CN108707119A - A kind of preparation method of Momelotinib - Google Patents
A kind of preparation method of Momelotinib Download PDFInfo
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- CN108707119A CN108707119A CN201810660288.3A CN201810660288A CN108707119A CN 108707119 A CN108707119 A CN 108707119A CN 201810660288 A CN201810660288 A CN 201810660288A CN 108707119 A CN108707119 A CN 108707119A
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- 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
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
Abstract
The present invention relates to the preparation fields of organic synthesis and bulk pharmaceutical chemicals, and in particular to a kind of preparation method of Momelotinib includes the following steps：(1) 4- (4- nitrobenzophenones) morpholine is prepared by 4- nitro-chlorobenzenes and morpholine, and after through reduction 4- morpholinyl phenylamines are prepared；(2) it is reacted with cyanamide by 4- morpholinyl phenylamines and 1- (4- morpholino phenyls) guanidine is prepared；(3) it is reacted with aminoacetonitrile HCl salt by 4- acetylbenzoic acids and 4- acetyl group-N- (cyano methyl) benzamide is prepared；(4) it is reacted with N,N-dimethylformamide dimethylacetal by 4- acetyl group-N- (cyano methyl) benzamides and N- (cyano methyl) -4- (3- (dimethylamino) acryloyl) benzamide is prepared；(5) Momelotinib is prepared by N- (cyano methyl) -4- (3- (dimethylamino) acryloyl) benzamides and the reaction of 1- (4- morpholino phenyls) guanidine.This method has the characteristics that raw material is easy to get, is concise in technology, easy to operate, high income, at low cost.
Description
Technical field
The present invention relates to the preparation fields of organic synthesis and bulk pharmaceutical chemicals, more particularly to a kind of to treat primary myeloma (MM)
The preparation method of drug Momelotinib and its intermediate.
Background technology
Momelotinib (CYT-387) is a kind of ATP competitiveness JAK1/JAK2 inhibitor, IC50 11nM/18nM, than
About high 10 times or so of JAK3 selectivity is acted on, is ground by Gilid Science Co. of the U.S. (Gilead Sciences, Inc.)
Hair, is currently in III phase clinical researches, for treating treatment primary myeloma.Chemical constitution Jak shown in formula I inhibits
Agent Momelotinib, entitled N- (cyano methyl) 4-[2-[[4- (4- morphines base) Ben Ji ]An Ji ]- 4- Mi Dingjis ]Benzene first
Amide：
Currently, the preparation about Momelotinib mainly uses following two methods：
Method one be YM BioCsiences companies patent publication No. WO2012149602, WO2009017838,
Using 4- cyanophenylboronic acids (3) or 4- ester groups phenyl boric acid (4) and dichloro pyrimidine (2) in WO2007089768, WO2007089768
Pyrimidine derivatives (5) and (6) are prepared in the coupling of heavy metal catalyst condition, synthetic route is as shown in Formula II.
This method uses expensive catalyst, such as：[1,1'Bis- (diphenylphosphino) Er Maotie ]Palladium chloride
((dppf)2PdCl2) catalysis has connection reaction, yield~60%, therefore cost is very high, and heavy metal is not easy to remove totally, influences product matter
Amount.It reacts and is prepared through coupling, substitution, ester hydrolysis, 4 steps of condensation with dichloro pyrimidine (2) with 4- ester groups phenyl boric acid (4)
Momelotinib, total recovery~40%.Said synthesis route is analyzed, reaction route is various, and by-product is complicated, to a certain degree
Upper restriction Momelotinib industrialized productions.
Method two (publication number CN105837515A, New and Practical Synthesis of Momelotinib)
In, 4- morpholinyl phenylamines (7) and the cyanamide aqueous solution of use flow back to obtain 1- (4- morpholino phenyls) guanidine (12)；4- acetyl group
Methyl benzoate (13) flows back to obtain 4- (3- (dimethylamino) acryloyl group) methyl benzoate (14) with DMF-DMA；By chemical combination
Object 12 and compound 14 plus alkali cyclization through diminishing solution obtain 4- (2- ((4- morpholino phenyls) amino) pyrimidine-4-yl) benzene first again
Target product MoMelotinib is made being reacted with aminoacetonitrile HCl salt, EDC, HOBT by compound 10, synthesis in sour (10)
Route is as shown in formula III.
This method is used for ester hydrolysis using lithium hydroxide, and yield is not high, and has a large amount of waste water productions, is unfavorable for ring
It protects in border.
Therefore, it is necessary to for the defect in the presence of the prior art, be improved the prior art, it is easy to provide a kind of raw material
It obtains, the Momelotinib preparation methods of concise in technology, easy to operate, economic and environment-friendly, yield higher and suitable industrialized production.
Invention content
For the defects in the prior art, the purpose of the present invention is to provide one kind have raw material is easy to get, concise in technology, behaviour
Make convenience, the preparation method of high income, Momelotinib at low cost.
The technical scheme is that：
A kind of preparation method of Momelotinib, includes the following steps：
(1) 4- (4- nitrobenzophenones) morpholine is prepared by 4- nitro-chlorobenzenes and morpholine, and after through reduction 4- is prepared
Morpholinyl phenylamine；
(2) it is reacted with cyanamide by 4- morpholinyl phenylamines and 1- (4- morpholino phenyls) guanidine is prepared；
(3) it is reacted with aminoacetonitrile HCl salt by 4- acetylbenzoic acids and 4- acetyl group-N- (cyano methyl) is prepared
Benzamide；
(4) by 4- acetyl group-N- (cyano methyl) benzamides and the N,N-dimethylformamide dimethylacetal system of reacting
It is standby to obtain N- (cyano methyl) -4- (3- (dimethylamino) acryloyl) benzamide；
(5) by N- (cyano methyl) -4- (3- (dimethylamino) acryloyl) benzamides and 1- (4- morpholino phenyls) guanidine
Momelotinib is prepared in reaction.
The preparation method of the Momelotinib, step (1) include：
(a) 4- nitro-chlorobenzenes are mixed with morpholine and alkali with solvent I, at room temperature~110 DEG C react 2~obtain 4- (4- for 24 hours
Nitrobenzophenone) morpholine；
(b) 4- (4- nitrobenzophenones) morpholine is mixed with solvent II, reducing agent I and acid is added, react 1 in room temperature~80 DEG C
~12h obtains 4- morpholinyl phenylamines；
Alternatively, 4- (4- nitrobenzophenones) morpholine is mixed with solvent II I, catalyst I is added, be passed through Hydrogen Vapor Pressure be 1~
5atm reacts 1~12h in room temperature~60 DEG C and obtains 4- morpholinyl phenylamines；
The 4- nitro-chlorobenzenes：Morpholine：The molar ratio of alkali is 1：1~2：1~3；The alkali is selected from potassium carbonate, carbonic acid
Sodium or potassium tert-butoxide；The solvent I is selected from N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, acetonitrile or acetone；It is described
Solvent II be selected from water, ethyl alcohol, methanol or acetic acid；The reducing agent I is selected from iron powder, zinc powder or stannous chloride；The acid
Selected from hydrochloric acid or sulfuric acid；The solvent II I is selected from methanol, ethyl alcohol or tetrahydrofuran；The catalyst I be selected from Raney's nickel or
Palladium-carbon.
The preparation method of the Momelotinib, step (2) include：
4- morpholinyl phenylamines are mixed with solvent, be added acid and cyanamide, at 50~100 DEG C react 2~for 24 hours, be prepared into
To 1- (4- morpholino phenyls) guanidine；
The 4- morpholinyl phenylamines：Acid：The molar ratio of cyanamide is 1：1~5：1~5；The solvent be selected from methanol,
Ethyl alcohol or water；The acid is selected from hydrochloric acid, nitric acid.
The preparation method of the Momelotinib, step (3) include：
4- acetylbenzoic acids, aminoacetonitrile HCl salt, condensing agent, organic base are mixed with solvent, in 0~60 DEG C of reaction
2~for 24 hours, obtain 4- acetyl group-N- (cyano methyl) benzamide；
The 4- acetylbenzoic acids：Aminoacetonitrile HCl salt：Condensing agent：The molar ratio of organic base is 1：1~3：1~
3：1~6；The solvent is selected from N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, dimethyl sulfoxide (DMSO) or acetonitrile；It is described
Condensing agent be selected from 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides/I-hydroxybenzotriazole, 2- (7- aoxidize
Benzotriazole)-N, N, N',N'Tetramethylurea hexafluorophosphoric acid ester or O- benzotriazole-tetramethylurea hexafluorophosphate；Institute
The organic base stated is selected from triethylamine, diisopropylamino ethamine or pyridine.
The preparation method of the Momelotinib, step (4) include：
4- acetyl group-N- (cyano methyl) benzamides and N,N-dimethylformamide dimethylacetal and solvent is mixed
It closes, 2~4d is reacted at 50~120 DEG C, N- (cyano methyl) -4- (3- (dimethylamino) acryloyl) benzamide is prepared；
Described 4- acetyl group-N- (cyano methyl) benzamide：Mole of N,N-dimethylformamide dimethylacetal
Than being 1：3~5；The solvent is selected from toluene, glycol dimethyl ether or tetrahydrofuran.
The preparation method of the Momelotinib, step (5) include：
1- (4- morpholino phenyls) guanidines are mixed with 4- acetyl group-N- (cyano methyl) benzamides and solvent, 50~
140 DEG C of 1~3d of reaction, obtain Momelotinib；
Described 1- (4- morpholino phenyls) guanidine：The molar ratio of 4- acetyl group-N- (cyano methyl) benzamide is 1：0.8
~1.2；The solvent is selected from acetonitrile, glycol dimethyl ether, diethylene glycol dimethyl ether, acetone or N,N-dimethylformamide.
The present invention design philosophy be：Using raw material that is relatively conventional and being easy to get, by the reaction condition of non high temperature high pressure,
Convergence type synthesis strategy is taken, carrys out industrial production antitumor drug Momelotinib using minimum step, there is good application
Foreground.
Compared with the existing technology, advantages of the present invention and advantageous effect are：
(1) present invention with relatively conventional 4- nitro-chlorobenzenes, 4- acetyl group-N- (cyano methyl) benzamide, cyanamide,
Aminoacetonitrile HCl salt etc. is starting material, and intermediate steps are usual using morpholine, n,N-Dimethylformamide dimethylacetal etc.
Product and Conventional solvents have the advantages that raw material is easy to get.
(2) concise in technology of this method, reaction step is few, and reaction condition is mild, and operation is more convenient；In addition, post-processing
Method is simple and convenient, reduces experimental waste discharge, amplification is suitble to prepare.
(3) this method uses convergence type synthesis strategy, is conducive to improve total recovery, reduces chemical synthesis risk, is more suitable for
It is prepared in amplification.
(4) each step yield of this method and total recovery are high, and reaction condition and raw material are simple, can reduce cost.Targeted
Conjunction object is antitumor drug Momelotinib, is currently in III phase clinical researches, so after being conducive to bulk pharmaceutical chemicals listing
Industrialized production promotes the development of economic technology, there is good application prospect.
(5) method two introduced with respect to the background art, reduce a step ester hydrolysis, improve yield, reduce cost with
And the discharge of waste water, waste material.
Description of the drawings
Fig. 1 is the 1H NMR spectras of 4- (4- nitrobenzophenones) morpholine.
Fig. 2 is the 1H NMR spectras of 4- morpholinyl phenylamines.
Fig. 3 is the HPLC collection of illustrative plates of 4- morpholinyl phenylamines.
Fig. 4 is 1- (4- morpholino phenyls) guanidine 1H NMR spectras.
Fig. 5 is 1- (4- morpholino phenyls) guanidine LC-MS collection of illustrative plates.
Fig. 6 is compound 4- acetyl group-N- (cyano methyl) benzamide (15)1H NMR figures.
Fig. 7 is the liquid chromatogram of compound 4- acetyl group-N- (cyano methyl) benzamide (15).
Fig. 8 is the mass spectrogram of compound 4- acetyl group-N- (cyano methyl) benzamide (15).
Fig. 9 is compound N-(cyano methyl) -4- (3- (dimethylamino) acryloyl) benzamide (16)1H NMR figures.
Figure 10 is the liquid chromatogram of compound N-(cyano methyl) -4- (3- (dimethylamino) acryloyl) benzamide (16)
Figure.
Figure 11 is the mass spectrogram of compound N-(cyano methyl) -4- (3- (dimethylamino) acryloyl) benzamide (16).
Figure 12 is the 1H NMR spectras of compound Momelotinib.
Figure 13 is the 13C NMR spectras of compound Momelotinib.
Figure 14 is the LC-MS spectrograms of compound Momelotinib.
Figure 15 is the HPLC spectrograms of compound Momelotinib.
Specific implementation mode
In specific implementation process, the preparation method of Momelotinib of the present invention includes the following steps：
(1) 4- (4- nitrobenzophenones) morpholine is prepared by 4- nitro-chlorobenzenes and morpholine, and after through reduction 4- is prepared
Morpholinyl phenylamine；
(2) it is reacted with cyanamide by 4- morpholinyl phenylamines and 1- (4- morpholino phenyls) guanidine is prepared；
(3) it is reacted with aminoacetonitrile HCl salt by 4- acetylbenzoic acids and 4- acetyl group-N- (cyano methyl) is prepared
Benzamide；
(4) by 4- acetyl group-N- (cyano methyl) benzamides and N,N-dimethylformamide dimethylacetal (DMF-
DMA) N- (cyano methyl) -4- (3- (dimethylamino) acryloyl) benzamide is prepared in reaction；
(5) by N- (cyano methyl) -4- (3- (dimethylamino) acryloyl) benzamides and 1- (4- morpholino phenyls) guanidine
Momelotinib is prepared in reaction.
The route of synthesis is as shown in formula IV：
Step (1) is specially：
4- nitro-chlorobenzenes and morpholine and alkali are added in solvent I, stirred, under room temperature~110 DEG C (preferably 60~80 DEG C),
Reaction 2~for 24 hours (preferably 8~12h), after reaction, reaction solution is poured into ice water, is stirred, solid is precipitated, is filtered, is dried
It is dry, obtain 4- (4- nitrobenzophenones) morpholine；
4- (4- nitrobenzophenones) morpholine is mixed with solvent II, reducing agent I and acid is added, in room temperature~80 DEG C (preferably 60
~80 DEG C) reaction 1~12h (preferably 2~4h) reaction solution is filtered after reaction, ethyl acetate is added in mother liquor, stir
Liquid separation, organic phase is dry, concentrates, and obtains 4- morpholinyl phenylamines；
Alternatively, 4- (4- nitrobenzophenones) morpholine is mixed with solvent II I, catalyst I is added, be passed through hydrogen (pressure is 1~
5atm, preferably 1atm), reacting 1~12h (preferably 4~6h) in room temperature~60 DEG C (preferably room temperature) after reaction will be anti-
Liquid is answered to filter, mother liquor concentrations are dry, obtain 4- morpholinyl phenylamines；
The 4- nitro-chlorobenzenes：Morpholine：The molar ratio of alkali is 1：1~2：1~3；The alkali is selected from potassium carbonate, carbonic acid
Sodium, potassium tert-butoxide；The solvent I is selected from N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, acetonitrile or acetone；It is described
Solvent II be selected from water, ethyl alcohol, methanol, acetic acid；The reducing agent I is selected from iron powder, zinc powder, stannous chloride；The acid choosing
From hydrochloric acid, sulfuric acid；The solvent II I is selected from methanol, ethyl alcohol, tetrahydrofuran；Catalyst I is selected from Raney's nickel, palladium-carbon.
Step (2) is specially：
4- morpholinyl phenylamines are mixed with solvent, are stirred, acid is added, the cyanamide aqueous solution prepared in advance is added, are heated,
2~for 24 hours (preferably 10~16h) are reacted at 50~100 DEG C (preferably 70~90 DEG C), after reaction, solvent is recovered under reduced pressure, it will
Reaction solution is alkalized with sodium hydrate aqueous solution to pH>12, solid is precipitated, filters, washes, drying obtains 1- (4- morpholinyl benzene
Base) guanidine.
The 4- morpholinyl phenylamines：Acid：The molar ratio of cyanamide is 1：1~5：1~5；The solvent be selected from methanol,
Ethyl alcohol, water；The acid is selected from hydrochloric acid, nitric acid.
Step (3) is specially：
4- acetylbenzoic acids, aminoacetonitrile HCl salt, condensing agent, organic base are mixed with solvent, stirred, in 0~60
DEG C (preferably room temperature) reaction 2~for 24 hours (preferably 10~16h), after reaction, by reaction solution pour into dilute hydrochloric acid (a concentration of 12~
In 18wt%), solid is precipitated in stirring, filters, and washing, drying obtains 4- acetyl group-N- (cyano methyl) benzamide.
The 4- acetylbenzoic acids：Aminoacetonitrile HCl salt：Condensing agent：The molar ratio of organic base is 1：1~3：1~
3：1~6；The solvent be selected from N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, dimethyl sulfoxide (DMSO), acetonitrile (preferably N,
Dinethylformamide)；The condensing agent is selected from 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides
(EDCI)/I-hydroxybenzotriazole (HOBT), 2- (7- aoxidizes benzotriazole)-N, N, N',N'Tetramethylurea hexafluorophosphoric acid ester
(HATU), O- benzotriazole-tetramethylurea hexafluorophosphate (HBTU) (preferably EDCI/HOBT)；The organic base is selected from
Triethylamine, diisopropylamino ethamine, pyridine (preferably triethylamine).
Step (4) is specially：
Solvent is added in 4- acetyl group-N- (cyano methyl) benzamide, is stirred at room temperature, n,N-Dimethylformamide is added
Dimethylacetal (DMF-DMA), heating react 2~4d (preferably 3~4d, day), instead at 50~120 DEG C (preferably 90~110 DEG C)
After answering, reaction solution is cooled to room temperature, and solid is precipitated, and filters, and recrystallization obtains N- (cyano methyl) -4- (3- (dimethylamino)
Acryloyl) benzamide.
Described 4- acetyl group-N- (cyano methyl) benzamide：The molar ratio of DMF-DMA is 1：3~5；Described is molten
Agent is selected from toluene, glycol dimethyl ether, tetrahydrofuran (preferably toluene).
Step (5) is specially：
By 1- (4- morpholino phenyls) guanidines and N- (cyano methyl) -4- (3- (dimethylamino) acryloyl) benzamides and molten
Agent mixes, stirring, reacts 1~3d (preferably 2d, day) at 50~140 DEG C (preferably 90~110 DEG C), reaction solution is cooled to room temperature, analysis
Go out solid, filters, obtain Momelotinib.
Described 1- (4- morpholino phenyls) guanidine：N- (cyano methyl) -4- (3- (dimethylamino) acryloyl) benzamide
Molar ratio be 1：0.8~1.2；The solvent is selected from acetonitrile, glycol dimethyl ether, diethylene glycol dimethyl ether, acetone, N, N-
Dimethylformamide (preferably acetonitrile, glycol dimethyl ether).
Technical scheme of the present invention is illustrated below in conjunction with specific embodiment.
The preparation (1) of 1 4- of embodiment (4- nitrobenzophenones) morpholine
Morpholine (4.36g, 0.05mol) is added in 100mL eggplant-shape bottles, n,N-Dimethylformamide 40mL is added, in
It is stirred at room temperature, 4- nitro-chlorobenzenes (7.88g, 0.05mol) and potassium carbonate (10.37g, 0.075mol) is added, be heated to 70 DEG C, use
Thin-layer chromatography (TLC) tracking is reacted, and TLC displays, which are reacted, after 12h terminates.Stop heating, it, will be anti-after reaction solution is cooled to room temperature
It answers liquid to be poured slowly into the 100mL mixture of ice and water of stirring, there is yellow solid generation, after stirring 0.5h, suction filtration obtains yellow
Solid dries to obtain light yellow solid 4- (4- nitrobenzophenones) morpholine 9.3g, yield 89%.
1H NMR(400MHz,DMSO-d6):δ 3.41 (m, 4H), 3.74 (m, 4H), 7.04 (d, J=9.6Hz, 2H), 8.08
(d, J=9.6Hz, 2H).As seen from Figure 1, compound structure is correct.
The preparation (1) of 2 4- morpholinyl phenylamines of embodiment
4- (4- nitrobenzophenones) morpholines (8.33g, 0.04mol) are added in 250mL eggplant-shape bottles, 100mL tetrahydrochysenes are added
Furans is stirred at room temperature, and Raney's nickel 6g is added, and after taking out 3 vacuum, is passed through hydrogen (pressure 1atm) through hydrogen balloon, room temperature is anti-
It answers, is tracked and reacted with thin-layer chromatography (TLC), TLC displays, which are reacted, after 10h terminates, and reaction solution diatomite is filtered, tetrahydrochysene furan is used in combination
Mutter (20mL × 2) wash diatomite, tetrahydrofuran is evaporated to obtain off-white color color solid 4- morpholinyl phenylamine 7.91g, yield
94.5%.
1H NMR(400MHz,DMSO-d6):δ 2.87 (m, 4H), 3.69 (m, 4H), 4.57 (s, 2H), 6.51 (d, J=
8.8Hz, 2H), 6.68 (d, J=8.8Hz, 2H).Compound structure is correct it can be seen from Fig. 2-Fig. 3, and product purity is
99.6%.
The preparation (1) of 3 1- of embodiment (4- morpholino phenyls) guanidine
Compound 4- morpholinyl phenylamines (8.9g, 0.05mol) are added in 250mL eggplant-shape bottles, 100mL ethyl alcohol is added,
It is stirred when room temperature, hydrochloric acid (10.5mL, 0.126mol) is added and adds NH after being heated to 90 DEG C2CN (6.3g, 0.15mol)
With 10mL H2The solution that O is prepared is tracked with thin-layer chromatography (TLC) and is reacted, and TLC displays, which are reacted, after 12h terminates, will be in reaction solution
Ethyl alcohol steams, and after having steamed, 35mL H are added2O stirs 20min, insoluble impurity is removed by filtration, by filtrate with a concentration of 20wt%'s
NaOH aqueous solutions are adjusted to alkalinity (pH>12), there are a large amount of solids after ice-water bath stirring, filter, drying obtains 1- (4- morpholinyl benzene
Base) guanidine 6.92g, yield 78%.
1H NMR(400MHz,DMSO-d6):δ 2.98 (m, 4H), 3.72 (m, 4H), 4.99 (brs, 4H), 6.67 (d, J=
6.8Hz, 2H), 6.80 (d, J=6.8Hz, 2H)；ESI-MS(m/z)221.2(M+H)+.The compound it can be seen from Fig. 4-Fig. 5
Structure is correct.
The preparation (1) of embodiment 4 4- acetyl group-N- (cyano methyl) benzamide
4- acetylbenzoic acids (10g, 0.061mol) are added in 500mL eggplant-shape bottles, N, N- dimethyl formyls is added
Amine (150mL), triethylamine (18mL, 13.5g), HOBt (9.7g, 0.071mol), stir 10min, wait for that solid is basic at room temperature
EDCI (13.8g, 0.071mol) is added after dissolving, continues to stir 1h, aminoacetonitrile HCl salt (6.16g, 0.067mol) is added
Room temperature reaction is tracked with thin-layer chromatography (TLC) and is reacted, and TLC displays, which are reacted, after 4h terminates, and has a large amount of solids to generate, by reaction solution
It pours into dilute hydrochloric acid (a concentration of 12~18wt%), stirs 30 minutes, solid is precipitated, filter, washing, drying obtains 4- acetyl
Base-N- (cyano methyl) benzamide 11.7g, yield 95%.
1H NMR(400MHz,CDCl3):δ 2.65 (s, 3H), 4.42 (d, J=5.7Hz, 2H), 6.69 (s, 1H), 7.88
(d, J=8.6Hz, 2H), 8.05 (d, J=8.6Hz, 2H).ESI-MS(m/z)203.1[M+H]+.It can be seen from Fig. 6-Fig. 8
Compound structure is correct, liquid phase purity 96.9%.
HPLC：Column:InertSustain C18(250mm×4.6mm×5μm)；Detection:220nm；Flow velocity:0.8mL/
min；Temperature:30℃；Injection volume:1μL；Solvent:Methanol；Concentration:0.2mg/mL；Run time:20min；Mobile phase：Water/first
Alcohol=20/80；tR=3.958min；Purity:96.9wt%.
The preparation (1) of embodiment 5N- (cyano methyl) -4- (3- (dimethylamino) acryloyl) benzamide
By 4- acetyl group-N- (cyano methyl) benzamide (1g, 4.94mmol) and DMF-DMA (2.7g, 0.022mol)
It is placed in 100mL eggplant-shape bottles, 20mL toluene is added, is warming up to 115 DEG C of return stirrings, tracked and reacted with thin-layer chromatography (TLC), 3d
TLC displays reaction terminates afterwards, has a large amount of solids to generate after reaction solution is cooled to room temperature, is taken out after reaction solution is cooled to room temperature
Filter, recrystallization, obtains N- (cyano methyl) -4- (3- (dimethylamino) acryloyl) benzamide 0.86g, yield 69.2%.
1H NMR(400MHz,DMSO-d6) δ 2.92 (s, 3H), 3.17 (s, 3H), 4.34 (d, J=5.2Hz, 2H), 5.87
(d, J=12.1Hz, 1H), 7.76 (d, J=12.1Hz, 1H), 7.92 (d, J=8.0Hz, 2H), 8.00 (d, J=8.0Hz,
2H), 9.30 (t, J=8.0Hz, 1H).ESI-MS(m/z)258.2[M+H]+.It can be seen that by Fig. 9-Figure 11, it can be seen that change
It is correct to close object structure, liquid phase purity 98.4%.
HPLC：Column:InertSustain C18(250mm×4.6mm×5μm)；Detection:220nm；Flow velocity:0.8mL/
min；Temperature:30℃；Injection volume:1μL；Solvent:Methanol；Concentration:0.2mg/mL；Run time:20min；Mobile phase：Water/first
Alcohol (triethylamine that 0.1wt% is added)=10/90；tR=3.764min；Purity:98.4wt%.
The preparation (1) of embodiment 6Momelotinib
By N- (cyano methyl) -4- (3- (dimethylamino) acryloyl) benzamides (0.14g, 0.5mmol) and 1- (4-
Quinoline base phenyl) guanidine (0.12g, 0.5mmol) is placed in 50mL eggplant-shape bottles, and when room temperature, 10mL acetonitriles are added, are heated to 100 DEG C
Reflux is tracked with thin-layer chromatography (TLC) and is reacted, and TLC displays, which are reacted, after 2d terminates, and is had after reaction solution is cooled to room temperature a large amount of solid
Body generates, and filters, and dries, and recrystallization obtains Momelotinib (0.16g), yield 76.7%.
1H NMR(DMSO-d6,δ):3.06 (m, 4H), 3.75 (m, 4H), 4.36 (d, J=5.6Hz, 2H), 6.94 (d, J=
10.4Hz, 2H), 7.40 (d, J=5.2Hz, 1H), 7.68 (d, J=10.4Hz, 2H), 8.03 (d, J=9.2Hz, 2H), 8.27
(d, J=9.2Hz, 2H), 8.54 (d, J=5.2Hz, 1H), 9.34 (t, J=5.6Hz, 1H), 9.51 (s, 1H)13CNMR
(100MHz,DMSO-d6):δ28.2,49.8,66.7,108.5,116.1,117.9,120.9,127.4,128.4,133.3,
135.0,140.5,146.8,159.7,160.9,162.9,166.7.ESI-MS(m/z)415.2(M+H)+.By Figure 12-Figure 15
As can be seen that compound structure is correct, liquid phase purity 99.1%.
HPLC：Column:InertSustain C18(250mm×4.6mm×5μm)；Detection:220nm；Flow velocity:0.8mL/
min；Temperature:30℃；Injection volume:1μL；Solvent:Methanol；Concentration:0.2mg/mL；Run time:15min；Mobile phase：Water/first
Alcohol (triethylamine that 0.1wt% is added)=10/90；tR=3.527min；Purity:99.1wt%.
The preparation (2) of 7 4- of embodiment (4- nitrobenzophenones) morpholine
Morpholine (13.1g, 0.15mol) is added in 1L eggplant-shape bottles, acetonitrile 300mL is added, is stirred at room temperature, 4- is added
Nitro-chlorobenzene (28.3g, 0.18mol) and potassium carbonate (31.1g, 0.225mol), are heated to flow back, with thin-layer chromatography (TLC) with
Track reacts, and TLC displays, which are reacted, after 18h terminates.Stop heating, after reaction solution is cooled to room temperature, 220mL acetonitriles are fallen in concentration, will
Residue is poured slowly into the 300mL mixture of ice and water of stirring, there is yellow solid generation, and after stirring 0.5h, suction filtration obtains Huang
Color solid dries to obtain light yellow solid 4- (4- nitrobenzophenones) morpholine 25.5g, yield 82%.
Spectrogram is detected with embodiment 1.
The preparation (2) of 8 4- morpholinyl phenylamines of embodiment
4- (4- nitrobenzophenones) morpholines (600g, 2.88mol) are added in reaction kettle, 6L ethyl alcohol and 6L water is added, adds
Enter reduced iron powder (600g, 10.74mol), the hydrochloric acid (1.5L, 17.28mol) of a concentration of 18wt% is added, is heated to 80 DEG C instead
Answer, tracked and reacted with thin-layer chromatography (TLC), after 2h TLC displays reaction terminates, reaction solution diatomite is filtered, by mother liquor concentrations,
~160mL ethyl alcohol is recycled, ethyl acetate 200mL is added into residue, stirs liquid separation, organic phase is recovered under reduced pressure solvent, obtains
To solid, drying obtains off-white color color solid 4- morpholinyl phenylamine 416g, yield 81%.
Spectrogram is detected with embodiment 2.
The preparation (2) of 9 1- of embodiment (4- morpholino phenyls) guanidine
Compound 4- morpholinyl phenylamines (9.0g, 0.05mol) are added in 250mL eggplant-shape bottles, 120mL methanol is added,
It is stirred when room temperature, the aqueous solution of nitric acid (9.6mL, 0.13mol) of a concentration of 65wt% is added, is heated to reflux；Add concentration
For the NH of 50wt%2CN aqueous solutions (13g, 0.15mol) are tracked with thin-layer chromatography (TLC) and are reacted, TLC displays reaction knot after 18h
Methanol in reaction solution is steamed~90mL by beam, and after having steamed, 20mLH is added2O stirs 20min, is removed by filtration insoluble impurity, will filter
Liquid is adjusted to alkalinity (pH> with the NaOH aqueous solutions of a concentration of 20wt%;12), there are a large amount of solids after ice-water bath stirring, filter, dry
It is dry to obtain 1- (4- morpholino phenyls) guanidine 6.9g, yield 78%.
Spectrogram is detected with embodiment 3.
The preparation (2) of embodiment 10 4- acetyl group-N- (cyano methyl) benzamide
4- acetylbenzoic acids (10g, 0.061mol) are added in 100mL eggplant-shape bottles, dimethyl sulfoxide (DMSO) is added
(30mL), pyridine (10mL, 9.65g), HATU (14.7g, 0.12mol), stir 10min at room temperature, wait for that clear solution becomes muddy
When turbid, continue to stir 1h, aminoacetonitrile HCl salt (5g, 0.054mol) is added and reacts at room temperature, is tracked with thin-layer chromatography (TLC) anti-
It answers, TLC displays, which are reacted, after 4h terminates, and by freezing, filtering, pickling is spin-dried for, and column chromatography obtains crude product 30.5g.Crude product column
Chromatograph (PE:EA=2:1) 4- acetyl group-N- (cyano methyl) benzamide 10.7g, yield 72% are obtained.
Spectrogram is detected with embodiment 4.
The preparation (2) of embodiment 11N- (cyano methyl) -4- (3- (dimethylamino) acryloyl) benzamide
By 4- acetyl group-N- (cyano methyl) benzamide (1g, 4.94mmol) and DMF-DMA (2.7g, 0.022mol)
It is placed in 100mL eggplant-shape bottles, 20mL DMF is added, are warming up to 115 DEG C of return stirrings, tracked and reacted with thin-layer chromatography (TLC), 3d
TLC displays reaction terminates afterwards, has a large amount of solids to generate after reaction solution is cooled to room temperature, is taken out after reaction solution is cooled to room temperature
Filter, recrystallization, obtains N- (cyano methyl) -4- (3- (dimethylamino) acryloyl) benzamide 0.72g, yield 57.8%.
Spectrogram is detected with embodiment 5.
The preparation (2) of embodiment 12Momelotinib
By N- (cyano methyl) -4- (3- (dimethylamino) acryloyl) benzamides (0.14g, 0.5mmol) and 1- (4-
Quinoline base phenyl) guanidine (0.12g, 0.5mmol) is placed in 50mL eggplant-shape bottles, when room temperature, 10mL glycol dimethyl ethers, heating is added
It flows back to 100 DEG C, is tracked and reacted with thin-layer chromatography (TLC), TLC displays, which are reacted, after 2d terminates, after reaction solution is cooled to room temperature
There are a large amount of solids to generate, filter, dry, recrystallization obtains Momelotinib (0.10g), yield 67.6%.
Spectrogram is detected with embodiment 6.
Embodiment the result shows that, this method is with 4- nitro-chlorobenzenes, morpholine, 4- acetylbenzoic acids, cyanamide, aminoacetonitriles
Hydrochloride, DMF-DMA etc. are raw material, are substituted, are condensed, at the 6 step popular response such as guanidine, cyclization, target compound is prepared
Momelotinib, total recovery is 31% or more；In terms of 4- acetylbenzoic acids, this method prepares the total recovery of Momelotinib
Up to 52%.
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 can solve present disclosure and implement according to this, and the protection model of the present 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 (6)
1. a kind of preparation method of Momelotinib, which is characterized in that include the following steps：
(1) 4- (4- nitrobenzophenones) morpholine is prepared by 4- nitro-chlorobenzenes and morpholine, and after through reduction 4- morpholines are prepared
Base aniline；
(2) it is reacted with cyanamide by 4- morpholinyl phenylamines and 1- (4- morpholino phenyls) guanidine is prepared；
(3) it is reacted with aminoacetonitrile HCl salt by 4- acetylbenzoic acids and 4- acetyl group-N- (cyano methyl) benzene first is prepared
Amide；
(4) it is reacted and is prepared into N,N-dimethylformamide dimethylacetal by 4- acetyl group-N- (cyano methyl) benzamides
To N- (cyano methyl) -4- (3- (dimethylamino) acryloyl) benzamide；
(5) it is reacted by N- (cyano methyl) -4- (3- (dimethylamino) acryloyl) benzamides and 1- (4- morpholino phenyls) guanidine
Momelotinib is prepared.
2. the preparation method of Momelotinib according to claim 1, which is characterized in that step (1) includes：
(a) 4- nitro-chlorobenzenes are mixed with morpholine and alkali with solvent I, at room temperature~110 DEG C react 2~obtain 4- (4- nitros for 24 hours
Phenyl) morpholine；
(b) 4- (4- nitrobenzophenones) morpholine is mixed with solvent II, reducing agent I and acid is added, 1 is reacted in room temperature~80 DEG C~
12h obtains 4- morpholinyl phenylamines；
Alternatively, 4- (4- nitrobenzophenones) morpholine is mixed with solvent II I, catalyst I is added, it is 1~5atm to be passed through Hydrogen Vapor Pressure,
1~12h, which is reacted, in room temperature~60 DEG C obtains 4- morpholinyl phenylamines；
The 4- nitro-chlorobenzenes：Morpholine：The molar ratio of alkali is 1：1~2：1~3；The alkali be selected from potassium carbonate, sodium carbonate or
Potassium tert-butoxide；The solvent I is selected from N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, acetonitrile or acetone；Described is molten
Agent II is selected from water, ethyl alcohol, methanol or acetic acid；The reducing agent I is selected from iron powder, zinc powder or stannous chloride；The acid is selected from
Hydrochloric acid or sulfuric acid；The solvent II I is selected from methanol, ethyl alcohol or tetrahydrofuran；The catalyst I is selected from Raney's nickel or palladium-
Carbon.
3. the preparation method of Momelotinib according to claim 1, which is characterized in that step (2) includes：
4- morpholinyl phenylamines are mixed with solvent, be added acid and cyanamide, at 50~100 DEG C react 2~for 24 hours, 1- is prepared
(4- morpholino phenyls) guanidine；
The 4- morpholinyl phenylamines：Acid：The molar ratio of cyanamide is 1：1~5：1~5；The solvent is selected from methanol, ethyl alcohol
Or water；The acid is selected from hydrochloric acid, nitric acid.
4. the preparation method of Momelotinib according to claim 1, which is characterized in that step (3) includes：
4- acetylbenzoic acids, aminoacetonitrile HCl salt, condensing agent, organic base are mixed with solvent, in 0~60 DEG C react 2~
For 24 hours, 4- acetyl group-N- (cyano methyl) benzamide is obtained；
The 4- acetylbenzoic acids：Aminoacetonitrile HCl salt：Condensing agent：The molar ratio of organic base is 1：1~3：1~3：1
~6；The solvent is selected from N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, dimethyl sulfoxide (DMSO) or acetonitrile；The contracting
Mixture is selected from 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides/I-hydroxybenzotriazole, (7- aoxidizes benzo to 2-
Triazole)-N, N, N',N'Tetramethylurea hexafluorophosphoric acid ester or O- benzotriazole-tetramethylurea hexafluorophosphate；Described
Organic base is selected from triethylamine, diisopropylamino ethamine or pyridine.
5. the preparation method of Momelotinib according to claim 1, which is characterized in that step (4) includes：
4- acetyl group-N- (cyano methyl) benzamides are mixed with n,N-Dimethylformamide dimethylacetal and solvent,
50~120 DEG C of 2~4d of reaction, are prepared N- (cyano methyl) -4- (3- (dimethylamino) acryloyl) benzamide；
Described 4- acetyl group-N- (cyano methyl) benzamide：The molar ratio of N,N-dimethylformamide dimethylacetal is
1：3~5；The solvent is selected from toluene, glycol dimethyl ether or tetrahydrofuran.
6. the preparation method of Momelotinib according to claim 1, which is characterized in that step (5) includes：
1- (4- morpholino phenyls) guanidines are mixed with 4- acetyl group-N- (cyano methyl) benzamides and solvent, at 50~140 DEG C
1~3d is reacted, Momelotinib is obtained；
Described 1- (4- morpholino phenyls) guanidine：The molar ratio of 4- acetyl group-N- (cyano methyl) benzamide is 1：0.8~
1.2；The solvent is selected from acetonitrile, glycol dimethyl ether, diethylene glycol dimethyl ether, acetone or N,N-dimethylformamide.
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