CN113698317A - Synthetic method of apatamide, intermediate and synthetic method thereof - Google Patents
Synthetic method of apatamide, intermediate and synthetic method thereof Download PDFInfo
- Publication number
- CN113698317A CN113698317A CN202010429864.0A CN202010429864A CN113698317A CN 113698317 A CN113698317 A CN 113698317A CN 202010429864 A CN202010429864 A CN 202010429864A CN 113698317 A CN113698317 A CN 113698317A
- Authority
- CN
- China
- Prior art keywords
- compound
- formula
- acid
- apatamide
- reaction
- 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.)
- Pending
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
- C07C237/40—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to a carbon atom of a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/04—Systems containing only non-condensed rings with a four-membered ring
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to the technical field of drug synthesis, discloses a synthetic method of apatamide, an intermediate and a synthetic method thereof, and solves the problems that the synthetic process of apatamide in the prior art is complex in operation, high in production cost, not suitable for industrialization and not friendly to environment. The compound of formula VIII is prepared into a compound of formula VII through a one-pot method, the compound of formula VII is prepared into an intermediate compound of apatamide with a formula IV through the one-pot method, and the compound of formula IV and the compound of formula II are cyclized to obtain the compound of formula I. The method has the advantages of simple operation, less working procedures, low production cost and high product yield and purity.
Description
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a synthetic method of apatamide, an intermediate and a synthetic method thereof.
Background
Apatamide (apalcuamide), chemical name 4- [7- (6-cyano-5-trifluoromethylpyridin-3-yl) -8-oxo-6-thioxo-5, 7-diazaspiro [3.4] oct-5-yl ] -2-fluoro-N-methylbenzamide, structure of which is shown in formula I, is a second generation androgen receptor antagonist that was vigorously developed for use in non-metastatic castration resistant prostate cancer (M0-CRPC). Apatamide:
apatamide is a derivative of diarylthiohydantoin, consisting of a pyridine ring, a benzene ring, cyclobutane and thiohydantoin ring systems connected together, the synthesis of which proceeds mainly around the connection of arylamines and the construction of thiohydantoin ring systems, as shown below.
The synthetic route of the apatamide is generally divided into a type of [3+2] and a type of [4+1], and the specific scheme is shown in the following table:
among them, the synthesis route of the "[ 3+2] type" has two main routes: a process for synthesizing the compound of formula I, such as 201180009819.9, 200780019654.7, 200780020099.X and the improvement on the synthesis process of apatamide (J.Med.Industrials, 2018, 49(4)), features that the alpha-aminonitrile and thioisocyanate are cyclized by [3+2 ]. The method comprises the following specific steps:
the synthesis method uses highly toxic sodium cyanide, and some synthesis methods adopt microwave methods, so that the difficulty of industrial scale-up production is increased, and the synthesis method is not suitable for industrial production.
The second [3+2] route is the synthesis used to prepare compounds of formula I, for example 201610985993.1, 201711271655.2, 201711474542.2, by the [3+2] cyclization of α -carbamates with thioisocyanates, as follows:
the synthesis method has the advantages that the yield of each step is low, the cost is high, the reaction process and the post-treatment process are complicated, the optimization of intermediate purification in each step is not considered in detail, and the method is not suitable for industrial production and the like; therefore, the reaction process and post-treatment conditions in each step of the [3+2] path need to be further optimized and designed, so as to achieve the purposes of improving efficiency and yield and reducing cost, and meet the requirement of industrial production of the bulk drug.
The [4+1] type preparation route of apatamide is a synthetic method in which alpha-aminoamide and thiocarbonyl compound undergo [4+1] cyclization to prepare a compound shown in a formula I, such as 201580069602.5, and specifically comprises the following steps:
the synthetic route requires the use of stoichiometric amounts of copper salts; and the final step of the [4+1] cyclization needs to use expensive thiocarbonyl compounds, so the cost is high.
Therefore, the synthetic method of apatamide has the advantages of simple process, few working procedures, simple and convenient operation and low production cost, and becomes a problem to be solved by technical personnel in the field.
Disclosure of Invention
One of the purposes of the invention is to provide a synthetic method of apatamide, which has the advantages of simple process, less working procedures, simple and convenient operation, conventional reaction in each step, mild conditions, no requirement on other special equipment and suitability for industrial production.
The second purpose of the invention is to provide an intermediate for synthesizing apatamide.
The invention also aims to provide a synthetic method of the intermediate.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows:
the intermediate for synthesizing the apatamide has a structure shown in a formula IV:
(ii) a Wherein R is methyl or methoxy; preferably, R is 4-methyl or 4-methoxy.
The invention provides a synthesis method of an apatamide intermediate, which takes a compound shown in a formula VIII as an initial raw material, generates a compound shown in a formula VII through esterification-aminolysis reaction, and generates a compound shown in a formula IV through coupling-carboxylic acid alkylation reaction, wherein the reaction formula is as follows:
(ii) a Wherein, X1、X2Are each halogen, preferably, X1、X2Each independently selected from chlorine, bromine and iodine.
In some embodiments, both the esterification-aminolysis reaction and the coupling-carboxylic acid alkylation are carried out in a one-pot reaction.
In some embodiments, after reacting a compound of formula VIII with an acid or a reagent capable of hydrolyzing to an acid in an alcoholic medium to form an ester, the ester is cleaved with one-pot methylamine to form a compound of formula VII;
the acid or the reagent capable of being hydrolyzed into acid is organic acid, inorganic acid or the mixture thereof; preferably concentrated sulfuric acid or POCl3Thionyl chloride; more preferably thionyl chloride;
the alcohol medium is selected from one or more of methanol, ethanol, propanol and benzyl alcohol.
In some embodiments, the compound of formula viii is dissolved in an alcoholic medium and an acid is added under inert gas; the inert gas is preferably nitrogen.
In some embodiments, the temperature of the esterification reaction is from 35 to 55 deg.C, preferably from 40 to 50 deg.C; the temperature of the aminolysis reaction is 15-35 ℃, preferably 20-30 ℃.
In some embodiments, the compound of formula VII and the compound of formula VI are subjected to coupling reaction under the action of a catalyst, an acid-binding agent, a ligand and an aprotic polar solvent, and then are subjected to alkylation reaction with the compound of formula V to generate a compound of formula IV through a one-pot carboxylic acid reaction;
the catalyst is copper salt, preferably CuCl, CuBr or CuI;
the acid-binding agent is sodium carbonate, potassium carbonate, cesium carbonate or potassium tert-butoxide;
the ligand is 2-acetyl cyclohexanone or tetramethyl ethylene diamine;
the aprotic polar solvent is DMF or DMAc.
In some embodiments, after the coupling reaction is complete, the compound of formula V is added to the reaction system to effect alkylation of the carboxylic acid.
In some embodiments, the coupling reaction is a ullmann coupling reaction.
In the technical scheme of the invention, the coupling reaction is carried out at a high temperature of 80-150 ℃, preferably at a temperature of 115-130 ℃.
The coupling reaction is carried out under the protection of inert gas, and the inert gas is preferably nitrogen.
The alkylation reaction temperature of the carboxylic acid is 25-90 ℃; preferably 55-65 ℃.
In the technical scheme of the invention, the dosage ratio of the materials is as follows: (eq means molar equivalent ratio)
| Material(s) | Interval of equivalence ratio | Preferably the equivalence ratio |
| A compound of the formula VII | 1.0eq | 1.0eq |
| A compound of formula VI | 1.0eq～2.0eq | 1.1～1.5eq |
| Catalyst and process for preparing same | 0.01eq～0.5eq | 0.05eq |
The invention provides a synthesis method of apatamide, which comprises the steps of cyclizing a compound shown in a formula IV and a compound shown in a formula II to obtain the apatamide shown in the formula I; the reaction formula is as follows:
wherein R is methyl or methoxy; preferably, R is 4-methyl or 4-methoxy.
Specifically, the compound of formula IV and the compound of formula II are cyclized by [3+2] under the combined action of a low-polarity solvent and a polar aprotic solvent to obtain the compound of formula I;
preferably, the low polarity solvent is selected from acetonitrile and toluene;
preferably, the polar aprotic solvent is selected from DMF, DMAc, and DMSO.
In some embodiments, the synthetic method of apatamide comprises the following materials in the following dosage ratio: (eq means molar equivalent ratio)
| Material(s) | Interval of equivalence ratio | Preferably the equivalence ratio |
| A compound of formula IV | 1.0eq | 1.0eq |
| A compound of formula II | 2.0eq～3.0eq | 2.5eq |
In some embodiments, the compound of formula II is prepared from a compound of formula III in the presence of thiophosgene:
in some embodiments, the methods of preparing compounds of formula II provided herein optionally comprise a post-treatment step, specifically: after the reaction is finished, evaporating most of the solvent, adding the low-polarity solvent and the adsorbent into the residue, stirring and filtering to remove impurities;
preferably, the low polarity solvent is selected from petroleum ether, n-hexane and n-heptane; the adsorbent is selected from the group consisting of alumina, activated carbon and column chromatography silica gel.
English abbreviations for compounds or groups described in the present invention are:
DMF: n, N-dimethylformamide
DMSO, DMSO: dimethyl sulfoxide
DMAc: n, N-dimethyl acetamide
Compared with the prior art, the invention has the following beneficial effects:
the invention has scientific design and simple operation, adopts the one-pot method to operate, reduces the cost and reduces the working procedures. In the invention, the compound of the formula VII is prepared from the compound of the formula VIII, and the compound of the formula IV is prepared from the compound of the formula VII, which are operated by a one-pot method, thereby simplifying the process steps, shortening the production period, reducing the production energy consumption, achieving the purposes of more economy and more suitability for industrial production.
In the invention, in the process of preparing the compound of the formula VII by using the compound of the formula VIII, the used materials are cheap and easy to obtain, the reaction selectivity is better, the byproducts are less, the post-treatment is simple, and the target product can be obtained only by crystallization and filtration; compared with the method for preparing the amide by directly using the carboxylic acid through the acyl chloride, the method reduces the reaction steps, avoids the extraction and concentration operations in the conventional preparation method of the acyl chloride, and has simpler and more convenient process operation.
In the invention, in the reaction for preparing the compound shown in the formula IV by using the compound shown in the formula VII as a raw material through a one-pot method, the temperature is regulated and controlled in stages; and the final product can be separated out from the reaction system only by crystallization, and the product can be obtained after recrystallization, so that the process is simple and convenient, and the yield and the purity are high.
In the invention, the R group adopts methyl or methoxyl, and the benzyl group is modified and optimized, so that the method has very obvious effect advantage. As methyl or methoxy is introduced into benzyl, the activity of the benzyl is improved, and thus the yield of the compound of the formula IV and the yield of the compound of the formula I are greatly improved. In addition, experiments of the invention show that when the compound IV-A is taken as an example, compared with R ═ H, because a methyl group or a methoxy group is introduced, the compound IV-A is beneficial to precipitation from a water phase, obtains a better crystallization and solidification effect, and is beneficial to separation and purification of an intermediate.
In the reaction for preparing the compound of the formula II by using the compound of the formula III as a raw material, the target compound of the formula II belongs to a compound with low polarity and high boiling point, and the refining and purification of the compound of the formula II are difficult to realize. The existing method is limited to column chromatographic separation and high-temperature reduced pressure distillation, and has great purification difficulty and extremely high cost. The invention unexpectedly discovers that the impurities related to the reaction are mostly large-polarity impurities, so the invention can achieve the purification purpose by adding a small amount of adsorbent into a low-polarity solvent and filtering the mixture through hot pulping, thereby greatly saving the industrialized production cost and avoiding the problems that the traditional column chromatography is not suitable for industrialized production and needs to consume a lot of solvent and manpower; the safety of high-temperature reduced pressure distillation is poor, and the energy consumption of production is higher.
According to the one-pot method, a plurality of reaction processes are operated in one pot, and multiple steps of processes are coordinated, so that the reaction environment of each step of process needs to be coordinated. The invention successfully maintains the low cost advantage of the one-pot method and ensures the yield and quality purity of the product through ingenious design and careful exploration on the reaction process.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
The instrument comprises the following steps:
the structure of the compounds was determined by nuclear magnetic resonance (1HNMR) or Mass Spectrometry (MS).
The NMR spectrum method adopts Bruker superconducting NMR spectrometer (instrument model: BRUKERAVANCE 400 NMR spectrometer); solvent DMSO-d6, temperature 22 ℃;
LC-MS detection adopts: agilent 6120B Ms liquid chromatography-single four-level rod, positive ion mode, ESI ionization source, scanning range 50 m/z-3000 m/z;
and (3) determining the purity of the intermediate compound in each step by using a high performance liquid chromatograph (HPLC-UV), wherein a detector is as follows: ultraviolet (UV) detector, chromatography column: boston Uni C18.
The abbreviations of the reagents referred to in the examples have the following Chinese meanings:
the features and properties of the present invention are described in further detail below with reference to examples.
Example 1
The embodiment discloses a method for synthesizing an N-methyl-4-bromo-2-fluorobenzamide compound shown as a formula VII-A by a one-pot method, which specifically comprises the following steps:
dissolving a compound of 4-bromo-2-fluorobenzoic acid (60g, 0.27mol) of a compound of formula VIII-A in methanol (180mL), dropwise adding 19.5g of thionyl chloride under the protection of nitrogen, heating to 45 +/-5 ℃ after dropwise adding is finished, slowly cooling to 25 +/-5 ℃ after raw materials completely react, slowly dropwise adding 100g of methylamine water solution (25-30 wt%), keeping the temperature at 25 +/-5 ℃ after dropwise adding is finished, reacting for 2 hours, slowly dropwise adding 1000mL of purified water, and continuously stirring for two hours after dropwise adding is finished. Filtering, and collecting filter cake to obtain 62.5g of intermediate N-methyl-4-bromo-2-fluorobenzamide (compound of formula VII-A), yield 98%, purity 99.92% by HPLC detection, and maximum impurity amount 0.04%.
A compound of formula VII-A: LC-MS: m/z 231.9[ M +1]]+、233.9[M+3]+
1H NMR(400MHz，DMSO-d6)δ8.25(s，1H)，7.64-7.52(m，2H)，7.46(d，J＝8.3Hz，1H)，2.80(d，J＝4.8Hz，3H).
Example 2
The embodiment discloses a method for synthesizing a compound 4-methoxybenzyl-1- ((3-fluoro-4- (methylcarbamoyl) phenyl) amino) cyclobutyl ester of formula IV-A by a one-pot method, which specifically comprises the following steps:
60g of the compound of formula VII-A (1.0eq), 1.1eq of the compound of formula VI-A formula I-aminocyclobutanecarboxylic acid (32g), 3eq K2CO3(107g) Adding 0.05eq CuCl (1.2g) and 0.05eq tetramethylethylenediamine (1.5g) into 360ml DMF, reacting at 115-130 ℃ for 4-6 h under the protection of nitrogen, cooling to 60 +/-5 ℃, dropwise adding 1.1eq 4-methoxybenzyl chloride (40g) of the compound V-A, reacting for 1h, cooling to room temperature, dropwise adding 90ml concentrated ammonia water, dropwise adding 300ml purified water, and stirring for 1h after dropwise adding. Filtering to obtain a filter cake. Heating the filter cake and 300ml of ethyl acetate to 75 +/-5 ℃ for dissolving, stirring for 15min, controlling the temperature to be more than 70 ℃, dropwise adding 100ml of petroleum ether, naturally cooling the temperature to room temperature after dropwise adding, stirring for 0.5h, and filtering to obtain 83g of a compound 4A, wherein the yield is 87%, the purity is 99.00% through HPLC detection, and the maximum impurity amount is 0.24%.
A compound of formula IV-A: LC-MS: 387.2[ M +1] M/z]+
1H NMR(400MHz,DMSO-d6)δ7.68(t,J＝5.3Hz,1H),7.59(t,J＝8.7Hz,1H),7.32(s,1H),7.20(d,J＝8.3Hz,2H),6.88(d,J＝8.3Hz,2H),6.32(d,J＝8.2Hz,1H),6.10(d,J＝14.2Hz,1H),5.11(s,2H),3.76(s,3H),2.84(d,J＝4.6Hz,3H),2.76–2.62(m,2H),2.32–2.18(m,2H),2.11–1.91(m,2H).
Experimental example 3
This example discloses a method for synthesizing a compound of formula ii from a compound of formula iii, specifically:
dissolving the compound of the formula III 5-amino-3-trifluoromethyl-2-cyanopyridine (100g, 1.0eq) in 0.5L of acetone, dropwise adding 1.2eq of thiophosgene (74g), reacting at room temperature for 1-3 h, distilling under reduced pressure to remove most of the solvent, adding 1.0L of n-hexane and 50g of neutral alumina into the residue, heating to 40 +/-5 ℃, stirring for 1 hour, filtering and concentrating to obtain 105g of the compound of the formula II, namely a white-like solid, 5-isothiocyanato-3-trifluoromethyl-2-cyanopyridine, wherein the yield is 86%, and the purity is 99.10% and the maximum impurity content is 0.68% through HPLC detection.
A compound of formula II
1H NMR(400MHz,DMSO-d6)δ9.04(d,J＝2.2Hz,1H),8.57(d,J＝2.3Hz,1H).
Example 4
This example discloses a process for the synthesis of 4- [7- (6-cyano-5-trifluoromethylpyridin-3-yl) -8-oxo-6-thioxo-5, 7-diazaspiro [3.4] oct-5-yl ] -2-fluoro-N-methylbenzamide, a compound of formula I, from a compound of formula IV-A and a compound of formula II, in which:
74g of the compound of the formula IV-A, DMF (8ml) and acetonitrile (1000ml) are added to a reaction flask under nitrogen protection, the temperature is raised to 80 +/-5 ℃, 108g of an acetonitrile solution (150ml) of the compound of the formula II is slowly added dropwise, the dropwise addition is carried out 8 times (once per hour) uniformly in total, and the stirring is carried out for 24 hours after the dropwise addition is finished. The reaction solution is concentrated to dryness, isopropanol (800ml) is added, the temperature is raised to 85 plus or minus 5 ℃, the mixture is stirred for 2 hours, the temperature is slowly lowered to 0 plus or minus 5 ℃, and the mixture is stirred for 12 hours. Filtering, leaching a filter cake twice by using 150ml of isopropanol to obtain a crude product of the compound shown in the formula I; and then isopropanol is used for repeated crystallization once, and the operation is carried out as above, so that 84g of the refined product of the compound shown in the formula I is obtained, the yield is 88%, the purity is 99.92% through HPLC detection, and the maximum impurity amount is 0.08%.
A compound of formula I: LC-MS: m/z 478.1[ M +1]+
1H NMR(400MHz,DMSO-d6)δ9.23(d,J＝2.0Hz,1H),8.77(d,J＝2.0Hz,1H),8.54–8.39(m,1H),7.92(t,J＝8.0Hz,1H),7.50(dd,J＝10.5,1.8Hz,1H),7.43(dd,J＝8.1,1.8Hz,1H),2.89(d,J＝4.6Hz,3H),2.78–2.66(m,2H),2.64–2.49(m,2H),2.11–1.98(m,1H),1.72–1.55(m,1H).
The embodiments described above are some, but not all embodiments of the invention. The detailed description of the embodiments of the present invention is not intended to limit the scope of the invention as claimed, but is merely representative of selected embodiments of the invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Claims (11)
1. An intermediate for synthesizing apatamide, which has a structure shown in formula IV:
wherein R is methyl or methoxy; preferably, R is 4-methyl or 4-methoxy.
2. The method for synthesizing the intermediate as claimed in claim 1, wherein the compound of formula viii is used as a starting material, and the compound of formula vii is subjected to esterification-aminolysis reaction to produce the compound of formula vii, and the compound of formula vii is subjected to coupling-carboxylic acid alkylation reaction to produce the compound of formula iv, wherein the reaction formula is as follows:
wherein, X1、X2Are all halogen; preferably, X1、X2Each independently selected from chlorine, bromine and iodine.
3. A process for the synthesis of an intermediate as claimed in claim 2, wherein the compound of formula viii is reacted with an acid or a reagent capable of hydrolysing to an acid in an alcoholic medium to form an ester, which is then hydrolysed with one-pot methylamine to form the compound of formula vii;
the acid or the reagent capable of being hydrolyzed into acid is organic acid, inorganic acid or the mixture thereof; preferably concentrated sulfuric acid or POCl3Or thionyl chloride; more preferably thionyl chloride;
the alcohol medium is selected from one or more of methanol, ethanol, propanol and benzyl alcohol.
4. The method for synthesizing the intermediate according to claim 2, wherein the compound of formula VII and the compound of formula VI are subjected to coupling reaction under the action of a catalyst, an acid-binding agent, a ligand and an aprotic polar solvent, and then are subjected to alkylation reaction with the compound of formula V by a one-pot carboxylic acid to generate the compound of formula IV;
the catalyst is copper salt, preferably CuCl, CuBr or CuI;
the acid-binding agent is sodium carbonate, potassium carbonate, cesium carbonate or potassium tert-butoxide;
the ligand is 2-acetyl cyclohexanone or tetramethyl ethylene diamine;
the aprotic polar solvent is DMF or DMAc.
5. The method for synthesizing intermediates according to claim 4, wherein the coupling reaction is carried out at a high temperature of 80-150 ℃, preferably 115-130 ℃;
the alkylation reaction temperature of the carboxylic acid is 25-90 ℃; preferably 55-65 ℃.
6. The method for synthesizing the intermediate as claimed in claim 4, wherein the molar equivalent ratio of the compound of formula VII, the compound of formula VI and the catalyst is 1.0: 1.0-2.0: 0.01 to 0.5; preferably 1.0: 1.1-1.5: 0.05.
7. a synthetic method of apatamide is characterized in that a compound shown in a formula IV and a compound shown in a formula II are cyclized to obtain a compound shown in a formula I, and the reaction formula is as follows:
wherein R is methyl or methoxy; preferably, R is 4-methyl or 4-methoxy.
8. The process for the synthesis of apatamide as claimed in claim 7, wherein the compound of formula IV and the compound of formula ii are cyclized by [3+2] in the presence of a low polar solvent and a polar aprotic solvent to give the compound of formula i;
preferably, the low polarity solvent is selected from acetonitrile and toluene;
preferably, the polar aprotic solvent is selected from DMF, DMA and DMSO.
9. A process for the synthesis of apatamide as claimed in claim 8, wherein the molar equivalent ratio of compound of formula IV to compound of formula ii is 1.0: 2.0 to 3.0; preferably 1.0: 2.5.
10. a process for the synthesis of apatamide as claimed in claim 8, wherein the compound of formula ii is prepared from a compound of formula iii in the presence of thiophosgene:
11. the synthesis method according to claim 10, characterized by optionally comprising a post-treatment step, wherein the post-treatment step is to add a low-polarity solvent and an adsorbent, and remove impurities by stirring and filtering;
preferably, the low polarity solvent is selected from petroleum ether, n-hexane and n-heptane; the adsorbent is selected from aluminum oxide, activated carbon and column chromatography silica gel.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010429864.0A CN113698317A (en) | 2020-05-20 | 2020-05-20 | Synthetic method of apatamide, intermediate and synthetic method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010429864.0A CN113698317A (en) | 2020-05-20 | 2020-05-20 | Synthetic method of apatamide, intermediate and synthetic method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN113698317A true CN113698317A (en) | 2021-11-26 |
Family
ID=78645504
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010429864.0A Pending CN113698317A (en) | 2020-05-20 | 2020-05-20 | Synthetic method of apatamide, intermediate and synthetic method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN113698317A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115197084A (en) * | 2022-07-11 | 2022-10-18 | 中国船舶重工集团公司第七一八研究所 | Preparation method of enzalutamide key intermediate |
| CN115536634A (en) * | 2022-10-17 | 2022-12-30 | 上海博悦生物科技有限公司 | Synthetic method of apatamide |
-
2020
- 2020-05-20 CN CN202010429864.0A patent/CN113698317A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115197084A (en) * | 2022-07-11 | 2022-10-18 | 中国船舶重工集团公司第七一八研究所 | Preparation method of enzalutamide key intermediate |
| CN115536634A (en) * | 2022-10-17 | 2022-12-30 | 上海博悦生物科技有限公司 | Synthetic method of apatamide |
| CN115536634B (en) * | 2022-10-17 | 2024-06-11 | 上海博悦生物科技有限公司 | Synthesis method of apatamide |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU2008237749B2 (en) | Process for the preparation of gefitinib | |
| CN109942576B (en) | Irbinitinib and preparation method of intermediate | |
| CN113698317A (en) | Synthetic method of apatamide, intermediate and synthetic method thereof | |
| CN107778223A (en) | A kind of preparation method of maleic acid betrixaban | |
| US20200190056A1 (en) | Processes for the preparation of niraparib and intermediates thereof | |
| KR20050042502A (en) | Process for the preparation of 4-(3'-chloro-4'-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline | |
| CN108976164A (en) | The preparation method of chiral piperidine amine compounds and the recovery method of chiral resolving agent | |
| CN101462974A (en) | Process for synthesizing 5-aminovaleric acid hydrochloride | |
| CN108456238A (en) | The preparation method of shellfish chlolic acid derivatives difficult to understand and shellfish cholic acid difficult to understand | |
| CN114671867B (en) | Preparation method of tocartinib intermediate 7-hydroxy- [1,2,4] triazolo [1,5-a ] pyridine | |
| CN111100042B (en) | Preparation method of 2-methoxy-5-sulfonamide benzoic acid | |
| CN113912609B (en) | Preparation method of natural alkaloid tryptanthrin and derivatives thereof | |
| CN109721552B (en) | Preparation method of gefitinib | |
| CN110563721A (en) | Preparation method of azasetron hydrochloride | |
| EP3026047A1 (en) | Method for producing heterocyclic compound | |
| CN112409354B (en) | Synthesis process of 7-fluoroimidazo [1,2-A ] pyridine and intermediate thereof | |
| CN113354573B (en) | Method for large-scale production of alpha, alpha-terpyridine | |
| CN112457243B (en) | Synthesis method of 7-bromo-5-methoxyquinoline | |
| CN109810052A (en) | A kind of highly selective Ah pa replaces the simple and convenient process for preparing of Buddhist nun | |
| CN115417869B (en) | Synthesis method of 6-bromoimidazole [1.2A ] pyridine-3-formamide | |
| CN109721551B (en) | Preparation method of 3, 4-dihydro-7-methoxy-4-oxoquinazolin-6-ol acetate | |
| CN117209437A (en) | Preparation method of aminoquinazolinone derivative | |
| CN112898277B (en) | Preparation method of afatinib intermediate | |
| CN116589372A (en) | Synthesis method of Orientinib intermediate | |
| CN115785081A (en) | Preparation method of raltitrexed |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |