106083759B CN 106083759 B CN106083759 B CN 106083759B CN 201610415303 A CN201610415303 A CN 201610415303A CN 106083759 B CN106083759 B CN 106083759B
- Authority
- CN
- China
- Prior art keywords
- ethyl
- methacrylate
- methoxyphenyl
- carbamoyl
- thiazolyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/38—Nitrogen atoms
- C07D277/44—Acylated amino or imino radicals
- C07D277/46—Acylated amino or imino radicals by carboxylic acids, or sulfur or nitrogen analogues thereof
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Thiazole And Isothizaole Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
The invention relates to the field of organic chemistry, in particular to a brand new synthesis process of eltrombopag. The invention takes 2-methoxy-1, 3-diacetylbenzene as raw material to prepare an intermediate 3- (2-aminothiazolyl-4-yl) -2-methoxyacetophenone (4), then the intermediate reacts with (E) -ethyl 3- (2, 6-dichloro-4- (chloroformyl) phenyl) -2-methacrylate (5) to obtain a key intermediate (E) -ethyl 3- (4- ((4- (3-acetyl-2-methoxyphenyl) thiazolyl-2-yl) carbamoyl) -2, 6-dichlorophenyl) -2-methacrylate (6), the key intermediate undergoes catalytic reduction and halogenation, and (4) performing hydrolysis reaction to obtain the target compound of the eltrombopag. The method has the advantages of easily obtained raw materials, mild reaction conditions, simple and convenient operation, good stability and activity of the catalyst, high total yield and convenience for large-scale preparation and production of the eltrombopag.
Description
Technical Field
The invention relates to the field of organic chemistry, in particular to the field of organic pharmacy, and more particularly relates to a brand new synthesis process of eltrombopag.
Background
Lusutrombopag (Lusutrombopag) is a small molecule Thrombopoietin (TPO) receptor antagonist used for the treatment of patients undergoing elective surgery for thrombocytopenia associated with chronic liver disease. The Chinese name of the Lutroppopa is: (E) -3- [2, 6-dichloro-4- [ [4- [3- [ (1S) -1-hexyloxyethyl ] -2-methoxyphenyl ] -1, 3-thiazolyl-2-yl ] carbamoyl) phenyl ] -2-methacrylic acid having the chemical structure shown in formula (1):
lusutrombopag (Lusutrombopag) was developed by salt Seimith corporation (Shionogi) and was approved by the Japanese drug and medical administration (PMDA) for the first global approval by 2015 at 9, 28. The preparation method of the compound disclosed in WO2009017098A1/US8530668B2 is as follows: using 3-bromo-2-methoxyacetophenone as an initiator, carrying out catalytic reduction and haloalkane substitution to obtain an intermediate (S) -1-bromo-3- (1- (hexyloxy) ethyl) -2-methoxybenzene, reacting with 2-chloro-N-methoxy-N-methylacetamide in the presence of a Grignard reagent to obtain an intermediate, cyclizing the intermediate with thiourea to obtain an intermediate (S) -4- (3- (1- (hexyloxy) ethyl) -2-methoxyphenyl) thiazolyl-2-amine, and reacting with (E) -3, 5-dichloro-4- (3-ethoxy-2-methyl-3-oxopropyl-1-en-1-yl) benzoic acid, to obtain (S, E) -ethyl 3- (2, 6-chloro-4- ((4- (3- (1- (hexyloxy) ethyl) -2-methoxyphenyl) thiazolyl-2-yl) carbamoyl) phenyl) -2-methacrylic acid ethyl ester, and then hydrolyzing to obtain the target compound, namely the eltrombopag. The reaction formula is as follows:
this synthetic route for rotpob is long, time consuming and low in yield. In the period, a format reagent is needed, the reaction condition is harsh, the cost is high, the operation is complicated, the impurities are more, and the large-scale industrial production is not facilitated.
Disclosure of Invention
Aiming at the defects in the prior art, the invention provides a brand-new synthesis process of the eltrombopag. The specific synthetic route is as follows:
(a) halogenating 2-methoxy-1, 3-diacetylbenzene (2) to obtain 3-acetyl-2-methoxy-alpha-halogenated acetophenone (3), wherein R1 is Cl, Br and I. The reaction formula is as follows:
(b) 3-acetyl-2-methoxyl-alpha-halogenated acetophenone (3) and thiourea undergo a cyclization reaction to obtain 3- (2-aminothiazolyl-4-yl) -2-methoxyacetophenone (4), and the reaction formula is as follows:
(c)3- (2-aminothiazolyl-4-yl) -2-methoxyacetophenone (4) and (E) -ethyl 3- (2, 6-dichloro-4- (chloroformyl) phenyl) -2-methacrylate (5) are reacted to give (E) -ethyl 3- (4- ((4- (3-acetyl-2-methoxyphenyl) thiazolyl-2-yl) carbamoyl) -2, 6-dichlorophenyl) -2-methacrylate (6), wherein R2 ═ C1-5 alkyl, C1-5 alkoxymethyl, aryl. The reaction formula is as follows:
(d) (E) -ethyl 3- (4- ((4- (3-acetyl-2-methoxyphenyl) thiazolyl-2-yl) carbamoyl) -2, 6-dichlorophenyl) -2-methacrylate (6), by asymmetric catalytic reduction to give (S, E) -ethyl 3- (2, 6-dichloro-4- ((4- (3- (1-hydroxyethyl) -2-methoxyphenyl) thiazolyl-2-yl) carbamoyl) phenyl) -2-methacrylate (7), wherein R2 ═ C1-5 alkyl, C1-5 alkoxymethyl, aryl, benzyl; the chiral catalyst is: a complex of 3, 5-bis (3-methylbut-2-yl) salicylaldehyde Schiff base zinc corresponding to L-valine, L-phenylalanine, L-leucine and L-alanine, and a reducing agent is sodium borohydride/methanol-tetrahydrofuran, sodium borohydride/cerium trichloride. The reaction formula is as follows:
(e) (S, E) -ethyl 3- (2, 6-dichloro-4- ((4- (3- (1-hydroxyethyl) -2-methoxyphenyl) thiazolyl-2-yl) carbamoyl) phenyl) -2-methacrylate (7) and 1-halohexane (8) are subjected to substitution reaction to obtain (S, E) -ethyl 3- (2, 6-dichloro-4- ((4- (3- (1- (hexyloxy) ethyl) -2-methoxyphenyl) thiazolyl-2-yl) carbamoyl) phenyl) -2-methacrylate (9), wherein R2 ═ C1-5 alkyl, C1-5 alkoxymethyl, aryl, benzyl; r3 ═ Cl, Br, I, p-toluenesulfonate, trifluoromethanesulfonate, methylsulfonate; the reaction formula is as follows:
(f) (S, E) -ethyl 3- (2, 6-dichloro-4- ((4- (3- (1- (hexyloxy) ethyl) -2-methoxyphenyl) thiazolyl-2-yl) carbamoyl) phenyl) -2-methacrylate (9) is hydrolyzed to obtain a target compound, namely the eltrombopag (1), and the reaction formula is as follows:
in conclusion, the reaction formula of the brand-new synthesis process of the eltrombopag provided by the invention is as follows:
compared with the prior art, the novel synthesis process of the eltrombopag provided by the invention overcomes the defects of the prior art, and provides a novel synthesis process of the eltrombopag with simplicity, convenience and high optical purity. Meanwhile, the raw materials are easy to obtain, the reaction condition is mild, the operation is simple and convenient, the catalyst is easy to prepare, has good stability and activity, and is convenient for large-scale preparation and production of the eltrombopag, and the total yield of the eltrombopag prepared by the method is obviously improved and can reach more than 80%.
Detailed Description
In order to make the technical means, the creation characteristics, the achievement purposes and the effects of the invention easy to understand, the invention is further described with the specific embodiments.
Example 1
(a) Preparation of 3-acetyl-2-methoxy- α -haloacetophenone: 50ml of ethanol and 9.6g (50mmol) of 2-methoxy-1, 3-diacetylbenzene are added into a reactor with magnetic stirring, 0.26ml (1eq) of liquid bromine is added at the temperature of-5 ℃ in one step, the reaction temperature is controlled between-5 ℃ and 5 ℃ until the color of the bromine is basically disappeared, then the ethanol is evaporated under reduced pressure, 100ml of ice water is added, ethyl acetate is extracted for three times (50ml x3), saturated sodium bicarbonate is washed to be neutral, saturated common salt water is washed, magnesium sulfate is dried, and an organic solvent is evaporated to obtain a white-like solid 3-acetyl-2-methoxy-alpha-halogenated acetophenone (13.4g, the yield is 99 percent), and the crude product is directly used for the next reaction without separation.
(b) Preparation of 3- (2-aminothiazolyl-4-yl) -2-methoxyacetophenone: in a reactor equipped with magnetic stirring, 13.4g (49.4mmol) of 3-acetyl-2-methoxy- α -haloacetophenone and 100ml of ethanol were added, followed by 3.75g (49.4mmol) of thiourea, and after refluxing under heating for 6 hours, cooling and removing ethanol by evaporation under reduced pressure were carried out to obtain 3- (2-aminothiazolyl-4-yl) -2-methoxyacetophenone as a reddish semi-oily solid (11.7g, yield 95%), which was used in the next reaction without separation.
(c) Preparation of (E) -ethyl 3- (4- ((4- (3-acetyl-2-methoxyphenyl) thiazolyl-2-yl) carbamoyl) -2, 6-dichlorophenyl) -2-methacrylate: installing a reaction device, dissolving 15.2g (47.1mmol) of (E) -ethyl 3- (2, 6-dichloro-4- (chloroformyl) phenyl) -2-methacrylate in 120ml of Tetrahydrofuran (THF), adding 5.3g (52.5mmol) of triethylamine, controlling the temperature below 5 ℃, slowly adding 11.7g (47.1mmol) of 3- (2-aminothiazolyl-4-yl) -2-methoxyacetophenone obtained in the previous step, gradually returning to room temperature, detecting by Thin Layer Chromatography (TLC) and finishing the reaction, evaporating THF under reduced pressure, adding 150ml of ice water, extracting three times (3x50ml) of ethyl acetate, washing twice with water, combining organic phases, drying with anhydrous sodium sulfate, and evaporating an organic solvent to obtain a semi-oily solid (E) -ethyl 3- (4- ((4- (3-acetyl-2-methoxyphenyl) thiazolyl-2- Yl) carbamoyl) -2, 6-dichlorophenyl) -2-methacrylate 24.5g (46.1mmol, yield 98%) and the crude product was used in the next reaction without isolation.
(d) Preparation of (S, E) -ethyl 3- (2, 6-dichloro-4- ((4- (3- (1-hydroxyethyl) -2-methoxyphenyl) thiazolyl-2-yl) carbamoyl) phenyl) -2-methacrylate: in a three-necked flask equipped with mechanical stirring, the catalyst L-valine 3, 5-bis (3-methylbut-2-yl) salicylaldehyde Schiff base zinc complex (0.01mol, 1.5 mol%) (referring to the amount of the substance with the catalyst being 1.5% of the substrate) and 150mL anhydrous THF and 15mL methanol were added at-5 deg.C, 24.6g (46.2mmol) of the (E) -ethyl 3- (4- ((4- (3-acetyl-2-methoxyphenyl) thiazolyl-2-yl) carbamoyl) -2, 6-dichlorophenyl) -2-methacrylate formed in the above step was added, stirring was carried out for 10min, and 1.83g (48.4mmol) of NaBH was added in portions4After the reaction is finished for 6 hours, diluted hydrochloric acid is added for quenching, the reaction product is adjusted to be neutral, the reaction product is carefully poured into cold water, semi-oily light yellow solid is separated out, and 22.7g (yield is 92%) of (S, E) -ethyl 3- (2, 6-dichloro-4- ((4- (3- (1-hydroxyethyl) -2-methoxyphenyl) thiazolyl-2-yl) carbamoyl) phenyl) -2-methacrylate is obtained after drying, and the crude product is directly used for the next reaction without separation.
(E) The reaction scheme for the asymmetric catalytic conversion of (E) -ethyl 3- (4- ((4- (3-acetyl-2-methoxyphenyl) thiazolyl-2-yl) carbamoyl) -2, 6-dichlorophenyl) -2-methacrylate to S, E) -ethyl 3- (2, 6-dichloro-4- ((4- (3- (1-hydroxyethyl) -2-methoxyphenyl) thiazolyl-2-yl) carbamoyl) phenyl) -2-methacrylate is shown in scheme 5.
TABLE I parameters for the conversion of Compound 6 to Compound 7 by asymmetric catalysis
The second table shows the parameters of the compound 6 in the 3, 5-bis (3-methylbut-2-yl) salicylaldehyde Schiff base zinc complex corresponding to L-valine and the conversion of the compound 7 by sodium borohydride/cerium trichloride through asymmetric catalytic reduction reaction
TABLE 1 parameters for the asymmetric catalytic conversion of Compound 6 to Compound 7
Entry | Solvent | A | B | Time(h) | Yield(%) | ee(%) |
1 | THF/MeOH | L-Valine | NaBH4 | 6 | 92.0 | 95.1 |
2 | THF/MeOH | L-Phenylalanine | NaBH4 | 6 | 90.2 | 87.9 |
3 | THF/MeOH | L-Leucine | NaBH4 | 6 | 86.4 | 84.3 |
4 | THF/MeOH | L-Alanine | NaBH4 | 6 | 86.7 | 86.9 |
5 | THF | L-Valine | NaBH4/CeCl3 | 6 | 98.0 | 98.8 |
6 | THF | L-Phenylalanine | NaBH4/CeCl3 | 6 | 95.1 | 96.2 |
7 | THF | L-Leucine | NaBH4/CeCl3 | 6 | 97.6 | 97.3 |
8 | THF | L-Alanine | NaBH4/CeCl3 | 6 | 92.3 | 96.0 |
Wherein A represents the corresponding amino acid of the catalyst; b represents a reducing agent type
TABLE 2 conversion of Compound 6 to a Compound by asymmetric catalytic reduction of a Zinc 3, 5-bis (3-methylbut-2-yl) salicylaldehyde Schiff base complex corresponding to L-valine and sodium borohydride/cerium trichlorideParameters of object 7
Entry | Solvent | Time(h) | Yield(%) | ee(%) |
1 | THF/MeOH | 4 | 90.3 | 96.4 |
2 | THF/MeOH | 6 | 96.1 | 91.1 |
3 | THF/MeOH | 8 | 93.4 | 93.5 |
4 | THF/MeOH | 10 | 91.6 | 87.6 |
5 | THF | 6 | 98.0 | 98.8 |
6 | THF | 8 | 96.3 | 95.2 |
7 | THF | 12 | 88.7 | 96.5 |
8 | THF | 15 | 84.6 | 94.2 |
(e) Preparation of (S, E) -ethyl 3- (2, 6-dichloro-4- ((4- (3- (1- (hexyloxy) ethyl) -2-methoxyphenyl) thiazol-2-yl) carbamoyl) phenyl) -2-methacrylate: 150ml of THF is added into a three-necked flask with mechanical stirring, 22.7g (42.6mmol) of the product (S, E) -ethyl 3- (2, 6-dichloro-4- ((4- (3- (1-hydroxyethyl) -2-methoxyphenyl) thiazolyl-2-yl) carbamoyl) phenyl) -2-methacrylate generated in the previous step is added and dissolved, 7g (42.6mmol) of 1-bromohexane is added, 6.5g (1.1eq) of anhydrous potassium carbonate is added, the reaction is carried out at room temperature for 12h, TLC tracking is carried out, after the substitution reaction is finished, the solid is filtered off, and the organic solvent is evaporated under reduced pressure to obtain a semi-oily solid (S, E) -ethyl 3- (2, 6-dichloro-4- ((4- (3- (1- (hexyloxy) ethyl) -2-methoxyphenyl) thiazolyl-2-yl) ammonia Carbamoyl) phenyl) -2-methacrylate (25.2g, 96% yield) the crude product was used in the next reaction without isolation.
(f) Preparation of (E) -3- [2, 6-dichloro-4- [ [4- [3- [ (1S) -1-hexyloxyethyl ] -2-methoxyphenyl ] -1, 3-thiazol-2-yl ] carbamoyl) phenyl ] -2-methacrylic acid 100ml of THF and 25.2g (40.7mmol) of the product (S, E) -ethyl 3- (2, 6-dichloro-4- ((4- (3- (1- (hexyloxy) ethyl) -2-methoxyphenyl) thiazol-2-yl) carbamoyl) phenyl) -2-methacrylate from the preceding reaction were added to a three-necked flask equipped with mechanical stirring, and after the solvent 1.64g of sodium hydroxide and 100ml of water were added, heating to 60 ℃ for reaction for 5h, TLC tracing the reaction completion of raw materials, cooling to room temperature, evaporating most of organic solvent, adding 2N diluted hydrochloric acid dropwise to adjust pH 2-3, precipitating yellow solid, filtering, and pulping with methyl tert-butyl ether for 2-3 times to obtain (E) -3- [2, 6-dichloro-4- [ [4- [3- [ (1S) -1-hexyloxyethyl ] -2-methoxyphenyl ] -1, 3-thiazolyl-2-yl ] carbamoyl) phenyl ] -2-methacrylic acid (23.8g, yield 99%) as white solid powder.
The foregoing shows and describes the general principles and broad features of the present invention and advantages thereof. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are merely illustrative of the principles of the invention, but that various changes and modifications may be made without departing from the spirit and scope of the invention, which fall within the scope of the invention as claimed. The scope of the invention is defined by the appended claims and equivalents thereof.
Claims (3)
1. The synthesis process of the lotrpopa is characterized by comprising the following steps of:
(a) the 2-methoxy-1, 3-diacetylbenzene (2) is subjected to halogenation reaction to obtain the 3-acetyl-2-methoxy-alpha-halogenated acetophenone (3), and the reaction formula is as follows:
(b) 3-acetyl-2-methoxyl-alpha-halogenated acetophenone (3) and thiourea undergo a cyclization reaction to obtain 3- (2-aminothiazolyl-4-yl) -2-methoxyacetophenone (4), and the reaction formula is as follows:
(c)3- (2-aminothiazolyl-4-yl) -2-methoxyacetophenone (4) and (E) -ethyl 3- (2, 6-dichloro-4- (chloroformyl) phenyl) -2-methacrylate (5) react to obtain (E) -ethyl 3- (4- ((4- (3-acetyl-2-methoxyphenyl) thiazolyl-2-yl) carbamoyl) -2, 6-dichlorophenyl) -2-methacrylate (6), and the reaction formula is as follows:
(d) (E) -ethyl 3- (4- ((4- (3-acetyl-2-methoxyphenyl) thiazolyl-2-yl) carbamoyl) -2, 6-dichlorophenyl) -2-methacrylate (6), and the (S, E) -ethyl 3- (2, 6-dichloro-4- ((4- (3- (1-hydroxyethyl) -2-methoxyphenyl) thiazolyl-2-yl) carbamoyl) phenyl) -2-methacrylate (7) is obtained by catalytic reduction of a chiral catalyst and a reducing agent, and the reaction formula is as follows:
(e) (S, E) -ethyl 3- (2, 6-dichloro-4- ((4- (3- (1-hydroxyethyl) -2-methoxyphenyl) thiazolyl-2-yl) carbamoyl) phenyl) -2-methacrylate (7) and 1-halohexane (8) are subjected to substitution reaction to obtain (S, E) -ethyl 3- (2, 6-dichloro-4- ((4- (3- (1- (hexyloxy) ethyl) -2-methoxyphenyl) thiazolyl-2-yl) carbamoyl) phenyl) -2-methacrylate (9), which has the reaction formula:
(f) (S, E) -ethyl 3- (2, 6-dichloro-4- ((4- (3- (1- (hexyloxy) ethyl) -2-methoxyphenyl) thiazolyl-2-yl) carbamoyl) phenyl) -2-methacrylate (9) is hydrolyzed to obtain a target compound, namely the eltrombopag (1), and the reaction formula is as follows:
(a) in step (a), R1 ═ Cl, Br, or I;
(b) in step (C), R2 ═ C1-5 alkyl, C1-5 alkoxymethyl, or aryl;
(c) in step (d), R2 ═ C1-5 alkyl, C1-5 alkoxymethyl, or aryl;
(d) in step (e), R2 ═ C1-5 alkyl, C1-5 alkoxymethyl, or aryl; r3 ═ Cl, Br, I, p-toluenesulfonate, trifluoromethanesulfonate or methylsulfonate.
2. The process for synthesizing rotpop as claimed in claim 1, wherein: in step (d), the chiral catalyst is: a complex of 3, 5-bis (3-methylbut-2-yl) salicylaldehyde Schiff base zinc corresponding to L-valine, L-phenylalanine, L-leucine or L-alanine, the molecular formula of the complex is shown as follows, and the reducing agent is sodium borohydride/methanol-tetrahydrofuran or sodium borohydride/cerium trichloride;
R4=-CH3,-CH2ph, -i-Pr or-i-Bu.
3. The process for synthesizing rotpop as claimed in claim 1, wherein:
(a) taking a compound 2-methoxy-1, 3-diacetylbenzene as a raw material, and obtaining an intermediate which is 3-acetyl-2-methoxy-alpha-halogenated acetophenone through a halogenation reaction;
(b) taking a compound 3-acetyl-2-methoxyl-alpha-halogenated acetophenone as a raw material, and performing cyclization reaction on thiourea to obtain an intermediate 3- (2-aminothiazolyl-4-yl) -2-methoxyacetophenone;
(c) the key intermediate obtained by using a compound 3- (2-aminothiazolyl-4-yl) -2-methoxyacetophenone as a raw material and reacting an intermediate (E) -ethyl 3- (2, 6-dichloro-4- (chloroformyl) phenyl) -2-methacrylate is (E) -ethyl 3- (4- ((4- (3-acetyl-2-methoxyphenyl) thiazolyl-2-yl) carbamoyl) -2, 6-dichlorophenyl) -2-methacrylate;
(d) taking a compound (E) -ethyl 3- (4- ((4- (3-acetyl-2-methoxyphenyl) thiazolyl-2-yl) carbamoyl) -2, 6-dichlorophenyl) -2-methacrylate as a raw material, and obtaining a key intermediate (S, E) -ethyl 3- (2, 6-dichloro-4- ((4- (3- (1-hydroxyethyl) -2-methoxyphenyl) thiazolyl-2-yl) carbamoyl) phenyl) -2-methacrylate by asymmetric catalytic reduction;
(e) taking a compound (S, E) -ethyl 3- (2, 6-dichloro-4- ((4- (3- (1-hydroxyethyl) -2-methoxyphenyl) thiazolyl-2-yl) carbamoyl) phenyl) -2-methacrylate as a raw material, and carrying out substitution reaction on the raw material and 1-halogenated hexane to obtain an intermediate (S, E) -ethyl 3- (2, 6-dichloro-4- ((4- (3- (1- (hexyloxy) ethyl) -2-methoxyphenyl) thiazolyl-2-yl) carbamoyl) phenyl) -2-methacrylate;
(f) the target compound, namely the eltrombopag (1), is obtained by hydrolyzing a compound (S, E) -ethyl 3- (2, 6-dichloro-4- ((4- (3- (1- (hexyloxy) ethyl) -2-methoxyphenyl) thiazolyl-2-yl) carbamoyl) phenyl) -2-methacrylate serving as a raw material.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201610415303.9A CN106083759B (en) | 2016-06-15 | 2016-06-15 | Brand-new synthesis process of lutofopa |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201610415303.9A CN106083759B (en) | 2016-06-15 | 2016-06-15 | Brand-new synthesis process of lutofopa |
Publications (2)
Publication Number | Publication Date |
---|---|
CN106083759A CN106083759A (en) | 2016-11-09 |
CN106083759B true CN106083759B (en) | 2022-02-15 |
Family
ID=57846612
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201610415303.9A Active CN106083759B (en) | 2016-06-15 | 2016-06-15 | Brand-new synthesis process of lutofopa |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN106083759B (en) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN109311831B (en) * | 2017-02-14 | 2021-07-09 | 四川科伦药物研究院有限公司 | Crystal form of 4-phenylthiazole derivative and preparation method thereof |
CN109970678B (en) * | 2017-12-28 | 2024-03-08 | 四川科伦药物研究院有限公司 | Amorphous 4-phenylthiazole derivative, and preparation method and application thereof |
WO2019233328A1 (en) * | 2018-06-08 | 2019-12-12 | 四川科伦药物研究院有限公司 | Crystal form of 4-phenylthiazole derivative and preparation method thereof |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101809008A (en) * | 2007-07-31 | 2010-08-18 | 盐野义制药株式会社 | Pharmaceutical composition containing optically active compound having thrombopoietin receptor agonist activity and intermediate thereof |
CN103228277A (en) * | 2010-09-30 | 2013-07-31 | 盐野义制药株式会社 | Preparation for improving solubility of poorly soluble drug |
WO2015093586A1 (en) * | 2013-12-20 | 2015-06-25 | 塩野義製薬株式会社 | Methods respectively for producing optically active compound having agonistic activity on thrombopoietin receptors and intermediate of said compound |
-
2016
- 2016-06-15 CN CN201610415303.9A patent/CN106083759B/en active Active
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101809008A (en) * | 2007-07-31 | 2010-08-18 | 盐野义制药株式会社 | Pharmaceutical composition containing optically active compound having thrombopoietin receptor agonist activity and intermediate thereof |
CN103228277A (en) * | 2010-09-30 | 2013-07-31 | 盐野义制药株式会社 | Preparation for improving solubility of poorly soluble drug |
WO2015093586A1 (en) * | 2013-12-20 | 2015-06-25 | 塩野義製薬株式会社 | Methods respectively for producing optically active compound having agonistic activity on thrombopoietin receptors and intermediate of said compound |
Non-Patent Citations (1)
Title |
---|
Synthesis and free radical scavenging activity of 2-alkyl/arylchalcogenyl-N-(4-aryl-1,3-thiazol-2-yl)acetamide compounds;Lucas Wolf等;《Tetrahedron Letters》;20160122;第57卷;第1031–1034页 * |
Also Published As
Publication number | Publication date |
---|---|
CN106083759A (en) | 2016-11-09 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN102786516B (en) | Method for synthesizing rivaroxaban | |
JP7087103B2 (en) | Roxadustat synthesis method and its intermediate compounds | |
US8884033B2 (en) | Process for preparing aminobenzoylbenzofuran derivatives | |
CN101941927B (en) | Method for analyzing (1R, 2R)-2-amino-1-(4-(methylsulfonyl)-phenyl)-1,3-propylene glycol as intermediate of florfenicol | |
CN103384663B (en) | For the preparation of the synthesis of the intermediate of bent of Ansai and derivative thereof | |
CN106083759B (en) | Brand-new synthesis process of lutofopa | |
CN103012388B (en) | A preparation method for razaxaban and intermediate thereof, and midbody compound | |
CN107663190B (en) | Preparation method of nilapanib and intermediate thereof and intermediate compound | |
CN102666496B (en) | New preparation of 2-(2-n-butyl-4-hydroxy-6-methyl-pyrimidine-5-yl)-n,n-dimethylacetamide | |
CN105646285B (en) | One kind dimension Lactel sieve intermediate and its preparation method and application | |
CN107056756A (en) | A kind of method for preparing high-purity Losartan | |
CN102001979B (en) | Preparation method of 2-(2', 2'-difluoroethoxyl)-6-trifluoromethyl phenyl propyl sulfide | |
CN114315609B (en) | Technological method for preparing cis-2-aminocyclohexanol | |
CN109456253A (en) | A kind of method of chiral induction synthesis (S) -3- (4- bromophenyl)-piperidines or its salt | |
JP2023532362A (en) | Method for producing phenylisoxazoline compound | |
CN101528673A (en) | Method for producing asymmetric copper complex crystal | |
CN109897013B (en) | Preparation method of selective PPAR delta agonist GW501516 | |
CN105189467B (en) | The method for preparing pyridazinone compound | |
KR101435741B1 (en) | Novel voriconazole intermediate and synthesis of voriconazole | |
JP5448572B2 (en) | Acetyl compound, method for producing the acetyl compound, and method for producing a naphthol compound using the acetyl compound | |
CN104672180A (en) | Chiral preparation method of [(1S)-3-methyl-1-[[(2R)-2-methylepoxyethyl]carbonyl]butyl]tert-butyl carbamate | |
CN113024577B (en) | Preparation method of anti-apoptosis protein selective inhibitor | |
JP5197063B2 (en) | Process for producing methyl 2-bromo-3- {4- [2- (5-ethyl-2-pyridyl) ethoxy] phenyl} propionate | |
CN113072471B (en) | Lifeiste intermediate and preparation method thereof | |
JP5371090B2 (en) | Method for producing monosulfonic acid ester |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |