Nothing Special   »   [go: up one dir, main page]

CN110669015A - Preparation method of FGFR inhibitor - Google Patents

Preparation method of FGFR inhibitor Download PDF

Info

Publication number
CN110669015A
CN110669015A CN201810719247.7A CN201810719247A CN110669015A CN 110669015 A CN110669015 A CN 110669015A CN 201810719247 A CN201810719247 A CN 201810719247A CN 110669015 A CN110669015 A CN 110669015A
Authority
CN
China
Prior art keywords
group
compound
formula
reacting
general formula
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN201810719247.7A
Other languages
Chinese (zh)
Inventor
林其先
吕文川
袁钧
方建
宋俊
赵伟
梁旭锋
刘永维
沈磊
赵成浩
王永欣
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shanghai Blue Technology Co Ltd
Original Assignee
Shanghai Blue Technology Co Ltd
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Shanghai Blue Technology Co Ltd filed Critical Shanghai Blue Technology Co Ltd
Priority to CN201810719247.7A priority Critical patent/CN110669015A/en
Publication of CN110669015A publication Critical patent/CN110669015A/en
Pending legal-status Critical Current

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
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/18—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
    • C07C2603/06—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members
    • C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings
    • C07C2603/12—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings only one five-membered ring
    • C07C2603/18—Fluorenes; Hydrogenated fluorenes
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to FGFR inhibitor of formula (R) -6- (2-fluorophenyl) -N- (3- (2- ((2-methoxyethyl) amino) ethyl) phenyl) -5, 6-dihydrobenzo [ h]The invention discloses a synthetic method of quinazoline-2-amine (I), belonging to the field of organic synthesis.

Description

Preparation method of FGFR inhibitor
Technical Field
The invention relates to a novel synthesis method of FGFR inhibitor (R) -6- (2-fluorophenyl) -N- (3- (2- ((2-methoxyethyl) amino) ethyl) phenyl) -5, 6-dihydrobenzo [ h ] quinazoline-2-amine (I).
Background
The Fibroblast Growth Factor Receptor (FGFR) family is composed of four members (FGFR1, FGFR2, FGFR3 and FGFR4), which belong to the kinase family of receptor tyrosine kinases, with FGF binding leading to FGFR dimerization followed by receptor autophosphorylation and activation of downstream signaling pathways. Receptor activation is sufficient to restore and activate specific downstream signaling partners involved in the regulation of diverse processes such as cell growth, cell metabolism, and cell survival. Thus, FGF/FGFR signaling pathways have a multi-effect role in many biological processes critical for tumor cell proliferation, migration, infiltration, angiogenesis, and cell.
At present, a plurality of FGFR inhibitors are in clinical stage, wherein Derazaniib, the chemical name of (R) -6- (2-fluorophenyl) -N- (3- (2- ((2-methoxyethyl) amino) ethyl) phenyl) -5, 6-dihydrobenzo [ h ] quinazolin-2-amine (I) is in clinical stage III, and is used for drugs for potential treatment of solid tumors such as cholangiocarcinoma, and a synthetic method of the process is disclosed in a patent application WO 2017106639.
Figure BDA0001718277980000011
Firstly, converting (R) -4- (2-fluorophenyl) -3, 4-dihydronaphthalene-1 (2H) -ketone (compound A) into (R, E) -2- ((dimethylamino) methylene) -4- (2-fluorophenyl) -3, 4-dihydronaphthalene-1 (2H) -ketone (compound B), then reacting with 3- (2-hydroxyethyl) phenylguanidine methanesulfonate (compound C) to obtain (R) -2- (3- ((6- (2-fluorophenyl) -5, 6-dihydrobenzo [ H ] quinazolin-2-yl) amino) phenyl) ethanol (compound D), then reacting with methanesulfonyl chloride to obtain (R) -2- (3- ((6- (2-fluorophenyl) -5, 6-dihydrobenzo [ h ] quinazolin-2-yl) amino) phenyl) ethanol mesylate (compound E) is treated with 2-methoxyethylamine to obtain (R) -6- (2-fluorophenyl) -N- (3- (2- ((2-methoxyethyl) amino) ethyl) phenyl) -5, 6-dihydrobenzo [ h ] quinazolin-2-amine (compound I). The method adopts a linear synthesis process, and the use efficiency of the raw material chiral compound A is not high; in addition, the synthesis of the compound C in WO2010078421 is complicated and difficult to purify, and the industrial production of the target compound is greatly influenced.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention aims to provide a synthesis method for preparing Derazatinib, (R) -6- (2-fluorophenyl) -N- (3- (2- ((2-methoxyethyl) amino) ethyl) phenyl) -5, 6-dihydrobenzo [ h ] quinazolin-2-amine (I) or pharmaceutically acceptable salts thereof:
Figure BDA0001718277980000021
wherein:
(i) reacting a compound of formula (IA) or a salt thereof with a compound of formula (IB) in a solvent to give a compound of formula (IC);
Figure BDA0001718277980000023
(ii) optionally removing the protecting group PG from the compound of formula (IC) to obtain a compound of formula (I);
wherein: PG is selected from a hydrogen atom or an N protecting group.
Preferably, PG is selected from a hydrogen atom, a formyl group, an acetyl group, a methoxycarbonyl group, an ethoxycarbonyl group, a benzyloxycarbonyl group, a tert-butoxycarbonyl group, an allyloxycarbonyl group, a benzyl group, a p-methoxybenzyl group or a 2- (trimethylsilyl) ethoxymethyl chloride.
More preferably, PG is selected from benzyloxycarbonyl.
In a preferred embodiment of the present invention, a process for preparing a compound of formula (I), wherein in step (I):
the feeding molar ratio of the general formula (IA) to the general formula (IB) is 3: 1-1: 3, preferably the ratio is 2: 1-1: 1, and more preferably the ratio is 1.4: 1;
the solvent is selected from methanol, ethanol, isopropanol, n-butanol, ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, and methyl tert-butylThe solvent is a single or mixed solvent of an ether, dioxane, acetonitrile, N-dimethylformamide, N-dimethylacetamide and N-methylpyrrolidone, preferably a mixed solvent of ethanol and 2-methyltetrahydrofuran, and more preferably VEthanol：V(2-methyltetrahydrofuran)1: 2; and,
the reaction temperature is 0-150 ℃, and the preferable reaction temperature is 80 ℃.
In a preferred embodiment of the present invention, a process for preparing a compound of formula (I), wherein in step (ii):
reducing the compound of the general formula (IC) in the presence of palladium on carbon under hydrogen condition;
the reaction temperature is 0-150 ℃, and the preferable reaction temperature is 25 ℃;
the solvent is selected from methanol, ethanol, isopropanol, N-butanol, ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, dioxane, acetonitrile, N-dimethylformamide, N-dimethylacetamide and N-methylpyrrolidone, or their mixture, preferably tetrahydrofuran;
wherein: PG is selected from the group consisting of a hydrogen atom, a formyl group, an acetyl group, a methoxycarbonyl group, an ethoxycarbonyl group, a benzyloxycarbonyl group, a tert-butoxycarbonyl group, an allyloxycarbonyl group, a benzyl group, a p-methoxybenzyl group and a 2- (trimethylsilyl) ethoxymethyl chloride.
In a preferred embodiment of the present invention, the process for preparing a compound of formula (I), wherein the reaction conditions for removing the protecting group in step (ii) are selected from the group consisting of:
carrying out hydrogen reduction reaction under the catalysis of palladium carbon;
carrying out hydrogen reduction reaction under the catalysis of palladium carbon and in the presence of ammonia gas;
carrying out hydrogen reduction reaction under the catalysis of palladium carbon and in the presence of acetic acid;
carrying out hydrogen reduction reaction under the catalysis of palladium carbon and in the presence of potassium acetate;
reacting trimethyl iodosilane in acetonitrile;
reacting trimethyl bromosilane in trifluoroacetic acid and methyl phenyl sulfide;
reacting boron tribromide in dichloromethane;
reacting boron trichloride in dichloromethane;
reacting 6N hydrochloric acid under reflux conditions;
reacting lithium borohydride in methanol or ethanol;
reacting sodium borohydride and trimethylchlorosilane in methanol or ethanol;
reacting 40% potassium hydroxide in methanol and water;
reacting boron trifluoride diethyl etherate in ethanethiol and dichloromethane;
reacting boron trifluoride diethyl etherate in dimethyl sulfide and dichloromethane;
the preferred reaction conditions are: and (3) carrying out hydrogen reduction reaction in the presence of palladium carbon.
Wherein: PG is selected from benzyloxycarbonyl.
A synthetic process for the preparation of a compound of formula (IA) or a salt thereof, said process comprising:
Figure BDA0001718277980000031
(a) reacting the compound of the general formula (Ia) with the compound of the general formula (Ib) in a solvent to obtain a compound of a general formula (Ic);
Figure BDA0001718277980000041
(b) the compound of the general formula (Ic) is further deprotected to give a compound of the general formula (IA) or a salt thereof.
Figure BDA0001718277980000042
Wherein:
g is a protecting group for N, preferably selected from formyl, acetyl, methoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl, tert-butoxycarbonyl or allyloxycarbonyl; preferably tert-butoxycarbonyl;
PG is selected from a hydrogen atom or a protective group for N, preferably from a hydrogen atom, formyl group, acetyl group, methoxycarbonyl group, ethoxycarbonyl group, benzyloxycarbonyl group, tert-butoxycarbonyl group, allyloxycarbonyl group, benzyl group, p-methoxybenzyl group or 2- (trimethylsilyl) ethoxymethyl group, preferably benzyloxycarbonyl group.
A synthetic process for the preparation of a compound of formula (IA) or a salt thereof, wherein in step (a):
the molar ratio of formula (Ia) to formula (Ib) is 1:2 to 2:1, preferably the ratio is 1: 1;
the reaction temperature is 0-120 ℃, and the preferable reaction temperature is 50 ℃;
the reaction solvent is selected from methanol, ethanol, isopropanol, N-butanol, ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, dioxane, acetonitrile, N-dimethylformamide, N-dimethylacetamide or N-methylpyrrolidone or a mixed solvent; preferably, the reaction solvent is 2-methyltetrahydrofuran.
A synthetic process for the preparation of a compound of formula (IA) or a salt thereof, wherein the deprotection conditions in step (b) are selected from the group consisting of:
reacting the compound of the general formula (Ic) with hydrochloric acid in a methanol solvent;
reacting the compound of the general formula (Ic) with trifluoroacetic acid in a dichloromethane solvent;
reacting the compound of formula (Ic) with methanesulfonic acid in dichloromethane; or,
reacting the compound of formula (Ic) with p-toluenesulfonic acid monohydrate in tetrahydrofuran;
the preferred reaction conditions are: the compound of formula (Ic) is reacted with p-toluenesulfonic acid monohydrate in tetrahydrofuran.
A synthetic method for preparing a compound represented by the general formula (IA) or a salt thereof, wherein the salt of the general formula (IA) is selected from hydrochloride, sulfate, phosphate, acetate, trifluoroacetate, trifluoromethanesulfonate, p-toluenesulfonate or sulfonate.
A compound of formula (IA) or a salt thereof, which is an intermediate in the preparation of a compound of formula (I):
Figure BDA0001718277980000043
wherein:
PG is selected from a hydrogen atom or an N protecting group;
PG is preferably selected from a hydrogen atom, a formyl group, an acetyl group, a methoxycarbonyl group, an ethoxycarbonyl group, a benzyloxycarbonyl group, a tert-butoxycarbonyl group, an allyloxycarbonyl group, a benzyl group, a p-methoxybenzyl group or a 2- (trimethylsilyl) ethoxymethyl chloride; more preferably a benzyloxycarbonyl group.
Wherein the salt is selected from the group consisting of hydrochloride, sulfate, phosphate, acetate, trifluoroacetate, triflate, p-toluenesulfonate, or sulfonate.
The invention simply and efficiently prepares guanidine compounds of general formula (IA) and salts thereof, and reacts with compound A ((R) -4- (2-fluorophenyl) -3, 4-dihydronaphthalene-1 (2H) -ketone) to synthesize the compound of formula (I). Compared with the preparation method of the compound C in WO2010078421, the synthesis operation of the compound (IA) and the salt thereof in the general formula is convenient and easy to purify, and meanwhile, the efficiency is remarkably improved due to the adoption of a convergent synthesis strategy.
Detailed description of the invention
Unless stated to the contrary, some of the terms used in the specification and claims of the present invention are defined as follows:
"formyl" refers to-C (═ O) CH3；
"acetyl" means-C (═ O) CH2CH3；
"Methoxycarbonyl" means-C (═ O) OCH3；
"ethoxycarbonyl" refers to-C (═ O) OCH2CH3；
"benzyloxycarbonyl" means-C (═ O) OCH2-a phenyl group;
"tert-butoxycarbonyl" refers to-C (═ O) OC (CH)3)3；
"allyloxycarbonyl" means-C (═ O) OCH2CH＝CH2；
"benzyl" means-CH2-a phenyl group;
"P-methoxybenzyl" refers to p-OCH3-a benzyl group;
"2- (trimethylsilyl) ethoxymethyl" means; -CH2OCH2CH2Si(CH3)3。
"Boc" refers to tert-butoxycarbonyl;
"Cbz" refers to benzyloxycarbonyl.
In the invention, the compound A and the compound 1h represent the compound with the same structure; compound B, compound of formula (IB) and compound 1i characterize compounds of the same structure.
Detailed Description
The present invention will be further described with reference to the following examples, which are not intended to limit the scope of the present invention.
Examples
The examples show the preparation of representative compounds represented by formula (I) and the associated structural identification data. It must be noted that the following examples are intended to illustrate the invention and are not intended to limit the invention.1The H NMR spectrum was obtained using a Bruker instrument (400MHz) and the chemical shifts were expressed in ppm. Tetramethylsilane internal standard (0.00ppm) was used.1Method for H NMR expression: s is singlet, d is doublet, t is triplet, m is multiplet, br is broadened, dd is doublet of doublet, dt is doublet of triplet. If a coupling constant is provided, it is in Hz.
The mass spectrum is measured by an LC/MS instrument, and the ionization mode can be ESI or APCI.
The thin layer chromatography silica gel plate adopts HSGF254 of tobacco yellow sea or GF254 of Qingdao, the specification of the silica gel plate used by Thin Layer Chromatography (TLC) is 0.15 mm-0.2 mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm.
The column chromatography generally uses 200-300 mesh silica gel of the Tibet Huanghai silica gel as a carrier.
In the following examples, all temperatures are in degrees Celsius unless otherwise indicated, and unless otherwise indicated, the various starting materials and reagents are commercially available or synthesized according to known methods, and none of the commercially available materials and reagents are used without further purification, and unless otherwise indicated, commercially available manufacturers include, but are not limited to, Aldrich Chemical Company, ABCR GmbH & Co. KG, Acros Organics, Prov Chemical science Inc. and Sci Chemical science Inc., and the like.
CD3OD: deuterated methanol.
CDCl3: deuterated chloroform.
DMSO-d6: deuterated dimethyl sulfoxide.
The argon atmosphere means that the reaction flask is connected with an argon balloon having a volume of about 1L.
In the examples, the solution in the reaction is an aqueous solution unless otherwise specified.
Purifying the compound by silica gel column chromatography using an eluent system selected from the group consisting of: a: petroleum ether and ethyl acetate systems; b: dichloromethane and methanol systems; c: dichloromethane: ethyl acetate; d: petroleum ether: a dichloromethane system; the volume ratio of the solvent is different according to the polarity of the compound, and a small amount of acidic or basic reagent such as acetic acid or triethylamine can be added for adjustment.
Example 1
(R) -6- (2-fluorophenyl) -N- (3- (2- ((2-methoxyethyl) amino) ethyl) phenyl) -5, 6-dihydrobenzo [ h ] quinazolin-2-amine
Figure BDA0001718277980000071
First step of
3-Nitrophenyl Ethyl methane sulfonate
2- (3-Nitrophenyl) ethan-1-ol 1a (100g, 598mmol) was dissolved in 1L of dichloromethane, triethylamine (121g, 1.2mol,2eq) was added with stirring, methanesulfonyl chloride (137g, 1.2mol,2eq) was added dropwise to the reaction solution under cooling in an ice bath, and the reaction was carried out at room temperature for 1 hour after the addition. 500mL of water was added, the layers were separated, the aqueous phase was extracted with dichloromethane (500mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give 3-nitrophenylethyl methanesulfonate 1b (110g,448mmol, yellow liquid), yield: 75 percent.
1H NMR(400MHz,CDCl3)δ8.07-8.21(m,2H),7.56-7.65(m,1H),7.49-7.56(m,1H),4.48(t,J＝6.60Hz,2H),3.19(t,J＝6.60Hz,2H),2.96(s,3H)
Second step of
2-methoxy-N- (3-nitrophenylethyl) ethan-1-amine
3-Nitrophenyl ethyl methanesulfonate 1b (100g,407mmol) was dissolved in 500mL of 2-methyltetrahydrofuran, and methoxyethylamine (220g, 2.85mol,7eq) was added with stirring to react at 70 ℃ for 3 hours. The reaction solution was concentrated under reduced pressure to give 2-methoxy-N- (3-nitrophenylethyl) ethan-1-amine 1c (92g,407mmol, yellow liquid), yield: 100 percent.
1H NMR(400MHz,CDCl3)δ8.01-8.15(m,2H),7.58(m,1H),7.40-7.52(m,1H),3.44-3.59(m,2H),3.35(s,3H),2.96(m,3H),2.77-2.89(m,2H),2.36(br.s.,1H).
The third step
(2-methoxyethyl) (3-nitrophenylethyl) carbamic acid benzyl ester
2-methoxy-N- (3-nitrophenylethyl) ethan-1-amine 1c (92g,407 mmol) was dissolved in 800mL of dichloromethane, triethylamine (83g, 815mmol,2eq) was added with stirring, and benzyl chloroformate (105g,615mmol,1.5eq) was added dropwise with cooling on an ice bath and reacted at room temperature for 2 hours. To the reaction mixture was added 200mL of water, extracted with dichloromethane (200mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give benzyl (2-methoxyethyl) (3-nitrophenylethyl) carbamate 1d (147g, 407mmol, yellow liquid), yield: 100 percent.
1H NMR(400MHz,DMSO-d6)δ7.48-7.77(m,2H),7.18-7.45(m,5H),4.85-5.18(m,2H),3.48-3.65(m,2H),3.33-3.49(m,4H),3.13-3.32(m,3H),2.95(d,J＝7.34Hz,2H).
The fourth step
(3-Aminophenylethyl) (2-methoxyethyl) carbamic acid benzyl ester
Dissolving (2-methoxyethyl) (3-nitrophenylethyl) benzyl carbamate 1d (147g, 407mmol) in 1L of ethanol, adding 1L of saturated ammonium chloride solution while stirring, adding zinc powder (100g, 1.54mol,3.8eq) in portions while cooling in an ice bath, and after the dropwise addition is finished, heating to reflux for 2 hours. The reaction solution was concentrated under reduced pressure to remove ethanol, the aqueous phase was extracted with ethyl acetate (500mL × 4), the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography to give benzyl (3-aminophenylethyl) (2-methoxyethyl) carbamate 1e (100g,304mmol, yellow liquid), yield: 74 percent.
1H NMR(400MHz,CDCl3)δ7.25-7.57(m,5H),6.96-7.16(m,1H),6.30-6.76(m,3H),5.02-5.27(m,2H),3.18-3.66(m,9H),3.00(br,2H),2.66-2.85(m,2H).
LCMS：M+H+＝329.5M+Na+＝351.5
The fifth step
N- [2- [3- [ (N, N' -bis (tert-butoxycarbonyl) guanidino) phenyl ] ethyl ] -N- (2-methoxyethyl) carbamic acid benzyl ester
Benzyl (3-aminophenylethyl) (2-methoxyethyl) carbamate 1e (100g,304 mmol), N, N '-di-tert-butoxycarbonyl-1H-1-guanidinopyrazole (95g,306mmol,1eq) were dissolved in 800mL of 2-methyltetrahydrofuran, reacted at 50 ℃ for 3 hours, and quenched by addition of N, N' -dimethylethylenediamine. Concentrating the reaction solution under reduced pressure, and purifying the residue by silica gel column chromatography to obtain
Benzyl N- [2- [3- [ (N, N' -bis (tert-butoxycarbonyl) guanidino) phenyl ] ethyl ] -N- (2-methoxyethyl) carbamate 1f (147g,257mmol, yellow solid), yield: 84 percent.
1H NMR(400MHz,CDCl3)δ11.68(br.s.,1H),10.13-10.55(m,1H),7.48-7.67(m,1H),7.15-7.48(m,7H),6.75-7.06(m,1H),5.14(d,J＝9.78Hz,2H),3.73(q,J＝7.09Hz,1H),3.20-3.64(m,8H),2.70-2.99(m,2H),1.37-1.73(m,18H)
The sixth step
(3-guanidinophenylethyl) (2-methoxyethyl) carbamic acid benzyl ester
Benzyl N- [2- [3- [ (N, N' -bis (tert-butoxycarbonyl) guanidino) amino ] phenyl ] ethyl ] -N- (2-methoxyethyl) carbamate 1f (147g,257mmol) was dissolved in 2.2L of tetrahydrofuran, and p-toluenesulfonic acid monohydrate (300g,1.57mol,6.0eq) was added with stirring and reacted at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give benzyl (3-guanidinophenylethyl) (2-methoxyethyl) carbamate 1g (95g,257mmol, brown solid), yield: 100 percent.
1H NMR(400MHz,CDCl3)δ7.76(s,1H),7.08-7.44(m,6H),6.88-7.07(m,2H),6.80(br,4H),4.85-5.13(m,2H),3.14-3.70(m,7H),2.66-2.93(m,2H),2.35(s,2H)
LCMS：M+H+＝371.3
Seventh step
(R, E) -2- ((dimethylamino) methylene) -4- (2-fluorophenyl) -3, 4-dihydronaphthalen-1 (2H) -one
(R) -4- (2-fluorophenyl) -3, 4-dihydronaphthalen-1 (2H) -one 1H (50g,208mmol) was dissolved in 100mL DMF-DMA and stirred at 80 ℃ overnight. After the reaction solution was cooled, 1L of petroleum ether was added, a large amount of solid was precipitated, the solid was filtered, washed with petroleum ether (200mL × 2), dried to give (R, E) -2- ((dimethylamino) methylene) -4- (2-fluorophenyl) -3, 4-dihydronaphthalen-1 (2H) -one 1i (50g,169mmol, yellow solid), the mother liquor was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give 1i (5g,17mmol, yellow solid) in yield: 89 percent.
1H NMR(400MHz,DMSO-d6)δ7.92(dd,J＝7.34,1.47Hz,1H),7.52-7.64(m,1H),7.32-7.46(m,2H),7.17-7.33(m,2H),7.05-7.15(m,1H),6.84-6.96(m,2H),4.42-4.53(m,1H),3.10-3.29(m,2H),3.02(s,6H)
Eighth step
Benzyl (R) - (3- ((6- (2-fluorophenyl) -5, 6-dihydrobenzo [ h ] quinazolin-2-yl) amino) phenethyl) (2-methoxyethyl) carbamate
1g (95g,257mmol,1.4eq) of benzyl (3-guanidinophenylethyl) (2-methoxyethyl) carbamate is dissolved in 400mL of ethanol and 800mL of 2-methyltetrahydrofuran solution, sodium ethoxide (8.7g,128mmol,0.75eq), (R, E) -2- ((dimethylamino) methylene) -4- (2-fluorophenyl) -3, 4-dihydronaphthalen-1 (2H) -one 1i (55g, 186mmol, 1.0eq) is added successively under argon protection and reacted at 80 ℃ overnight. Celite was filtered, the insoluble material was washed with a little ethyl acetate, and the filtrate was concentrated to silica gel column chromatography to purify (R) - (3- ((6- (2-fluorophenyl) -5, 6-dihydrobenzo [ h ] quinazolin-2-yl) amino) phenethyl) (2-methoxyethyl) carbamic acid benzyl ester 1j (70g, 116mmol, light yellow solid), yield: 62 percent.
1HNMR(400MHz,CDCl3)δ8.35-8.55(m,1H),8.17(br.s.,1H),7.15-7.70(m,12H),7.02-7.14(m,2H),6.70-7.00(m,3H),5.05-5.24(m,2H),4.70(t,J＝6.48Hz,1H),3.50-3.69(m,3H),3.26-3.50(m,6H),3.07-3.26(m,2H),2.78-3.02(m,2H)
LC-MS：M+H+＝603.6
The ninth step
(R) -6- (2-fluorophenyl) -N- (3- (2- ((2-methoxyethyl) amino) ethyl) phenyl) -5, 6-dihydrobenzo [ h ] quinazolin-2-amine
Benzyl (R) - (3- ((6- (2-fluorophenyl) -5, 6-dihydrobenzo [ h ] quinazolin-2-yl) amino) phenethyl) (2-methoxyethyl) carbamate 1j (70g, 116mmol) was dissolved in 700mL tetrahydrofuran and palladium on carbon (7g, 10% W/W,6.6mmol,0.57eq) was added. The reaction was carried out overnight at room temperature with hydrogen substitution three times. Palladium on carbon was removed by filtration through celite and purified by silica gel column chromatography to give the product (R) -6- (2-fluorophenyl) -N- (3- (2- ((2-methoxyethyl) amino) ethyl) phenyl) -5, 6-dihydrobenzo [ h ] quinazolin-2-amine (I) (40g, 85mmol, off-white solid) yield: 73 percent.
1H NMR(400MHz,CDCl3)δ2.15(br.s.,1H)2.84-2.94(m,4H)2.96-3.04(m,2H)3.17(qd,J＝15.36,6.48Hz,2H)3.35(s,3H)3.53(t,J＝5.14Hz,2H)4.69(t,J＝6.60Hz,1H)6.77(t,J＝7.70Hz,1H)6.88-6.98(m,2H)7.04-7.14(m,2H)7.16-7.25(m,2H)7.31(t,J＝7.82Hz,1H)7.38-7.51(m,2H)7.58(s,1H)7.63(d,J＝8.07Hz,1H)8.17(s,1H)8.44(d,J＝7.58Hz,1H)LCMS：M+H+＝469.5(M+2H+)/2＝235.1
HPLC：99.27％
ee：>98％
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.

Claims (12)

1. A synthetic process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof, said process comprising:
Figure FDA0001718277970000011
wherein:
Figure FDA0001718277970000012
(i) reacting a compound of formula (IA) or a salt thereof with a compound of formula (IB) in a solvent to give a compound of formula (IC);
Figure FDA0001718277970000013
(ii) optionally removing the protecting group PG from the compound of formula (IC) to obtain a compound of formula (I);
wherein: PG is selected from a hydrogen atom or an N protecting group.
2. The production process according to claim 1, wherein PG is selected from the group consisting of a hydrogen atom, a formyl group, an acetyl group, a methoxycarbonyl group, an ethoxycarbonyl group, a benzyloxycarbonyl group, a tert-butoxycarbonyl group, an allyloxycarbonyl group, a benzyl group, a p-methoxybenzyl group and a 2- (trimethylsilyl) ethoxymethyl group.
3. The method according to claim 1, wherein PG is selected from benzyloxycarbonyl.
4. The production method according to claim 1, wherein in step (i):
the feeding molar ratio of the general formula (IA) to the general formula (IB) is 3: 1-1: 3, preferably the ratio is 2: 1-1: 1, and more preferably the ratio is 1.4: 1;
the solvent is selected from methanol, ethanol, isopropanol, n-butanol, ethyl acetate, tetrahydrofuran, and 2-methyltetra-ethylTetrahydrofuran, methyl tert-butyl ether, dioxane, acetonitrile, N-dimethylformamide, N-dimethylacetamide and N-methylpyrrolidone, preferably a mixed solvent of ethanol and 2-methyltetrahydrofuran, more preferably a mixed solvent of ethanol and 2-methyltetrahydrofuran, wherein V isEthanol：V(2-methyltetrahydrofuran)＝1:2；
The reaction temperature is 0-150 ℃, and the preferable reaction temperature is 80 ℃.
5. The production method according to claim 2, wherein in step (ii):
reducing the compound of the general formula (IC) in the presence of palladium on carbon under hydrogen condition;
the reaction temperature is 0-150 ℃, and the preferable reaction temperature is 25 ℃;
the solvent is selected from methanol, ethanol, isopropanol, N-butanol, ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, dioxane, acetonitrile, N-dimethylformamide, N-dimethylacetamide and N-methylpyrrolidone, or their mixture, preferably tetrahydrofuran.
6. The production process according to claim 3, wherein the reaction conditions for deprotecting in step (ii) are selected from:
carrying out hydrogen reduction reaction under the catalysis of palladium carbon;
carrying out hydrogen reduction reaction under the catalysis of palladium carbon and in the presence of ammonia gas;
carrying out hydrogen reduction reaction under the catalysis of palladium carbon and in the presence of acetic acid;
carrying out hydrogen reduction reaction under the catalysis of palladium carbon and in the presence of potassium acetate;
reacting trimethyl iodosilane in acetonitrile;
reacting trimethyl bromosilane in trifluoroacetic acid and methyl phenyl sulfide;
reacting boron tribromide in dichloromethane;
reacting boron trichloride in dichloromethane;
reacting 6N hydrochloric acid under reflux conditions;
reacting lithium borohydride in methanol or ethanol;
reacting sodium borohydride and trimethylchlorosilane in methanol or ethanol;
reacting 40% potassium hydroxide in methanol and water;
reacting boron trifluoride diethyl etherate in ethanethiol and dichloromethane; or,
boron trifluoride diethyl etherate is reacted in dimethyl sulfide and dichloromethane.
The preferred reaction conditions are: and (3) carrying out hydrogen reduction reaction in the presence of palladium carbon.
7. A synthetic process for the preparation of a compound of formula (IA) or a salt thereof, said process comprising:
Figure FDA0001718277970000021
(a) reacting the compound of the general formula (Ia) with the compound of the general formula (Ib) in a solvent to obtain a compound of a general formula (Ic);
Figure FDA0001718277970000022
(b) the compound of the general formula (Ic) is further deprotected to give a compound of the general formula (IA) or a salt thereof.
Figure FDA0001718277970000031
Wherein:
g is a protecting group for N, preferably selected from formyl, acetyl, methoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl, tert-butoxycarbonyl or allyloxycarbonyl; preferably tert-butoxycarbonyl;
PG is selected from a hydrogen atom or a protective group for N, preferably from a hydrogen atom, formyl group, acetyl group, methoxycarbonyl group, ethoxycarbonyl group, benzyloxycarbonyl group, tert-butoxycarbonyl group, allyloxycarbonyl group, benzyl group, p-methoxybenzyl group or 2- (trimethylsilyl) ethoxymethyl group, preferably benzyloxycarbonyl group.
8. The method according to claim 7, wherein the step (a):
the molar ratio of formula (Ia) to formula (Ib) is 1:2 to 2:1, preferably the ratio is 1: 1;
the reaction temperature is 0-120 ℃, and the preferable reaction temperature is 50 ℃;
the reaction solvent is selected from methanol, ethanol, isopropanol, N-butanol, ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, dioxane, acetonitrile, N-dimethylformamide, N-dimethylacetamide or N-methylpyrrolidone or a mixed solvent; preferably, the reaction solvent is 2-methyltetrahydrofuran.
9. The process according to claim 7, wherein the conditions for removing the protecting group in the step (b) are selected from the group consisting of:
reacting the compound of the general formula (Ic) with hydrochloric acid in a methanol solvent;
reacting the compound of the general formula (Ic) with trifluoroacetic acid in a dichloromethane solvent;
reacting the compound of formula (Ic) with methanesulfonic acid in dichloromethane; or,
reacting the compound of formula (Ic) with p-toluenesulfonic acid monohydrate in tetrahydrofuran;
the preferred reaction conditions are: the compound of formula (Ic) is reacted with p-toluenesulfonic acid monohydrate in tetrahydrofuran.
10. The process according to claim 7, wherein the salt of formula (IA) is selected from the group consisting of hydrochloride, sulfate, phosphate, acetate, trifluoroacetate, triflate, p-toluenesulfonate and sulfonate.
11. A compound of formula (IA) or a salt thereof, which is an intermediate in the preparation of a compound of formula (I):
Figure FDA0001718277970000032
wherein:
PG is selected from a hydrogen atom or an N protecting group;
PG is preferably selected from a hydrogen atom, a formyl group, an acetyl group, a methoxycarbonyl group, an ethoxycarbonyl group, a benzyloxycarbonyl group, a tert-butoxycarbonyl group, an allyloxycarbonyl group, a benzyl group, a p-methoxybenzyl group or a 2- (trimethylsilyl) ethoxymethyl chloride; more preferably a benzyloxycarbonyl group.
12. A compound or salt thereof according to claim 11 wherein the salt is selected from the group consisting of hydrochloride, sulfate, phosphate, acetate, trifluoroacetate, triflate, p-toluenesulfonate and sulfonate.
CN201810719247.7A 2018-07-03 2018-07-03 Preparation method of FGFR inhibitor Pending CN110669015A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201810719247.7A CN110669015A (en) 2018-07-03 2018-07-03 Preparation method of FGFR inhibitor

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201810719247.7A CN110669015A (en) 2018-07-03 2018-07-03 Preparation method of FGFR inhibitor

Publications (1)

Publication Number Publication Date
CN110669015A true CN110669015A (en) 2020-01-10

Family

ID=69065824

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201810719247.7A Pending CN110669015A (en) 2018-07-03 2018-07-03 Preparation method of FGFR inhibitor

Country Status (1)

Country Link
CN (1) CN110669015A (en)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1761655A (en) * 2003-01-27 2006-04-19 安斯泰来制药有限公司 Thiazole derivatives and their use as VAP-1 inhibitors
CN102325755A (en) * 2008-12-30 2012-01-18 阿奎利公司 Substituted 5,6-dihydro-6-phenyl benzo [F] isoquinoline 99.9-2-amine compound
WO2017106639A1 (en) * 2015-12-17 2017-06-22 Arqule, Inc. Methods for preparing substituted 5,6-dihydro-6-phenylbenzo[f]isoquinolin-2-amine
CN107074769A (en) * 2014-09-05 2017-08-18 艾科尔公司 composition and method for treating proliferative disorders

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1761655A (en) * 2003-01-27 2006-04-19 安斯泰来制药有限公司 Thiazole derivatives and their use as VAP-1 inhibitors
CN102325755A (en) * 2008-12-30 2012-01-18 阿奎利公司 Substituted 5,6-dihydro-6-phenyl benzo [F] isoquinoline 99.9-2-amine compound
CN107074769A (en) * 2014-09-05 2017-08-18 艾科尔公司 composition and method for treating proliferative disorders
WO2017106639A1 (en) * 2015-12-17 2017-06-22 Arqule, Inc. Methods for preparing substituted 5,6-dihydro-6-phenylbenzo[f]isoquinolin-2-amine

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
ELENA BEJAN: "Enaminones in the Synthesis of New Polyaza Heterocycles", 《EUR. J. ORG. CHEM.》 *
刘鹰翔: "《药物合成反应（新世纪第二版）》", 31 August 2017, 中国中医药出版社 *

Similar Documents

Publication Publication Date Title
EP1491542B1 (en) Intermediate compounds for the preparation of imidazo-pyridine-derivatives
US8153801B2 (en) Process and intermediates for preparing integrase inhibitors
EP4043468A1 (en) Preparation method for glufosinate ammonium
EP2451786B1 (en) Improved process for the preparation of ambrisentan and novel intermediates thereof
CA2646795A1 (en) Process for the preparation of bosentan
KR20190013555A (en) Intermediates useful for the synthesis of a selective inhibitor against protein kinase and processes for preparing the same
EP3564219B1 (en) Process for preparing oxadiazacyclo compound and use thereof
CN111527067B (en) Process for the preparation of 1- [5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl ] -N-methylmethylamine monofumarate
EP2483246B1 (en) Process for preparing biphenyl imidazole compounds
EP0351126B1 (en) Process for the production of 02,2'-anhydro-1-(beta-D-arabinofuranosyl)thymine
CN110669015A (en) Preparation method of FGFR inhibitor
BG63721B1 (en) Method for the preparation of valacyclovir and relevant intermediate products
WO2012011939A2 (en) Synthesis of cyclopentaquinazolines
SU950188A3 (en) Process for producing derivatives of 4(5)-mercaptomethylimidazoles
EP4182294B1 (en) Method and intermediate compounds for the preparation of menaquinone mk-7
US8093384B2 (en) Processes for the preparation of alfuzosin
CN112135820B (en) Novel process for preparing diaminopyrimidine derivatives or acid addition salts thereof
US4897495A (en) Process for the preparation of pyrrolizine derivatives
KR100869165B1 (en) Process for preparing meropenem
CN110746459A (en) Preparation method of Avramide
JPWO2006083010A1 (en) Method for producing 4-acetylpyrimidine compound and crystal thereof
JP2024124589A (en) Capping agent precursor and method for producing the same, and method for synthesizing a capping agent
KR20240021198A (en) Method for preparing ERK inhibitors
CN118076620A (en) Process for producing 2' -modified pyrimidine nucleoside
CN117736152A (en) Synthesis method of dual endothelin receptor antagonist apixitan

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
WD01 Invention patent application deemed withdrawn after publication

Application publication date: 20200110

WD01 Invention patent application deemed withdrawn after publication