CN109956906A - A kind of preparation method for disliking La Geli key intermediate - Google Patents
A kind of preparation method for disliking La Geli key intermediate Download PDFInfo
- Publication number
- CN109956906A CN109956906A CN201910318994.4A CN201910318994A CN109956906A CN 109956906 A CN109956906 A CN 109956906A CN 201910318994 A CN201910318994 A CN 201910318994A CN 109956906 A CN109956906 A CN 109956906A
- Authority
- CN
- China
- Prior art keywords
- reaction
- compound
- preparation
- added
- acid
- 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.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/52—Two oxygen atoms
- C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
Abstract
The present invention relates to pharmaceutical fields; more particularly to a kind of preparation method for disliking La Geli key intermediate; using Boc-D- benzene glycinol simple and easy to get as starting material; replace and be deprotected six-step process comprising amination, amidation, arylation coupling, cyclization, benzylamine; the synthetic route starting material is simple and easy to get; reaction condition is more mild; post-processing is simple; it avoids having used noble metal catalyst; greatly reduce technique synthesis cost; obtained intermediate purity and yield is also very high, is very suitable to workshop large-scale production.
Description
Technical field
The present invention relates to pharmaceutical fields, and in particular to a kind of preparation method for disliking La Geli key intermediate.
Background technique
Orilissa is opened as oral preparation by AbbVie and Neurocrine Biosciences Inc (NBIX) jointly
Hair, medicine active constituent are elagolix, this is a kind of non-peptides gonadotropin-releasing hormone (GRH) GnRH receptor antagonist, is passed through
GnRH receptor in competitive binding pituitary gland inhibits endogenous GnRH signal.After Elagolix administration, it is raw to can lead to corpus luteum
Dose-dependent inhibition is presented in Cheng Su and follicle-stimulating hormone (FSH), eventually leads to ovarian sex hormone estradiol and progesterone water in blood circulation
Pancake is low, reduce endometriosis patients dysmenorrhea or non-menstrual period pelvic pain.
Using 1- [2- fluoro- 6- (trifluoromethyl) benzyl], urea is starting material in patent WO2009062087, with acetoacetate
Tert-butyl ester cyclization obtains uracil intermediate, reacts to obtain Boc radical protection using iodo, Suzuki coupling and aminoalkylation
Intermediate, finally be deprotected to obtain by acidolysis and dislike La Geli key intermediate.Shown in following synthetic route, the synthetic route
Noble metal has been used to carry out coupling reaction, yield is low, and it is at high cost, be not suitable for industrialized production.
Using 2- fluoro- 6- (trifluoromethyl) benzonitrile as starting material in patent US7056927B2, also by borine tetrahydrofuran
Original, then 1- [2- fluoro- 6- (trifluoromethyl) benzyl] urea is obtained with urea reaction, it obtains urinating with ketene dimer progress cyclization later phonetic
Pyridine intermediate, then with bromine carry out bromo-reaction, then carry out Mitsunobu reaction and Suzuki coupling reaction, finally and
Acidolysis, which is deprotected to obtain, dislikes La Geli intermediate.Shown in following synthetic route, which has used bromine, Isosorbide-5-Nitrae-dioxane etc.
The substance being more toxic, simultaneous reactions condition is more harsh, is not suitable for industrialization large-scale production.
In conclusion develop a kind of completely new synthesis route, for example, find starting material simple and easy to get, avoid it is expensive
Use, reduction reaction step of metallic catalyst etc. can substantially reduce production cost, so that disliking in La Geli key
The synthesis of mesosome meets industrial scale production.
Summary of the invention
The purpose of the present invention is to provide a kind of preparation methods for disliking La Geli key intermediate, with Boc- simple and easy to get
D- benzene glycinol is starting material, and reaction condition is more mild, and post-processing is simple, avoids having used noble metal catalyst, significantly
Technique synthesis cost is reduced, obtained intermediate purity and yield is also very high, is very suitable to workshop large-scale production.
The present invention provides a kind of preparation method for disliking La Geli key intermediate, takes the following technical solution, including with
Lower step:
(1) Boc-D- benzene glycinol and hydrazine hydrate are subjected to ammoxidation and obtain compound ii；
(2) compound ii and chloro-carbonic acid ester type compound are subjected to amidation process and obtain compounds Ⅳ；
Wherein, R1Represent alkyl, including but not limited to methyl, ethyl, n-propyl, isopropyl, normal-butyl, tert-butyl, benzyl or
Cyclopropyl；
(3) compound V and compound VI are subjected to arylation coupling reaction and obtain compound VII；
Wherein, X represents halogens chlorine, bromine, iodine；R2Represent alkyl, including but not limited to methyl, ethyl, n-propyl, allyl, different
Butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl or benzyl；
(4) compounds Ⅳ and compound VII are subjected to cyclization reaction and obtain compound VIII；
(5) compound VIII and the fluoro- 6- trifluoromethyl benzylamine of 2- are subjected to substitution reaction and obtain compound Ⅸ；
(6) compound Ⅸ is carried out to deprotection reaction in acid condition and obtains compound Ⅹ.
Preferably, when ammoxidation synthesizes compound ii, the chemical compounds I, phthalimide, the triphenyl that use
The molar ratio of phosphine and diethyl azodiformate is 1:1 ~ 1.2:1 ~ 1.5:1 ~ 1.5, further preferred 1:1.05:1.1:1.2；
Preferably, when ammoxidation synthesizes compound ii, the solvent that uses is DMF, DMAC or THF, further preferably
THF；
Preferably, when ammoxidation synthesizes compound ii, the amination reagent that uses is hydrazine hydrate or ammonium hydroxide, further excellent
Select hydrazine hydrate；
Preferably, the chloro-carbonic acid ester type compound used is methylchloroformate, chloromethane when amidation process synthesizes compounds Ⅳ
Acetoacetic ester, n-propyl chloroformate, isopropyl chlorocarbonate, butyl chloroformate, isobutylchloroformate, benzyl chloroformate or chloro-carbonic acid
Cyclopropyl ester, further preferred n-propyl chloroformate；
Preferably, when amidation process synthesizes compounds Ⅳ, the organic base that uses be piperidines, pyridine, triethylamine, diethylamine,
4- methyl morpholine or 4-dimethylaminopyridine, further preferred triethylamine；
Preferably, when amidation process synthesizes compounds Ⅳ, the molar ratio of compound ii, compound III and alkali be 1:1 ~ 5:1 ~
5, further preferred 1:4:4.
Preferably, the compound VI used is methyl acetoacetate, second when arylation coupling reaction synthesizes compound VII
Ethyl acetoacetic acid ethyl ester, acetoacetate n-propyl, acetoacetic acid allyl ester, isopropyl acetoacetate, isobutyl acetoacetate, acetyl second
The secondary butyl ester of acid, tert-butyl acetoacetate, acetoacetate n-pentyl ester, the just own ester of acetoacetate, further preferred ethyl acetoacetate；
Preferably, the coupling catalyst used is CuI, CuCl, CuI when arylation coupling reaction synthesizes compound VII2、CuO
Or Cu (OAc)2, further preferred Cu (OAc)2；
Coupling catalyst will affect reaction rate, but coupling catalyst selects when arylation coupling reaction synthesizes compound VII
With several in this programme, the yield of compound VII is greatly improved, especially selection Cu (OAc)2, effect becomes apparent from.
Preferably, reaction dissolvent uses DMF, DMAC or DMSO, into one when arylation coupling reaction synthesizes compound VII
Walk preferred DMF；
Preferably, the molar ratio of compound V, compound VI and catalyst is when arylation coupling reaction synthesizes compound VII
1:1 ~ 2:0.05 ~ 0.2, further preferred 1:1.2:0.1.
Preferably, reaction dissolvent uses benzene, toluene or dimethylbenzene, further excellent when cyclization reaction synthesizes compound VIII
Select toluene；
Preferably, when cyclization reaction synthesizes compound VIII, the catalyst that uses is p-methyl benzenesulfonic acid or benzene sulfonic acid, further excellent
Select p-methyl benzenesulfonic acid；
Preferably, the molar ratio of compounds Ⅳ, compound VII and p-methyl benzenesulfonic acid is 1 when cyclization reaction synthesizes compound VIII:
1:1 ~ 1.5, further preferred 1:1:1.2.
Preferably, when benzylamine substitution reaction synthesizes compound Ⅸ, the organic base that uses is triethylamine, diethylamine, two different
Propylethylamine or diazabicylo, further preferred triethylamine；
Preferably, benzylamine substitution reaction synthesize compound Ⅸ when, reaction dissolvent using benzene, toluene, methanol, ethyl alcohol, isopropanol,
Acetonitrile or tetrahydrofuran, further preferred ethyl alcohol；
Preferably, when benzylamine substitution reaction synthesizes compound Ⅸ, the fluoro- 6- trifluoromethyl benzylamine of compound VIII, 2- and organic base
Molar ratio be 1:1 ~ 1.5:1 ~ 2, preferably 1:1.1:1.2.
Preferably, the acid used is methanesulfonic acid or hydrochloric acid, further preferred first when deprotection reaction synthesizes compound Ⅹ
Sulfonic acid；
Preferably, reaction dissolvent uses ethyl acetate, isopropyl acetate or acetic acid fourth when deprotection reaction synthesizes compound Ⅹ
Ester, further preferred isopropyl acetate；
Preferably, the molar ratio of compound Ⅸ and methanesulfonic acid is 1:1 ~ 5, further when deprotection reaction synthesizes compound Ⅹ
It is preferred that 1:3.
By implementing above-mentioned technical proposal, the present invention is using Boc-D- benzene glycinol simple and easy to get as starting material, reaction
Condition is more mild, and post-processing is simple, avoids having used noble metal catalyst, greatly reduces technique synthesis cost, obtain
Intermediate purity and yield are also very high, are very suitable to workshop large-scale production.
Specific embodiment
In conjunction with implementing in detail below, the present invention is described in further detail, and protection content of the invention is not limited to
Following embodiment.Without departing from the spirit and scope of the invention, various changes and advantages that will be apparent to those skilled in the art
It is all included in the present invention, and with appended claims protection scope.Implement process of the invention, condition, reagent, reality
Proved recipe method etc. is among the general principles and common general knowledge in the art, the present invention is not special in addition to the following content specially referred to
Limit content.
Embodiment 1:
Ammoxidation: under ice bath, by 23.7g Boc-D- benzene glycinol, 15.5g phthalimide, 28.8g triphenyl
Phosphine, 20.9g diethyl azodiformate and 500mL tetrahydrofuran are added in reaction flask, stir 15min, are warmed to room temperature reaction 6h
Afterwards, concentration removes tetrahydrofuran, and 50mL ethyl alcohol is added and 250mL hydrazine hydrate continues back flow reaction 2h, reaction terminates, and dichloro is added
Methane extraction, concentration remove organic layer, obtain 23.5g intermediate II, purity 98.5%, weight yield 99%.
Amidation process: under ice bath, 21.2g compound ii, 36.4g triethylamine and 200mL acetonitrile being added in reaction flask,
44.1g n-propyl chloroformate is slowly added dropwise, drop finishes, end of reaction after insulation reaction 3.5h, reaction solution is poured into the analysis of 2L ice water admittedly,
It filters, 28.6g intermediate IV, purity 99.1%, weight yield 135% is obtained after drying.
Arylation coupling reaction: the chloro- 2- fluoroanisole of 32.2g 3-, 31.2g second is added in reaction flask nitrogen protection at room temperature
Ethyl acetoacetic acid ethyl ester and 160mL DMF are added 4g copper acetate after stirring dissolved clarification, are warming up to 50 DEG C of reaction 8h.It pours after reaction
300mL saturated aqueous ammonium chloride quenching reaction is added the extraction of 200mL ethyl acetate three times, merges organic layer, anhydrous sodium sulfate
It is concentrated to dryness after drying, obtains 25.8g intermediate VII, purity 99.3%, weight yield 80.2%.
Cyclization reaction: 25.8g compounds Ⅳ, 20.3g compound VII, 22.8g are added at room temperature, in reaction flask to toluene sulphur
Acid and 250mL toluene put up division box, start back flow reaction 7h, and after reaction plus triethylamine adjusts pH to alkalescent, drop
It to room temperature, is concentrated to dryness, the mashing of 250mL water is added, filtering obtains 36.8g intermediate VIII, purity 98.6%, weight yield after drying
142.6%。
Benzylamine substitution reaction: 37.6g compound VIII, the fluoro- 6- trifluoromethyl benzylamine of 17.0g 2-, 9.7g are added in reaction flask
Triethylamine and 150mL ethyl alcohol are warming up to reflux, and the extraction of 100mL ethyl acetate is added three times after reacting 8h, merges organic layer, nothing
It is concentrated to dryness after aqueous sodium persulfate is dry, obtains 45.5g intermediate Ⅸ, purity 98.7%, weight yield 121%.
Deprotection reaction: the above-mentioned intermediate Ⅸ of 32.3g, 14.4g methanesulfonic acid and 150mL acetic acid isopropyl are added in reaction flask
Ester rises to 60 DEG C of reactions overnight, and wet chemical is added and adjusts pH ≈ 8, stirring layering, and phosphate aqueous solution is added in organic layer,
Layering, water layer are slowly added to wet chemical and adjust pH ≈ 7-8, add isopropyl acetate extraction, stirring layering, organic layer
It washed once with water, saturated salt solution, finally dried, filtered with anhydrous sodium sulfate respectively, filtrate concentration is drawn among dry 25.2g
Body Ⅹ, purity 99.4%, weight yield 78%.
Embodiment 2:
Ammoxidation: with the operation of embodiment 1,500mL tetrahydrofuran will be added and be changed to 250mL DMF, by 250mL hydrazine hydrate
It is changed to 400mL ammonium hydroxide, finally obtains 22.5g intermediate II, purity 97.5%, weight yield 95%.
Amidation process: with the operation of embodiment 1,44.1g n-propyl chloroformate will be added dropwise and be changed to 44.1g chloro-carbonic acid second
Ester obtains 25g intermediate IV, purity 98.6%, weight yield 106.1%.
Arylation coupling reaction: with the operation of embodiment 1,4g copper acetate will be added and be changed to 2g stannous chloride, obtain 24.2g
Intermediate VII, purity 97.2%, weight yield 75%.
Cyclization reaction: with the operation of embodiment 1,22.8g p-methyl benzenesulfonic acid will be added and be changed to 28.5g p-methyl benzenesulfonic acid, most
35.2g intermediate VIII, purity 98.1%, weight yield 136.4% are obtained afterwards.
Benzylamine substitution reaction: with the operation of embodiment 1,9.7g triethylamine will be added and be changed to 8.2g diisopropylethylamine, obtain
To 41.8g intermediate Ⅸ, purity 97.2%, weight yield 111.2%.
Deprotection reaction: with the operation of embodiment 1,14.4g methanesulfonic acid will be added and be changed to 23.9g methanesulfonic acid, obtain 24.2g
Intermediate Ⅹ, purity 98.8%, weight yield 75%.
Embodiment 3:
Ammoxidation: with the operation of embodiment 1, the difference is that, 20.9g diethyl azodiformate will be added and be changed to 19.5g
Diethyl azodiformate, reaction time extend to 7 hours, continue back flow reaction 4 hours, obtain 21.8g intermediate II, purity
97.9%, weight yield 92%.
Amidation process: with the operation of embodiment 1,44.1g n-propyl chloroformate will be added dropwise and be changed to 44.1g chloro-carbonic acid first
Ester, insulation reaction 3 hours, obtain 24.5g intermediate IV, purity 98.5%, weight yield 115.6%.
Arylation coupling reaction: with the operation of embodiment 1,4g copper acetate will be added and be changed to 3g copper oxide, be warming up to 55 DEG C
Reaction 9 hours, obtains 25.1g intermediate VII, purity 98.2%, weight yield 78%.
Cyclization reaction: with the operation of embodiment 1,22.8g p-methyl benzenesulfonic acid will be added and be changed to 21.2g p-methyl benzenesulfonic acid, return
Stream reaction 8 hours, finally obtains 34.5g intermediate VIII, purity 97.2%, weight yield 133.7%.
Benzylamine substitution reaction: with the operation of embodiment 1,9.7g triethylamine will be added and be changed to 10.5g diethylamine, reaction 10 is small
When, obtain 41.5g intermediate Ⅸ, purity 98.1, weight yield 110.5%.
Deprotection reaction: with the operation of embodiment 1, the difference is that, temperature rises to 55 DEG C of reactions overnight, and 14.4g will be added
Methanesulfonic acid is changed to 20.7 hydrochloric acid, obtains 23.3g intermediate Ⅹ, purity 98.4%, weight yield 72%.
Embodiment 4:
Ammoxidation: with the operation of embodiment 1,28.8g triphenylphosphine will be added and be changed to 32.9g triphenylphosphine, room temperature reaction 8
Hour, back flow reaction 3 hours, obtain 23.4g intermediate II, purity 97.9%, weight yield 98.7%.
Amidation process: with the operation of embodiment 1, will be added 36.4g triethylamine and be changed to 32.5g 4-dimethylaminopyridine,
Insulation reaction 4 hours, obtain 27.8g intermediate IV, purity 97.9%, weight yield 131.2%.
Arylation coupling reaction: with the operation of embodiment 1,4g copper acetate will be added and be changed to 2g copper acetate, obtain in 24.7g
Mesosome VII, purity 98.5%, weight yield 76.7%.
Cyclization reaction: with the operation of embodiment 1,250mL toluene will be added and be changed to 250mL dimethylbenzene, finally obtain in 35.8g
Mesosome VIII, purity 98.1%, weight yield 138.8%.
Benzylamine substitution reaction: with the operation of embodiment 1,150mL ethyl alcohol will be added and be changed to 150mL acetonitrile, obtain in 33.9g
Mesosome Ⅸ, purity 97.3%, weight yield 90.2%.
Deprotection reaction: with the operation of embodiment 1,14.4g methanesulfonic acid will be added and be changed to 14.4g hydrochloric acid, obtain in 23.1g
Mesosome Ⅹ, purity 99.0%, weight yield 71.7%.
Embodiment 5:
Ammoxidation: with the operation of embodiment 1,15.5g phthalimide will be added and be changed to 14.8g phthalyl Asia
Amine obtains 22.1g intermediate II, purity 98.0%, weight yield 93.2%.
Amidation process: with the operation of embodiment 1,36.4g triethylamine will be added and be changed to 32.5g piperidines, obtain 26.8g
Intermediate IV, purity 98.7%, weight yield 126.4%.
Arylation coupling reaction: with the operation of embodiment 1,4g copper acetate will be added and be changed to 3g cuprous iodide, obtain 24.2g
Intermediate VII, purity 97.2%, weight yield 75.2%.
Cyclization reaction: with the operation of embodiment 1, will be added 22.8g p-methyl benzenesulfonic acid and be changed to 22.8g benzene sulfonic acid, finally
32.2g intermediate VIII, purity 96.6%, weight yield 124.8%.
Benzylamine substitution reaction: with the operation of embodiment 1,150mL ethyl alcohol will be added and be changed to 150mL isopropanol, obtain 34.2g
Intermediate Ⅸ, purity 97.1%, weight yield 132.6%.
Deprotection reaction: with the operation of embodiment 1,150mL isopropyl acetate will be added and be changed to 150mL ethyl acetate, obtain
To 23.8g intermediate Ⅹ, purity 98.8%, weight yield 73.7%.
Comparative example 1:
It is with the difference of embodiment 5:
Ammoxidation: with the operation of embodiment 1,500mL tetrahydrofuran will be added and be changed to 500mL DMAC, obtain in 21.4g
Mesosome II, purity 97.4%, weight yield 90.2%.
Comparative example 2:
It is with the difference of embodiment 5:
Amidation process: with the operation of embodiment 1,36.4g triethylamine will be added and be changed to 54.6g triethylamine, obtain among 24.5g
Body IV, purity 98.1%, weight yield 115.6%.
Comparative example 3:
It is with the difference of embodiment 5:
Arylation coupling reaction: with the operation of embodiment 1,4g copper acetate will be added and be changed to 1.5g copper powder, obtain 21.2g intermediate
VII, purity 95.2%, weight yield 65.8%.
Comparative example 4:
It is with the difference of embodiment 5:
Arylation coupling reaction: with the operation of embodiment 1,31.2g ethyl acetoacetate will be added and be changed to 46.1g acetoacetate benzyl
Ester obtains 22.3g intermediate VII, purity 94.4%, weight yield 69.2%.
Comparative example 5:
It is with the difference of embodiment 5:
Arylation coupling reaction: with the operation of embodiment 1,31.2g ethyl acetoacetate will be added and be changed to 42.5g acetoacetate second
Ester obtains 25.2g intermediate VII, purity 98.8%, weight yield 78.3%.
Comparative example 6:
It is with the difference of embodiment 5:
Benzylamine substitution reaction: with the operation of embodiment 1,150mL ethyl alcohol will be added and be changed to 150mL acetone, obtain 42.1g intermediate
Ⅸ, purity 96.5%, weight yield 112%.
Claims (16)
1. a kind of preparation method for disliking La Geli key intermediate, which is characterized in that using Boc-D- benzene glycinol as starting material,
Replace and be deprotected six-step process comprising amination, amidation, arylation coupling, cyclization, benzylamine.
2. preparation method according to claim 1, which comprises the following steps:
(1) Boc-D- benzene glycinol and amination reagent are subjected to ammoxidation and obtain compound ii；
(2) compound ii and chlorinating agent are subjected to amidation process and obtain compounds Ⅳ；
Wherein, R1Represent alkyl；
(3) compound V and compound VI are subjected to arylation coupling reaction and obtain compound VII；
Wherein, X represents halogen；R2Represent alkyl；
(4) compounds Ⅳ and compound VII are subjected to cyclization reaction and obtain compound VIII；
(5) compound VIII and the fluoro- 6- trifluoromethyl benzylamine of 2- are subjected to substitution reaction and obtain compound Ⅸ；
(6) compound Ⅸ is carried out to deprotection reaction in acid condition and obtains compound Ⅹ.
3. preparation method according to claim 2, which is characterized in that specific steps are as follows:
(1) ammoxidation: under ice bath, by Boc-D- benzene glycinol, phthalimide, triphenylphosphine, azoformic acid
Diethylester and solvent are added in reaction flask, stirring, after being warmed to room temperature reaction 6h ~ 8h, ethyl alcohol are added and amination reagent continues back
Stream reaction 2h ~ 4h, reaction terminate, extract, and concentration removes organic layer, obtains compound ii；
(2) amidation process: under ice bath, compound ii, organic base and acetonitrile being added in reaction flask, and chloro examination is slowly added dropwise
Agent is dripped and is finished, and end of reaction after 3 ~ 4h of insulation reaction, analysis is solid, filters, and compounds Ⅳ is obtained after drying；
(3) arylation coupling reaction: compound V, compound VI and solvent is added in reaction flask nitrogen protection at room temperature, stirs molten
Coupling catalyst is added after clear, is warming up to 50 ~ 60 DEG C of 8 ~ 10h of reaction, pours saturated aqueous ammonium chloride after reaction and be quenched
Reaction, extraction, organic layer are concentrated to dryness, and obtain compound VII；
(4) cyclization reaction: at room temperature, addition compounds Ⅳ, compound VII, catalysts and solvents in reaction flask, back flow reaction 7 ~
9h, after reaction plus triethylamine adjusts pH to alkalescent, is down to room temperature, is concentrated to dryness, water is added, be beaten, filters, after drying
Obtain compound VIII；
(5) it is molten that compound VIII, the fluoro- 6- trifluoromethyl benzylamine of 2-, organic base and reaction benzylamine substitution reaction: are added in reaction flask
Agent is warming up to reflux, and after reacting 8 ~ 10h, extraction, organic layer is concentrated to dryness, and obtains intermediate Ⅸ；
(6) deprotection reaction: being added intermediate Ⅸ, acid and solvent in reaction flask, rises to 50 ~ 60 DEG C of reactions overnight, stirring layering,
Phosphate aqueous solution, layering is added in organic layer, and water layer is added isopropyl acetate and extracts, stirring layering, organic layer water, saturated common salt
Water washed once respectively, finally be dried, filtered with anhydrous sodium sulfate, and filtrate concentration, which is drawn, does to obtain intermediate Ⅹ.
4. preparation method according to claim 2 or 3, which is characterized in that when ammoxidation synthesizes compound ii, use
Chemical compounds I, phthalimide, triphenylphosphine and diethyl azodiformate molar ratio be 1:1 ~ 1.2:1 ~ 1.5:1 ~
1.5。
5. preparation method according to claim 2 or 3, which is characterized in that when ammoxidation synthesizes compound ii, use
Amination reagent be hydrazine hydrate.
6. preparation method according to claim 2 or 3, which is characterized in that when amidation process synthesizes compounds Ⅳ, use
Chlorinating agent be methylchloroformate, ethyl chloroformate, n-propyl chloroformate, isopropyl chlorocarbonate, butyl chloroformate, chloromethane
Tert-butyl acrylate, benzyl chloroformate or chloro-carbonic acid cyclopropyl ester.
7. preparation method according to claim 2 or 3, which is characterized in that when amidation process synthesizes compounds Ⅳ, use
Organic base be piperidines, pyridine, triethylamine, diethylamine, 4- methyl morpholine or 4-dimethylaminopyridine.
8. preparation method according to claim 2 or 3, which is characterized in that when amidation process synthesizes compounds Ⅳ, chemical combination
The molar ratio of object II, compound III and organic base is 1:1 ~ 5:1 ~ 5.
9. preparation method according to claim 2 or 3, which is characterized in that when arylation coupling reaction synthesizes compound VII,
The compound VI used is methyl acetoacetate, ethyl acetoacetate, acetoacetate n-propyl, acetoacetic acid allyl ester, acetyl
The secondary butyl ester of isopropyl acetate, isobutyl acetoacetate, acetoacetate, tert-butyl acetoacetate, acetoacetate n-pentyl ester, acetyl second
The just own ester of acid.
10. preparation method according to claim 2 or 3, which is characterized in that arylation coupling reaction synthesizes compound VII
When, the coupling catalyst used is CuI, CuCl, CuI2, CuO or Cu (OAc)2；Compound V, compound VI and catalyst rub
You are than being 1:1 ~ 2:0.05 ~ 0.2.
11. preparation method according to claim 2 or 3, which is characterized in that when cyclization reaction synthesizes compound VIII, reaction
Solvent uses benzene, toluene or dimethylbenzene；The catalyst used is p-methyl benzenesulfonic acid or benzene sulfonic acid.
12. preparation method according to claim 2 or 3, which is characterized in that when cyclization reaction synthesizes compound VIII, chemical combination
The molar ratio of object IV, compound VII and p-methyl benzenesulfonic acid is 1:1:1 ~ 1.5.
13. preparation method according to claim 2 or 3, which is characterized in that when benzylamine substitution reaction synthesizes compound Ⅸ,
The organic base used is triethylamine, diethylamine, diisopropylethylamine or diazabicylo；Reaction dissolvent uses benzene, toluene, first
Alcohol, ethyl alcohol, isopropanol, acetonitrile or tetrahydrofuran.
14. preparation method according to claim 2 or 3, which is characterized in that when benzylamine substitution reaction synthesizes compound Ⅸ,
The molar ratio of the fluoro- 6- trifluoromethyl benzylamine of compound VIII, 2- and organic base is 1:1 ~ 1.5:1 ~ 2.
15. preparation method according to claim 2 or 3, which is characterized in that when deprotection reaction synthesizes compound Ⅹ, make
Acid is methanesulfonic acid or hydrochloric acid；Reaction dissolvent uses ethyl acetate, isopropyl acetate or butyl acetate.
16. preparation method according to claim 2 or 3, which is characterized in that when deprotection reaction synthesizes compound Ⅹ, change
The molar ratio for closing object Ⅸ and methanesulfonic acid is 1:1 ~ 5.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910318994.4A CN109956906B (en) | 2019-04-19 | 2019-04-19 | Preparation method of key intermediate of oxalagogri |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910318994.4A CN109956906B (en) | 2019-04-19 | 2019-04-19 | Preparation method of key intermediate of oxalagogri |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN109956906A true CN109956906A (en) | 2019-07-02 |
| CN109956906B CN109956906B (en) | 2021-01-29 |
Family
ID=67026368
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910318994.4A Active CN109956906B (en) | 2019-04-19 | 2019-04-19 | Preparation method of key intermediate of oxalagogri |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109956906B (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110483415A (en) * | 2019-08-21 | 2019-11-22 | 江苏海岸药业有限公司 | A kind of method for preparing purified for disliking La Geli intermediate |
| CN110669014A (en) * | 2019-11-14 | 2020-01-10 | 重庆医药高等专科学校 | Preparation method of oxalagogri intermediate |
| CN111116490A (en) * | 2020-01-15 | 2020-05-08 | 奥锐特药业股份有限公司 | Preparation and purification method of oxalagogri intermediate salicylate |
| CN111333586A (en) * | 2020-02-19 | 2020-06-26 | 诚达药业股份有限公司 | Preparation method of compound containing 6-methyl uracil structure |
| CN112694445A (en) * | 2019-10-22 | 2021-04-23 | 成都倍特药业股份有限公司 | Purification method of oxalaggrin sodium intermediate |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005007165A1 (en) * | 2003-07-07 | 2005-01-27 | Neurocrine Biosciences, Inc. | Pyrimidine-2, 4-dione derivatives as gonadotropin-releasing hormone receptor antagonists |
| WO2009062087A1 (en) * | 2007-11-07 | 2009-05-14 | Neurocrine Biosciences, Inc. | Processes for the preparation of uracil derivatives |
| CN108586359A (en) * | 2018-06-26 | 2018-09-28 | 杭州科巢生物科技有限公司 | A kind of synthetic method for disliking La Geli |
-
2019
- 2019-04-19 CN CN201910318994.4A patent/CN109956906B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005007165A1 (en) * | 2003-07-07 | 2005-01-27 | Neurocrine Biosciences, Inc. | Pyrimidine-2, 4-dione derivatives as gonadotropin-releasing hormone receptor antagonists |
| WO2009062087A1 (en) * | 2007-11-07 | 2009-05-14 | Neurocrine Biosciences, Inc. | Processes for the preparation of uracil derivatives |
| CN108586359A (en) * | 2018-06-26 | 2018-09-28 | 杭州科巢生物科技有限公司 | A kind of synthetic method for disliking La Geli |
Non-Patent Citations (2)
| Title |
|---|
| CHEN CHEN ET AL.: "Elagolix, Nonpeptide Antagonist of GnRH Receptor", 《J. MED. CHEM.》 * |
| 齐晓丽等: "6-甲基-尿嘧啶及其N-取代衍生物合成", 《西北大学学报(自然科学版)》 * |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110483415A (en) * | 2019-08-21 | 2019-11-22 | 江苏海岸药业有限公司 | A kind of method for preparing purified for disliking La Geli intermediate |
| CN110483415B (en) * | 2019-08-21 | 2022-12-30 | 江苏海岸药业有限公司 | Purification preparation method of oxalagogri intermediate |
| CN112694445A (en) * | 2019-10-22 | 2021-04-23 | 成都倍特药业股份有限公司 | Purification method of oxalaggrin sodium intermediate |
| CN112694445B (en) * | 2019-10-22 | 2023-07-28 | 成都倍特药业股份有限公司 | Purification method of oxaagole sodium intermediate |
| CN110669014A (en) * | 2019-11-14 | 2020-01-10 | 重庆医药高等专科学校 | Preparation method of oxalagogri intermediate |
| CN110669014B (en) * | 2019-11-14 | 2021-04-30 | 重庆医药高等专科学校 | Preparation method of oxalagogri intermediate |
| CN111116490A (en) * | 2020-01-15 | 2020-05-08 | 奥锐特药业股份有限公司 | Preparation and purification method of oxalagogri intermediate salicylate |
| CN111333586A (en) * | 2020-02-19 | 2020-06-26 | 诚达药业股份有限公司 | Preparation method of compound containing 6-methyl uracil structure |
Also Published As
| Publication number | Publication date |
|---|---|
| CN109956906B (en) | 2021-01-29 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN109956906A (en) | A kind of preparation method for disliking La Geli key intermediate | |
| TWI720803B (en) | Process for the preparation of a pde4 inhibitor | |
| JP6995178B2 (en) | Method for preparing cytotoxic benzodiazepine derivative | |
| WO2020147861A1 (en) | Electrochemical preparation method for β-trifluoromethylamide compound | |
| KR102625774B1 (en) | Synthesis of omecamtive mecarville | |
| CN110194776A (en) | A kind of synthetic method of Rui Lugeli | |
| CN112321602A (en) | Preparation method of Ruogeli drug intermediate | |
| CN113717149A (en) | Ruogeli key intermediate and preparation method thereof | |
| JP2010539237A5 (en) | ||
| CN105884691B (en) | A kind of method for preparing Dexmedetomidine and its intermediate | |
| CN110526859B (en) | Revinanexin intermediate, preparation method thereof and preparation method of Revinanexin | |
| WO2017071419A1 (en) | Method for preparing rociletinib | |
| CN107141261A (en) | Quinazoline compounds and preparation method thereof and the application in tyrosine kinase inhibitor is prepared | |
| CN113683651A (en) | Preparation method of GalNAc intermediate | |
| JP6289479B2 (en) | Method for synthesizing 2-amino-4,6-dimethoxybenzamide and other benzamide compounds | |
| CN105745191A (en) | Method for preparing silodosin and intermediate thereof | |
| CN111848546B (en) | 2- (aminomethyl) thiazole-5-nitrile and synthesis method thereof | |
| CN103059098A (en) | Preparation method of dutasteride | |
| CN114539216A (en) | Preparation method of Vonoprazan | |
| CN105523958B (en) | A kind of method for preparing Diarylthiohydantoin derivative key intermediate | |
| CN108658931A (en) | A kind of preparation method of Raltitrexed key intermediate | |
| CN108997236A (en) | A kind of preparation method of Anastrozole impurity | |
| CN103570724B (en) | The synthetic method of ponatinib | |
| CN111875557B (en) | Thiazole derivative and synthesis method thereof | |
| CN109970662A (en) | A method of it prepares and dislikes La Geli intermediate |
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 | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |