CN109988077A - A kind of synthetic method and intermediate of A Palu amine - Google Patents
A kind of synthetic method and intermediate of A Palu amine Download PDFInfo
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- CN109988077A CN109988077A CN201711474542.2A CN201711474542A CN109988077A CN 109988077 A CN109988077 A CN 109988077A CN 201711474542 A CN201711474542 A CN 201711474542A CN 109988077 A CN109988077 A CN 109988077A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
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- 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
- C07C237/30—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 hydrogen atoms or to acyclic carbon atoms
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- 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
Abstract
The present invention provides a kind of preparation methods that A Palu amine is new; use the bromo- N- methyl benzene methanamine amide of the fluoro- 4- of 2-, 1- Aminocyclobutyl carboxylic acid hydrochloride etc. for starting material; being substituted reaction and the synthesis yield of 1- ((3- fluoro- 4- (methylcarbamoyl) phenyl) amino) cyclobutane -1- carboxylic acid is prepared is more than 70%, and purity is 97.2% or more；Obtaining the synthesis yield of 1- ((3- fluoro- 4- (methylcarbamoyl) phenyl) amino) cyclobutane -1- carboxylate through esterification after and is more than 83%, and purity is 97.8% or more；Ring closure reaction finally is completed with 2- cyano -3- trifluoromethyl -5- isothiocyano pyridine and obtains A Palu amine, and yield is more than 68%, and purity is 98.1% or more.The invention provide it is a kind of be easy to get with raw material, concise in technology, easy to operate, high income, the preparation method of A Palu amine at low cost.
Description
Technical field
The invention belongs to field of medicine and chemical technology, and in particular to a kind of synthetic method and intermediate of A Palu amine.
Background technique
A Palu amine (Apalutamide, JNJ-56021927, ARN-509, JNJ-927), chemical structural formula such as formula III
It is shown, it is a kind of inhibitor for androgen (Androgen receptor (AR) antagonists), is developed, can be used by Johson & Johnson
In treatment prostate cancer.A Palu amine is currently in III phase clinical research, has a good application prospect.
The preparation method of A Palu amine mainly includes following two kinds at present:
The synthetic route of method one includes route I, route II and route III, it is open be documented in patent WO2007126765,
In WO2008119015, WO2011103202 and WO2014190895, content is as follows:
Compound 4- ((1- cyano cyclobutyl) amino) the fluoro- N-methyl-benzamide of -2- (APAL-009) and compound 2-
Cyano -3- trifluoromethyl -5- isothiocyano pyridine (APAL-008), reacts 20h under 80 DEG C of microwave conditions, obtains finished product Ah
Pa Shandong amine, yield 35%, as shown in route I.This method obtains the product of 22mg rank, but microwave reaction condition is unsuitable for amplifying
It generates, does not have industrial production value.Synthetic method such as route II and the route of 7 two kinds of raw materials of compound 10 and compound
Shown in III.
The synthesis such as route II institute of 4- ((1- cyano cyclobutyl) amino) fluoro- N-methyl-benzamide of -2- (APAL-009)
Show: after 2,4- difluoro benzoyl chlorides and methylamine-tetrahydrofuran solution amidation, under 190 DEG C of microwave conditions and to methoxybenzyl
Amine reacts to obtain APAL-012, yield 40%；APAL-012 obtains the fluoro- 4- Amino-N-methyl of key intermediate 2- through deprotection
Benzamide (APAL-013), then react to obtain 4- ((1- cyano cyclobutyl) amino) -2- with the Cymag of severe toxicity, cyclobutanone
Fluoro- N-methyl-benzamide (APAL-009), the total recovery of 4 steps reaction are 33%.The route, which uses, is not easy amplification production
Microwave reaction equipment, poisonous reagent Cymag etc., and column chromatographic purifying is needed, it is unfavorable for industrialized production.
The synthesis of 2- cyano -3- trifluoromethyl -5- isothiocyano pyridine (APAL-008) is as shown in route III: with 2- hydroxyl
Base -3- trifluoromethyl pyridine (APAL-015) is raw material, obtains the chloro- 3- fluoroform of 2- through nitrification, chlorination, catalytic hydrogen reduction
Base -5- aminopyridine (APAL-018), the total recovery about 50% of 3 steps reaction；Replace after and through Boc protection, cyano, be deprotected
To APAL-007,8 step overall yield of reaction 23%.
The synthetic route of method two is as shown in route IV, and open to be documented in patent WO2016100652, content is as follows:
Using APAL-007 (it is synthesized as shown in route III) and 1-Boc- amino cyclobutane -1- carboxylic acid as raw material, in CDI/
After DBU is catalyzed lower amidation, then hydrogen chloride takes off Boc and obtains 1- amino-N- (6- cyano -5- (trifluoromethyl) pyridine -3-) ring fourth
Alkane -1- carboxylic acid (APAL-022), the 2 step reaction yield are 80%；Compound 22 then with the fluoro- 4- chloro-n-methyl benzoyl of 2-
Amine (APAL-023) obtains APAL-024 through potassium acetate/copper powder catalytic coupling, and yield is about 90%；Compound 24 and thio chloromethane
Acid phenenyl ester reaction under DMAP catalysis obtains A Palu amine, yield 70%.
The route obtains the product of gram-grade scale.A Palu is prepared through 4 step subsequent reactions by APAL-007 in the route
Amine, APAL-007 is the critical component for determining the route cost, but the preparation of APAL-007 need to be through multistep reaction, Atom economy
It is lower, so that the route Material Cost is higher.In addition, having used Boc protecting group in raw material 1-Boc- amino cyclobutane -1- carboxylic acid
Group, increases reaction step, is also unfavorable for reducing cost.
Therefore, for the defect in the presence of the prior art, there is an urgent need to a kind of raw materials to be easy to get, simple process, be suitble to work
The production of industry metaplasia, high income, A Palu amine synthetic method at low cost, to meet the market demand.
Summary of the invention
The present invention is intended to provide a kind of synthetic method of A Palu amine, as shown in route V, this method raw material is easy to get, technique
Simplicity, high income, at low cost, suitable industrialized production.
Wherein, R is C1~C6Alkyl, C4~C8Naphthenic base or benzyl.As methyl, ethyl, propyl, isopropyl, butyl,
Isobutyl group, tert-butyl, amyl, base, cyclobutyl, cyclopenta, cyclohexyl, cyclooctyl or benzyl.
As shown in route V, the novel midbody compound of A Palu amine is synthesized, there is 1- ((the fluoro- 4- of 3- of Formulas I structure
(methylcarbamoyl) phenyl) amino) cyclobutane -1- carboxylic acid or Formula II structure 1- ((3- fluoro- 4- (methylcarbamoyl) benzene
Base) amino) cyclobutane -1- carboxylate,
Wherein, R is C1~C6Alkyl, C4~C8Naphthenic base or benzyl.As methyl, ethyl, propyl, isopropyl, butyl,
Isobutyl group, tert-butyl, amyl, base, cyclobutyl, cyclopenta, cyclohexyl, cyclooctyl or benzyl.
The preparation method packet of 1- ((3- fluoro- 4- (methylcarbamoyl) phenyl) amino) cyclobutane -1- carboxylic acid of Formulas I structure
It includes: under inert gas shielding, under catalyst action, the bromo- N- methyl benzene methanamine amide of the fluoro- 4- of 2- and 1- Aminocyclobutyl carboxylate
Hydrochlorate replaces the 1- ((3- fluoro- 4- (methylcarbamoyl) phenyl) amino) of production I structure in the organic solvent containing alkali
Cyclobutane -1- carboxylic acid.
The molar ratio of the bromo- N- methyl benzene methanamine amide of the fluoro- 4- of 2- and 1- Aminocyclobutyl carboxylic acid hydrochloride is 1:1~1.8,
Preferably 1:1.3~1.5.The amount ratio of the bromo- N- methyl benzene methanamine amide of the fluoro- 4- of 2- and organic solvent is 0.5~1mol/L, excellent
It is selected as 0.6~0.8mol/L.The molar ratio of the bromo- N- methyl benzene methanamine amide of the fluoro- 4- of 2- and catalyst is 1:0.2~0.4, preferably
For 1:0.2.
The temperature of substitution reaction is 100 DEG C~120 DEG C, preferably 110 DEG C.The time of substitution reaction is 6~16 hours, excellent
It is selected as 10~11 hours.
The inert gas is generally argon gas or nitrogen, preferably argon gas.
The organic solvent is non-protonic solvent, generally polar aprotic solvent, such as dimethylformamide
(DMF), dimethyl sulfoxide (DMSO), dimethyl acetamide (DMAC), N-Methyl pyrrolidone (NMP).
The alkali is inorganic base, generally potassium carbonate, sodium carbonate, saleratus, sodium bicarbonate, lithium carbonate, cesium carbonate etc.,
Preferably potassium carbonate.
The catalyst is metal salt, generally stannous chloride, protobromide ketone, cuprous iodide, preferably stannous chloride.
After substitution reaction, reaction solution extraction extracts organic phase after being filtered, washed, and acidizing crystal obtains 1-, and ((3- is fluoro-
4- (methylcarbamoyl) phenyl) amino) cyclobutane -1- carboxylic acid.
The preparation side of 1- ((3- fluoro- 4- (methylcarbamoyl) phenyl) amino) cyclobutane -1- carboxylate of Formula II structure
Method are as follows: 1- ((3- fluoro- 4- (methylcarbamoyl) phenyl) amino) cyclobutane -1- carboxylic acid and monohaloalkyl reagent RX of Formulas I structure
Or 1- ((3- fluoro- 4- (methylcarbamoyl) phenyl) amino) cyclobutane -1- carboxylic acid of alcohol roh esterification production II structure
Ester, wherein R C1~C6Alkyl, C4~C8Naphthenic base or benzyl, X F, Cl, Br or I.
The preparation method of 1- ((3- fluoro- 4- (methylcarbamoyl) phenyl) amino) cyclobutane -1- carboxylate can be alkali
Under the conditions of property, in non-protonic solvent, 1- ((3- fluoro- 4- (methylcarbamoyl) phenyl) amino) cyclobutane -1- carboxylic acid and list
Halogenating agent RX esterification generates 1- ((3- fluoro- 4- (methylcarbamoyl) phenyl) amino) cyclobutane -1- carboxylate.
The molar ratio of 1- ((3- fluoro- 4- (methylcarbamoyl) phenyl) amino) cyclobutane -1- carboxylic acid and monohaloalkyl reagent
For 1:1~1.5, preferably 1:1.2.1- ((3- fluoro- 4- (methylcarbamoyl) phenyl) amino) cyclobutane -1- carboxylic acid and non-matter
The amount ratio of sub- property solvent is 0.4~0.8mol/L, preferably 0.5mol/L.1- ((3- fluoro- 4- (methylcarbamoyl) phenyl)
Amino) molar ratio of cyclobutane -1- carboxylic acid and alkali is 1:1~1.5, preferably 1:1.2.
The temperature of the esterification is 35 DEG C~45 DEG C, preferably 40 DEG C.The esterification time be 2~3 hours, preferably 2
Hour.
The non-protonic solvent is polar aprotic solvent, generally dimethyl sulfoxide (DMSO), dimethyl formyl
Amine (DMF), dimethyl acetamide (DMAC) or N-Methyl pyrrolidone (NMP) etc., preferably dimethylformamide.
The alkali is inorganic base, generally potassium carbonate or sodium carbonate, sodium bicarbonate, saleratus etc., preferably carbonic acid
Potassium.
After above-mentioned esterification, into esterification reaction solution plus water or acetic acid and water, precipitating crystallization obtain 1- ((3-
Fluoro- 4- (methylcarbamoyl) phenyl) amino) cyclobutane -1- carboxylate.When acetic acid and water is added, the volume ratio of acetic acid and water
For 1:200~240.
The preparation method of 1- ((3- fluoro- 4- (methylcarbamoyl) phenyl) amino) cyclobutane -1- carboxylate can also be,
In the presence of catalyst, 1- ((3- fluoro- 4- (methylcarbamoyl) phenyl) amino) cyclobutane -1- carboxylic acid and alcohol roh 50 DEG C~90
Lactate synthesis 1- ((3- fluoro- 4- (methylcarbamoyl) phenyl) amino) cyclobutane -1- carboxylate under the conditions of DEG C.
The amount ratio of 1- ((3- fluoro- 4- (methylcarbamoyl) phenyl) amino) cyclobutane -1- carboxylic acid and alcohol be 0.25~
0.5mol/L, preferably 0.3~0.35mol/L.1- ((3- fluoro- 4- (methylcarbamoyl) phenyl) amino) cyclobutane -1- carboxylic
The molar ratio of acid and catalyst is 1:1~2.5, preferably 1:1~2.
The time of the esterification is 10~20 hours, preferably 10 hours.
The catalyst is inorganic acid, organic acid or carboxylic acid halides, and the inorganic acid is generally sulfuric acid, nitric acid, hydrobromic acid, salt
At least one of acid, phosphoric acid, preferably sulfuric acid；Organic acid is trifluoroacetic acid, p-methyl benzenesulfonic acid, Loprazolam, acetic acid；Institute
It states carboxylic acid halides and is generally acyl fluorides, acyl chlorides, acylbromide, thionyl chloride, phosphorus oxychloride or tribromo oxygen phosphorus, preferably chloroacetic chloride.
It after above-mentioned esterification, is successively concentrated, is extracted and is concentrated to get again solids, solids is recrystallizing
Cooling crystallization obtains 1- ((3- fluoro- 4- (methylcarbamoyl) phenyl) amino) cyclobutane -1- carboxylic after first dissolving by heating in solvent
Acid esters.Extracting extract liquor used is ethyl acetate and water, preferably isometric ethyl acetate and water.Extraction gained organic phase into
Row is concentrated again, it is preferable that is concentrated again after the extraction gained repeated washing of organic phase.Recrystallization solvent is methanol, ethyl alcohol, third
The alcohol reagents such as alcohol, isopropanol dissolve by heating as reflux dissolution.
The synthetic method of A Palu amine, step include: in organic solvent, to have Formula II structure under inert gas shielding
1- ((3- fluoro- 4- (methylcarbamoyl) phenyl) amino) cyclobutane -1- carboxylate and the different sulphur of 2- cyano -3- trifluoromethyl -5-
Ring closure reaction occurs for cyanopyridine, obtains A Palu amine；
Wherein, R is C1~C6Alkyl, C4~C8Naphthenic base or benzyl, as methyl, ethyl, propyl, isopropyl, butyl,
Isobutyl group, tert-butyl, amyl, base, cyclobutyl, cyclopenta, cyclohexyl, cyclooctyl or benzyl.
1- ((3- fluoro- 4- (methylcarbamoyl) phenyl) amino) cyclobutane -1- carboxylate and 2- cyano -3- fluoroform
The molar ratio of base -5- isothiocyano pyridine is 1:1~2, preferably 1:1.5~2.1- ((3- fluoro- 4- (methylcarbamoyl) benzene
Base) amino) amount ratio of cyclobutane -1- carboxylate and organic solvent is 1~1.5mol/L, preferably 1~1.4mol/L.
The inert gas is argon gas or nitrogen, preferably argon gas.
The organic solvent is dimethyl sulfoxide, dimethylformamide, dimethyl acetamide, N-Methyl pyrrolidone, second
Acid esters or its mixture, preferably dimethyl sulfoxide, acetic acid esters, dimethylformamide, dimethylformamide and acetic acid esters
The mixture of mixture or dimethyl sulfoxide and acetic acid esters.Acetic acid esters is methyl acetate, ethyl acetate, isopropyl acetate, second
Propyl propionate, butyl acetate etc., preferably ethyl acetate, isopropyl acetate.
The temperature of the ring closure reaction is 80~95 DEG C, preferably 85 DEG C；The ring closure reaction time is 7.5~9 hours,
Preferably 8 hours.
It after ring closure reaction, successively extracted, be concentrated, being recrystallized to give A Palu amine.Specifically: into reaction solution
Ethyl acetate and water extraction is added, extracts gained organic phase concentration, concentration gained concentrate or thickened solid are molten in recrystallization
Cooling crystallization after being dissolved by heating in agent.Extract used ethyl acetate and water be it is isometric, recrystallization solvent is isopropanol.It is described to add
Heat of solution is reflux dissolution.
In the present invention, the synthetic method of 2- cyano -3- trifluoromethyl -5- isothiocyano pyridine is conventional method, such as route
Shown in III.
Compared with the existing technology, advantage of the process is that
(1) reaction step of synthetic method of the present invention is few, and reaction condition is mild, and post-reaction treatment is easy, and operation is easy, keeps away
Exempt to reduce waste discharge using poisonous reagents such as Cymags, it is environmental-friendly, it is suitble to industrialized production.
(2) synthetic method of the present invention with the bromo- N- methyl benzene methanamine amide of the fluoro- 4- of 2-, 1- Aminocyclobutyl carboxylic acid hydrochloride,
2- cyano -3- trifluoromethyl -5- isothiocyano pyridine etc. is raw material, has many advantages, such as that raw material is easy to get, cost reduces.
(3) synthetic method of the present invention uses convergence type synthetic strategy, 1- ((3- fluoro- 4- (methylcarbamoyl) phenyl) ammonia
Base) synthesis yield of cyclobutane -1- carboxylic acid is more than 70%, and purity is 97.2% or more；1- ((the fluoro- 4- of 3- (methylcarbamoyl)
Phenyl) amino) synthesis yield of cyclobutane -1- carboxylate is more than 83%, and purity is 97.8% or more；The synthesis of A Palu amine is received
Rate is more than 68%, and purity is 98.1% or more；The yield and total recovery and each anti-of each reaction step can be improved in the method for the present invention
The synthesis purity of step is answered, while reducing synthesis risk, more conducively industrial amplification production, application prospect is good.
Specific embodiment
The synthetic method of A Palu amine of the present invention is illustrated combined with specific embodiments below, but implementation of the invention is simultaneously
It is not limited to following embodiment.
The preparation (1) of 1 1- of embodiment ((3- fluoro- 4- (methylcarbamoyl) phenyl) amino) cyclobutane -1- carboxylic acid
The bromo- N- methyl benzene methanamine amide (0.04mol) of the fluoro- 4- of 9.28g 2-, 9.1g 1- amino ring fourth are put into reaction flask
Yl carboxylic acid hydrochloride (0.06mol), 16.6g potassium carbonate (0.12mol), 1.55g CuI (0.008mol), 60mL DMF, are used in combination
Argon gas protection at room temperature vacuumizes 3 times, and 30min is stirred at room temperature, and argon gas displacement is heated to 110 DEG C of reactions, and solution is quickly in green
There is grey suspension solid, contact plate after 9h, raw material fully reacting after about 2h in color.
Ethyl acetate 100mL/ water 200mL is added after being cooled to room temperature, stirs 30min, liquid separation.Water intaking layer, with 37% lemon
Water layer pH is adjusted to 4 by aqueous acid 110mL, after having solid precipitation, ice-water bath to stir 1h, is filtered, dry, obtains 7.6g 1- ((3-
Fluoro- 4- (methylcarbamoyl) phenyl) amino) cyclobutane -1- carboxylic acid, yield 71.3%, liquid phase detection purity 97.2%.It is molten
Point: 222.3-225.8 DEG C.
1δ=12.57 (brs, 1H) H NMR (400MHz, DMSO), 7.63 (m, 1H), 7.46 (t, J=8.4Hz, 1H),
7.15 (s, 1H), 6.24 (dd, J=8.8,2.4Hz, 1H), 6.00 (dd, J=14.4,2.0Hz, 1H), 2.73 (d, J=
4.4Hz,3H),2.54-2.64(m,2H),2.11-2.16(m,2H),1.93-1.99(m,2H)。
ESI-MS(m/z)267.2[M+H]+, 533.3 [2M+H]+。
HPLC: chromatographic column: InertSustain C18(250mm×4.6mm×5μm)；Testing conditions: 220nm, flow velocity:
0.8mL/min, temperature: 30 DEG C, sample volume: 1 μ L；Solvent: methanol, concentration: 0.2mg/mL；Runing time: 15min；Mobile phase
A: water, Mobile phase B: methanol/triethylamine=100:0.1；Gradient: mobile phase A/Mobile phase B=10/90:tR=
2.495min, purity: 97.2%.
DMSO is used to replace DMF as solvent, yield 70.7%, purity 97%.
The preparation (2) of 2 1- of embodiment ((3- fluoro- 4- (methylcarbamoyl) phenyl) amino) cyclobutane -1- carboxylic acid
The bromo- N- methyl benzene methanamine amide (0.04mol) of the fluoro- 4- of 9.28g 2-, 9.1g 1- amino ring fourth are put into reaction flask
Yl carboxylic acid hydrochloride (0.06mol), 16.6g potassium carbonate (0.12mol), 0.8g CuCl (0.008mol), 60mL DMF, and
It is vacuumized 3 times with argon gas protection at room temperature, 30min is stirred at room temperature, be heated to 110 DEG C of reactions, solution is quickly in green, after 10h
Raw material fully reacting.
100mL ethyl acetate/200mL water is added after being cooled to room temperature, stirs 30min, liquid separation, layer of fetching water, with 37% lemon
Water layer pH is adjusted to 4 by aqueous acid 110mL, after having solid precipitation, ice-water bath to stir 1h, is filtered, dry, obtains 7.9g 1- ((3-
Fluoro- 4- (methylcarbamoyl) phenyl) amino) cyclobutane -1- carboxylic acid, yield 74.1%, liquid phase detection purity 97.9%.Spectrogram
Testing result is the same as embodiment 1.
The preparation (3) of 3 1- of embodiment ((3- fluoro- 4- (methylcarbamoyl) phenyl) amino) cyclobutane -1- carboxylic acid
The bromo- N- methyl benzene methanamine amide (0.08mol) of the fluoro- 4- of 18.6g 2-, 18.0g1- amino ring fourth are put into reaction flask
Yl carboxylic acid hydrochloride (0.11mol), 21.2g sodium carbonate (0.20mol), 1.6gCuCl (0.016mol), 100mLDMF, and in room
It is vacuumized 3 times with argon gas protection, 30min is stirred at room temperature, be heated to 110 DEG C of reactions, raw material fully reacting after 10h.
Ethyl acetate 250mL/ water 400mL is added after being cooled to room temperature, stirs 30min, liquid separation, layer of fetching water；.Water layer is with 10%
Hydrochloric acid is adjusted to pH~4, after having solid precipitation, ice-water bath to stir 1h, filters, dry, obtains 15.8g 1- ((3- fluoro- 4- (methyl ammonia
Formoxyl) phenyl) amino) cyclobutane -1- carboxylic acid, yield 74%, liquid phase detection purity 98.4%.Spectrogram testing result is the same as implementation
Example 1.
The preparation (1) of 4 1- of embodiment ((3- fluoro- 4- (methylcarbamoyl) phenyl) amino) cyclobutane -1- carboxylate methyl ester
5.3g 1- ((3- fluoro- 4- (methylcarbamoyl) phenyl) amino) cyclobutane -1- carboxylic acid is put into reaction flask
30min is stirred at room temperature in (0.02mol), 3.3g potassium carbonate (0.024mol), 40mL DMF, and 3.4gCH is added3I (0.024mol),
It is heated to 40 DEG C of reaction 2h, raw material fully reacting.
80mL water is added dropwise into reactant, 30 DEG C of stirring 1h after adding are filtered, and are washed 2 times.Solid is beaten 20min with water,
It filters, it is dry, obtain 5.1g white solid 1- ((3- fluoro- 4- (methylcarbamoyl) phenyl) amino) cyclobutane -1- carboxylic acid first
Ester, yield 91%, liquid phase detect purity 98.2%.Fusing point: 184.7 DEG C (dec.).
1δ=7.65 (m, 1H) H NMR (400MHz, DMSO), 7.46 (t, J=8.8Hz, 1H), 7.25 (s, 1H), 6.20
(dd, J=8.8,2.4Hz, 1H), 5.99 (dd, J=14.4,2.0Hz, 1H), 3.63 (s, 3H), 2.73 (d, J=4.4Hz,
3H),2.66-2.59(m,2H),2.22-2.15(m,2H),2.04-1.93(m,2H)。
ESI-MS(m/z)281.2[M+H]+, 561.3 [2M+H]+, 583.3 [2M+Na]+。
HPLC: chromatographic column: InertSustain C18(250mm×4.6mm×5μm)；Testing conditions: 220nm, flow velocity:
0.8mL/min, temperature: 30 DEG C, injection volume: 1 μ L；Solvent: methanol, concentration: 0.2mg/mL；Runing time: 15min, mobile phase
A: water, Mobile phase B: methanol/triethylamine=100:0.1, gradient: mobile phase A/Mobile phase B=10/90:tR=
2.743min, purity: 98.2%.
DMSO is used to replace DMF as solvent, yield 90.4%, purity 97.8%.
The preparation (2) of 5 1- of embodiment ((3- fluoro- 4- (methylcarbamoyl) phenyl) amino) cyclobutane -1- carboxylate methyl ester
5.3g 1- ((3- fluoro- 4- (methylcarbamoyl) phenyl) amino) cyclobutane -1- carboxylic acid is put into reaction flask
The stirring of (0.02mol), 60mL anhydrous methanol, is added 1.9g sulfuric acid (0.02mol), heating reflux reaction 20h, and raw material has reacted
Entirely.Solvent is recovered under reduced pressure, 60mL ethyl acetate and 60mL water is added in residue, stirs liquid separation, washed organic layer, and reduced pressure removes
Solvent is gone to obtain off-white powder 5.6g, 1- ((3- fluoro- 4- (methylcarbamoyl) phenyl) amino) cyclobutane -1- carboxylate methyl ester,
Yield 91%, liquid phase purity 98.3%.Spectrogram testing result is the same as embodiment 4.
The preparation (3) of 6 1- of embodiment ((3- fluoro- 4- (methylcarbamoyl) phenyl) amino) cyclobutane -1- carboxylate methyl ester
60mL anhydrous methanol is put into reaction flask, ice bath stirring is added dropwise 3.1g chloroacetic chloride (0.04mol), is then added
5.3g 1- ((3- fluoro- 4- (methylcarbamoyl) phenyl) amino) cyclobutane -1- carboxylic acid (0.02mol), heating reflux reaction
10h, raw material fully reacting.It is concentrated under reduced pressure and removes solvent, 60mL ethyl acetate and 60mL water is added in residue, stirs liquid separation, water
Organic layer is washed, removing solvent is concentrated under reduced pressure and obtains off-white powder 5.6g, 1- ((3- fluoro- 4- (methylcarbamoyl) phenyl) amino)
Cyclobutane -1- carboxylate methyl ester, yield 91%, liquid phase detect purity 98.8%.Spectrogram testing result is the same as embodiment 4.
The preparation of 7 1- of embodiment ((3- fluoro- 4- (methylcarbamoyl) phenyl) amino) cyclobutane -1- carboxylic acid, ethyl ester
60mL dehydrated alcohol is put into reaction flask, ice bath stirring is added dropwise to 3.1g chloroacetic chloride (0.04mol), is then added
5.3g 1- ((3- fluoro- 4- (methylcarbamoyl) phenyl) amino) cyclobutane -1- carboxylic acid (0.02mol), heating reflux reaction
10h, raw material fully reacting.It is concentrated under reduced pressure and removes solvent, 60mL ethyl acetate and 60mL water is added in residue, stirs liquid separation, water
Organic layer is washed, removing solvent is concentrated under reduced pressure and obtains 5.6g off-white powder, 1- ((3- fluoro- 4- (methylcarbamoyl) phenyl) amino)
Cyclobutane -1- carboxylic acid, ethyl ester, yield 90%.
1δ=7.65 (m, 1H) H NMR (400MHz, DMSO), 7.46 (t, J=8.8Hz, 1H), 7.25 (s, 1H), 6.21
(dd, J=8.8,2.4Hz, 1H), 5.99 (dd, J=14.4,2.0Hz, 1H), 4.10 (q, J=7.2Hz, 2H), 2.73 (d, J=
4.4Hz, 3H), 2.59-2.65 (m, 2H), 2.14-2.21 (m, 2H), 1.95-2.10 (m, 2H), 1.11 (t, J=7.2Hz,
3H)。
The preparation of 8 1- of embodiment ((3- fluoro- 4- (methylcarbamoyl) phenyl) amino) cyclobutane -1- carboxylic acid isopropyl
60mL isopropanol is put into reaction flask, ice bath stirring is added dropwise to 3.1g chloroacetic chloride (0.04mol), is then added
5.3g 1- ((3- fluoro- 4- (methylcarbamoyl) phenyl) amino) cyclobutane -1- carboxylic acid (0.02mol), heating reflux reaction
10h, raw material fully reacting.It is concentrated under reduced pressure and removes solvent, 60mL ethyl acetate and 60mL water is added in residue, stirs liquid separation, water
Organic layer is washed, removing solvent is concentrated under reduced pressure and obtains 5.6g off-white powder, 1- ((3- fluoro- 4- (methylcarbamoyl) phenyl) amino)
Cyclobutane -1- carboxylic acid isopropyl, yield 83%.
1δ=7.65 (m, 1H) H NMR (400MHz, DMSO), 7.47 (t, J=8.8Hz, 1H), 7.23 (s, 1H), 6.22
(dd, J=8.8,2.4Hz, 1H), 5.99 (dd, J=14.4,2.0Hz, 1H), 4.90 (m, 1H), 2.73 (d, J=4.4Hz,
3H), 2.63-2.58 (m, 2H), 2.22-2.13 (m, 2H), 2.00-1.95 (m, 2H), 1.11 (d, J=6.4Hz, 6H).
The preparation (1) of 9 A Palu amine of embodiment
2.0g 1- ((3- fluoro- 4- (methylcarbamoyl) phenyl) amino) cyclobutane -1- carboxylate methyl ester is put into reaction flask
(0.0071mol), 3.3g 2- cyano -3- trifluoromethyl -5- isothiocyano pyridine (APAL-008,0.0142mol) and 2mL
DMSO, 4mL ethyl acetate, argon gas protection are heated to 85 DEG C, and reaction 8h terminates.Add 60mL ethyl acetate, 60mL moisture liquid, has
Machine mutually dries the solid 6.1g for being concentrated to give brown.17mL isopropanol is added in the solid, and flow back 10min, is then stirred at room temperature, and is precipitated
A large amount of solids filter, and drying obtains 2.3g off-white powder shape A Palu amine, yield 68% (theoretical yield 3.4g), liquid phase purity
98.1%.
1H NMR(400MHz,CDCl3) δ=9.11 (d, J=2.0Hz, 1H), 8.37 (d, J=2.4Hz, 1H), 8.35
(dd, J=11.2,2.4Hz, 1H), 7.29 (dd, J=8.0,1.6Hz, 1H), 7.19 (dd, J=11.2,1.6Hz, 1H), 6.76
(m, 1H), 3.11 (d, J=4.4Hz, 3H), 2.80-2.70 (m, 2H), 2.64-2.53 (m, 2H), 2.35-2.22 (m, 1H),
1.80–1.70(m,1H)。
ESI-MS(m/z)478.2[M+H]+, 955.2 [2M+H]+, 583.3 [2M+Na]+。
HPLC: chromatographic column: InertSustain C18(250mm×4.6mm×5μm)；Testing conditions: 220nm；Flow velocity:
0.8mL/min；Temperature: 30 DEG C；Injection volume: 1 μ L；Solvent: methanol, concentration: 0.2mg/mL；Runing time: 15min；Mobile phase
A: water, Mobile phase B: methanol/triethylamine=100:0.1；Gradient: mobile phase A/Mobile phase B=10/90:tR=
4.089min, purity: 98.1%.
The preparation (2) of 10 A Palu amine of embodiment
2.0g 1- ((3- fluoro- 4- (methylcarbamoyl) phenyl) amino) cyclobutane -1- carboxylate methyl ester is put into reaction flask
(0.0071mol), 2.0g 2- cyano -3- trifluoromethyl -5- isothiocyano pyridine (APAL-008,0.00852mol) and 5mL
DMF, argon gas protection are heated to 85 DEG C, and reaction 8h terminates.Add 60mL ethyl acetate, 60mL moisture liquid, organic phase drying is concentrated to give
The solid of brown.Isopropanol 15mL is added in the solid, and flow back 10min, is then stirred at room temperature, a large amount of solids are precipitated, and filters, and dries
It is dry, obtain 2.67g off-white powder shape A Palu amine, yield 79%, liquid phase purity 99.2%.Spectrogram testing result is the same as embodiment 9.
The preparation (3) of 11 A Palu amine of embodiment
2.0g 1- ((3- fluoro- 4- (methylcarbamoyl) phenyl) amino) cyclobutane -1- carboxylate methyl ester is put into reaction flask
(0.0071mol), 2.0g 2- cyano -3- trifluoromethyl -5- isothiocyano pyridine (APAL-008,0.00852mol), 2mL
DMF and 4mL isopropyl acetate, argon gas protection are heated to 85 DEG C, and reaction 12h terminates.Add 60mL ethyl acetate, 60mL moisture liquid,
The dry solid for being concentrated to give brown of organic phase.15mL isopropanol is added in the solid, and flow back 10min, is then stirred at room temperature, and is precipitated big
Solid is measured, is filtered, drying obtains 2.6g off-white powder shape A Palu amine, yield 78%, liquid phase purity 99.2%.Spectrogram detection
As a result with embodiment 9.
The preparation (4) of 12 A Palu amine of embodiment
2.1g 1- ((3- fluoro- 4- (methylcarbamoyl) phenyl) amino) cyclobutane -1- carboxylic acid, ethyl ester is put into reaction flask
(0.007mol), 2.0g 2- cyano -3- trifluoromethyl -5- isothiocyano pyridine (APAL-008,0.0085mol), 2mL DMSO
With 4mL isopropyl acetate, argon gas protection is heated to 85 DEG C, and reaction 12h terminates.Add 60mL ethyl acetate, 60mL moisture liquid, has
Machine mutually dries the solid for being concentrated to give brown.15mL isopropanol is added in the solid, and flow back 10min, is then stirred at room temperature, and is precipitated a large amount of
Solid filters, and drying obtains 2.4g off-white powder shape A Palu amine, yield 72%.Spectrogram testing result is the same as embodiment 9.
The preparation (5) of 13 A Palu amine of embodiment
2.1g 1- ((3- fluoro- 4- (methylcarbamoyl) phenyl) amino) cyclobutane -1- carboxylic acid isopropyl is put into reaction flask
Ester (0.007mol), 2.0g 2- cyano -3- trifluoromethyl -5- isothiocyano pyridine (APAL-008,0.0085mol), 6mL
DMSO, argon gas protection are heated to 85 DEG C, and reaction 12h terminates.Add 60mL ethyl acetate, 60mL moisture liquid, the dry concentration of organic phase
Obtain the solid of brown.15mL isopropanol is added in the solid, and flow back 10min, is then stirred at room temperature, a large amount of solids are precipitated, and filters, and dries
It is dry, obtain 2.4g off-white powder shape A Palu amine, yield 71%.Spectrogram testing result is the same as embodiment 9.
It is pointed out that the technical concepts and features of above-described embodiment only to illustrate the invention, it is ripe its object is to allow
The personage for knowing this Project Technical cans understand the content of the present invention and implement it accordingly, and protection model of the invention can not be limited with this
It encloses.Any equivalent change or modification in accordance with the spirit of the invention should be covered by the protection scope of the present invention.
Claims (10)
1. synthesizing the midbody compound of A Palu amine, which is characterized in that be 1- ((3- fluoro- 4- (the methyl carbamyl of Formulas I structure
Base) phenyl) amino) and cyclobutane -1- carboxylic acid or Formula II structure 1- ((3- fluoro- 4- (methylcarbamoyl) phenyl) amino) ring fourth
Alkane -1- carboxylate,
Wherein, R is C1~C6Alkyl, C4~C8Naphthenic base or benzyl.
2. midbody compound according to claim 1, which is characterized in that the R is methyl, ethyl, propyl, isopropyl
Base, butyl, isobutyl group, tert-butyl, amyl, base, cyclobutyl, cyclopenta, cyclohexyl, cyclooctyl or benzyl.
3. the preparation method of midbody compound as claimed in claim 1 or 2, which is characterized in that the ((fluoro- 4- (first of 3- of 1- described in Formulas I
Base carbamyl) phenyl) amino) and cyclobutane -1- carboxylic acid preparation method the following steps are included:
Under inert gas shielding, under catalyst action, the bromo- N- methyl benzene methanamine amide of the fluoro- 4- of 2- and 1- Aminocyclobutyl carboxylic acid
Hydrochloride is in the organic solvent containing alkali, 1- ((3- fluoro- 4- (methylcarbamoyl) benzene of substitution reaction production I structure
Base) amino) cyclobutane -1- carboxylic acid.
4. the synthetic method of midbody compound according to claim 3, which is characterized in that the bromo- N- methylbenzene first of the fluoro- 4- of 2-
The molar ratio of amine amide and 1- Aminocyclobutyl carboxylic acid hydrochloride is 1:1~1.8, the amount ratio with organic solvent is 0.5~
1mol/L, the molar ratio with catalyst are 1:0.2~0.4.
5. the preparation method of midbody compound according to claim 1 or claim 2, which is characterized in that ((3- is fluoro- by 1- described in Formula II
4- (methylcarbamoyl) phenyl) amino) cyclobutane -1- carboxylate the preparation method comprises the following steps:
Under alkaline condition, in non-protonic solvent, 1- ((3- fluoro- 4- (methylcarbamoyl) phenyl) amino) ring of Formulas I structure
1- ((3- fluoro- 4- (methylcarbamoyl) phenyl) ammonia of butane -1- carboxylic acid and monohaloalkyl reagent RX esterification production II structure
Base) cyclobutane -1- carboxylate；
Or under catalyst action, 1- ((3- fluoro- 4- (methylcarbamoyl) phenyl) amino) cyclobutane -1- carboxylic of Formulas I structure
Acid with 50 DEG C~90 DEG C of alcohol roh under the conditions of esterification production II structure 1- ((3- fluoro- 4- (methylcarbamoyl) benzene
Base) amino) cyclobutane -1- carboxylate；
Wherein, R=C1~C6Alkyl, C4~C8Naphthenic base or benzyl, X F, Cl, Br or I.
6. the preparation method of midbody compound according to claim 5, which is characterized in that 1- ((the fluoro- 4- of 3- (methyl ammonia first
Acyl group) phenyl) amino) molar ratio of cyclobutane -1- carboxylic acid and monohaloalkyl reagent is 1:1~1.5, the use with non-protonic solvent
For amount than being 0.4~0.8mol/L, the molar ratio with alkali is 1:1~1.5.
7. the preparation method of midbody compound according to claim 5, which is characterized in that 1- ((the fluoro- 4- of 3- (methyl ammonia first
Acyl group) phenyl) amino) amount ratio of cyclobutane -1- carboxylic acid and alcohol is 0.25~0.5mol/L, the molar ratio with catalyst is 1:
1~2.5.
8. a kind of synthetic method of A Palu amine, which is characterized in that step includes: in organic solvent, to have under inert gas shielding
There are 1- ((3- fluoro- 4- (methylcarbamoyl) phenyl) amino) cyclobutane -1- carboxylate and 2- cyano -3- trifluoro of Formula II structure
Ring closure reaction occurs for methyl -5- isothiocyano pyridine, obtains A Palu amine；
Wherein, R is C1~C6Alkyl, C4~C8Naphthenic base or benzyl.
9. the synthetic method of A Palu amine according to claim 8, which is characterized in that 1- ((3- fluoro- 4- (methyl carbamyl
Base) phenyl) amino) and cyclobutane -1- carboxylate and 2- cyano -3- trifluoromethyl -5- isothiocyano pyridine molar ratio be 1:1~
2, the amount ratio with organic solvent is 1~1.5mol/L.
10. the synthetic method of A Palu amine described in claim 8, which is characterized in that the organic solvent is dimethyl sulfoxide, two
Methylformamide, dimethyl acetamide, N-Methyl pyrrolidone, acetic acid esters or its mixture.
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