98548-81-3

Synthetic route

methyl 4-(dimethylamino)but-2-enoate hydrochloride → trans-4-dimethylaminocrotonic acid hydrochloride (98548-81-3)

Conditions	Yield
With hydrogenchloride In water for 6h; Reflux;	98%

ethyl 4-(dimethylamino)crotonate (98552-51-3) → trans-4-dimethylaminocrotonic acid hydrochloride (98548-81-3)

Conditions	Yield
Stage #1: ethyl 4-(dimethylamino)crotonate With water; sodium hydroxide In ethanol at 0.25 - 0.55℃; for 0.1h; Stage #2: With hydrogenchloride In ethanol at 5℃; pH=1.5;	63%

4-bromocrotonic acid (13991-36-1, 20629-35-0) + dimethyl amine (124-40-3) → trans-4-dimethylaminocrotonic acid hydrochloride (98548-81-3)

Conditions	Yield
Stage #1: 4-bromocrotonic acid; dimethyl amine In tetrahydrofuran at 0℃; for 0.5h; Stage #2: With hydrogenchloride In water; isopropyl alcohol pH=2 - 3;	36%

4-dimethylaminocrotonic acid methyl ester hydrochloride (1259519-60-2) → trans-4-dimethylaminocrotonic acid hydrochloride (98548-81-3)

Conditions	Yield
With hydrogenchloride; sodium hydroxide In ethanol; isopropyl alcohol; acetone

trans-4-dimethylaminocrotonic acid hydrochloride (98548-81-3) + 3-cyano-6-amino-7-ethoxy-4-(3-ethynylanilino)quinoline (1246087-09-1) → C26H25N5O2

Conditions	Yield
Stage #1: trans-4-dimethylaminocrotonic acid hydrochloride With oxalyl dichloride In tetrahydrofuran; N,N-dimethyl-formamide at 10 - 20℃; for 1h; Large scale; Stage #2: 3-cyano-6-amino-7-ethoxy-4-(3-ethynylanilino)quinoline In tetrahydrofuran; 1-methyl-pyrrolidin-2-one; N,N-dimethyl-formamide at -20 - 0℃; for 1h; Temperature; Large scale;	99.1%

trans-4-dimethylaminocrotonic acid hydrochloride (98548-81-3) + (R)-5-fluoro-4’-((R)-3-(methoxymethyl)piperazin-1-yl)-2’-(((R)-1-methylpyrrolidin-2-yl)methoxy)-3,4,5,8’-tetrahydro-1H,6’H-spiro[naphthalene-2,7’-quinazoline] → (E)-4-(dimethylamino)-1-((R)-4-((R)-5-fluoro-2’-(((S)-1-methylpyrrolidin-2-yl)methoxy)-3,4,5’,8’-tetrahydro-1H,6’H-spiro[naphthalene-2,7’-quinazolin]-4’-yl)-2-(methoxymethyl)piperazin-1-yl)but-2-en-1-one

Conditions	Yield
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In acetonitrile for 0.25h;	92%

trans-4-dimethylaminocrotonic acid hydrochloride (98548-81-3) + 2-((S)-4-((S)-5-fluoro-2’-(((S)-1-methylpyrrolidin-2-yl)methoxy)-3,4,5’,8’-tetrahydro-1H,6’H-spiro[naphthalene-2,7’-quinazolin]-4’-yl)piperazin-2-yl)acetonitrile → 2-((S)-1-((E)-4-(dimethylamino)but-2-enoyl)-4((S)-5-fluoro-2’-(((S)-1-methylpyrrolidin-2-yl)methoxy)-3,4,5’,8’-tetrahydro-1H,6’H-spiro[naphthalene-2,7’-quinazolin]-4’-yl)piperazin-2-yl)acetonitrile

Conditions	Yield
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In acetonitrile at 20℃; for 16h;	78%

trans-4-dimethylaminocrotonic acid hydrochloride (98548-81-3) + phenethylamine (64-04-0) → 4-(dimethylamino)-N-phenethylbut-2-enamide

Conditions	Yield
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at -20 - 20℃; Inert atmosphere;	73%

trans-4-dimethylaminocrotonic acid hydrochloride (98548-81-3) + N-(6-amino-pyridin-2-yl)-N'-(3-chloro-4-fluorophenyl)-pyrimidine-4,6-diamine (1144561-28-3) → (E)-N-[6-(3-chloro-4-fluorophenylamino)pyrimidin-4-ylaminopyridin-2-yl]-4-(dimethylamino)but-2-enamide (1144561-29-4)

Conditions	Yield
Stage #1: trans-4-dimethylaminocrotonic acid hydrochloride With oxalyl dichloride; N,N-dimethyl-formamide In tetrahydrofuran at 0 - 20℃; for 2.5h; Stage #2: N-(6-amino-pyridin-2-yl)-N'-(3-chloro-4-fluorophenyl)-pyrimidine-4,6-diamine In tetrahydrofuran; 1-methyl-pyrrolidin-2-one at 0 - 20℃; for 2h;	69%

trans-4-dimethylaminocrotonic acid hydrochloride (98548-81-3) + 4-{[6-(amino)quinolin-4-yl]oxy}-N-(pyridin-2-yl)benzamide → 4-[6-{[(2E)-4-dimethylaminobut-2-enoyl]amino}quinolin-4-yl]oxy-N-(pyridin-2-yl)benzamide

Conditions	Yield
With pyridine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In tetrahydrofuran at 0℃; for 3h;	61%

trans-4-dimethylaminocrotonic acid hydrochloride (98548-81-3) + C22H23N7O → N-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-4-(dimethylamino)but-2-enamide

Conditions	Yield
With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane at 20℃; for 1.5h;	40%

trans-4-dimethylaminocrotonic acid hydrochloride (98548-81-3) + C12H14F3NO2 → C18H23F3N2O3

Conditions	Yield
Stage #1: trans-4-dimethylaminocrotonic acid hydrochloride With thionyl chloride In 1-methyl-pyrrolidin-2-one at 0℃; for 1h; Stage #2: C12H14F3NO2 With dmap; N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 20℃;	21%

trans-4-dimethylaminocrotonic acid hydrochloride (98548-81-3) → 4-N,N-dimethylaminocrotonoylchloride Hydrochloride (501332-27-0)

Conditions	Yield
With oxalyl dichloride; N,N-dimethyl-formamide In tetrahydrofuran at 0 - 20℃; for 3h;
With oxalyl dichloride In acetonitrile at 0 - 45℃; for 2.58333h;
With oxalyl dichloride In N,N-dimethyl-formamide at 0 - 30℃; for 2h; Reagent/catalyst; Solvent; Temperature;

trans-4-dimethylaminocrotonic acid hydrochloride (98548-81-3) + (S)-5-((3,5-dimethoxyphenyl)ethynyl)-7-(pyrrolidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine → (S)-1-(3-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidin-1-yl)-4-(dimethylamino)but-2-en-1-one

Conditions	Yield
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 0.0833333h;	3.9 mg
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 0.0833333h;	3.9 mg

trans-4-dimethylaminocrotonic acid hydrochloride (98548-81-3) + (S)-3-((3,5-dimethoxyphenyl)ethynyl)-1-(pyrrolidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine → (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)-4-(dimethylamino)but-2-en-1-one

Conditions	Yield
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide	2.3 mg
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide	2.3 mg

trans-4-dimethylaminocrotonic acid hydrochloride (98548-81-3) + C9H11IN6 → (S)-1-(3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)-4-(dimethylamino)but-2-en-1-one

Conditions	Yield
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide	458 mg

trans-4-dimethylaminocrotonic acid hydrochloride (98548-81-3) + 1-(azetidin-3-yl)-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine → 1-(3-{4-amino-3-[2-(3,5-dimethoxyphenyl)ethynyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl}azetidin-1-yl)-4-(dimethylamino)but-2-en-1-one

Conditions	Yield
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide

trans-4-dimethylaminocrotonic acid hydrochloride (98548-81-3) + 6-amino-7-ethoxy-4-((4-phenoxyphenyl)amino)quinoline-3-carbonitrile → (E)-N-(3-cyano-7-ethoxy-4-((4-phenoxyphenyl)amino)quinolin-6-yl)-4-(dimethylamino)but-2-enamide

Conditions	Yield
Stage #1: trans-4-dimethylaminocrotonic acid hydrochloride With oxalyl dichloride In tetrahydrofuran; N,N-dimethyl-formamide at 5 - 20℃; for 3h; Stage #2: 6-amino-7-ethoxy-4-((4-phenoxyphenyl)amino)quinoline-3-carbonitrile In tetrahydrofuran; 1-methyl-pyrrolidin-2-one; N,N-dimethyl-formamide	1.56 g

trans-4-dimethylaminocrotonic acid hydrochloride (98548-81-3) + 6-amino-4-((4-phenoxyphenyl)amino)quinoline-3-carbonitrile → (E)-N-(3-cyano-4-((4-phenoxyphenyl)amino)quinolin-6-yl)-4-(dimethylamino)but-2-enamide

Conditions	Yield
Stage #1: trans-4-dimethylaminocrotonic acid hydrochloride With oxalyl dichloride In tetrahydrofuran; N,N-dimethyl-formamide at 20℃; for 3h; Cooling with ice; Stage #2: 6-amino-4-((4-phenoxyphenyl)amino)quinoline-3-carbonitrile In tetrahydrofuran; 1-methyl-pyrrolidin-2-one; N,N-dimethyl-formamide at 20℃; for 4h; Cooling with ice;	39 mg

trans-4-dimethylaminocrotonic acid hydrochloride (98548-81-3) + 4-{[6-(amino)quinolin-4-yl]oxy}-N-(4-ethylpyridin-2-yl)benzamide → 4-[(6-{[(2E)-4-dimethylaminobut-2-enoyl]amino}quinolin-4-yl)oxy]-N-(4-ethylpyridin-2-yl)benzamide

Conditions	Yield
Stage #1: trans-4-dimethylaminocrotonic acid hydrochloride With oxalyl dichloride; N,N-dimethyl-formamide In acetonitrile at 60℃; for 0.5h; Stage #2: 4-{[6-(amino)quinolin-4-yl]oxy}-N-(4-ethylpyridin-2-yl)benzamide In 1-methyl-pyrrolidin-2-one; acetonitrile at 0 - 20℃;	22 mg

trans-4-dimethylaminocrotonic acid hydrochloride (98548-81-3) + (S)-tert-butyl 3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidine-1-carboxylate → (S)-1-(3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)-4-(dimethylamino)but-2-en-1-one

Conditions	Yield
Stage #1: tert-butyl (S)-3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidine-1-carboxylate With hydrogenchloride In 1,4-dioxane for 1h; Stage #2: trans-4-dimethylaminocrotonic acid hydrochloride With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide

trans-4-dimethylaminocrotonic acid hydrochloride (98548-81-3) → C21H19ClF3N5O2

Conditions	Yield
Multi-step reaction with 2 steps 1: oxalyl dichloride; N,N-dimethyl-formamide / tetrahydrofuran / 3 h / 0 - 20 °C 2: tetrahydrofuran / 0 - 20 °C View Scheme

trans-4-dimethylaminocrotonic acid hydrochloride (98548-81-3) → (E)-N-(4-(3-chloro-4-fluorophenylamino)-7-(3-methoxypropoxy)quinazolin-6-yl)-4-(dimethylamino)but-2-enamide

Conditions	Yield
Multi-step reaction with 2 steps 1: oxalyl dichloride / tetrahydrofuran; N,N-dimethyl-formamide / 0.5 h / 20 °C / Inert atmosphere 2: tetrahydrofuran; 1-methyl-pyrrolidin-2-one / 1 h View Scheme

trans-4-dimethylaminocrotonic acid hydrochloride (98548-81-3) → trans-4-dimethylamino crotonic acid chloride hydrochloride salt (1055943-40-2)

Conditions	Yield
With oxalyl dichloride In tetrahydrofuran; N,N-dimethyl-formamide at 20℃; for 0.5h; Inert atmosphere;

trans-4-dimethylaminocrotonic acid hydrochloride (98548-81-3) → (E)-4-(dimethylamino)-N-(3-(5-fluoro-4-(m-tolylamino)pyrimidin-2-ylamino)phenyl)but-2-enamide (1202755-89-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: oxalyl dichloride / acetonitrile / 2.58 h / 0 - 45 °C 2: 1-methyl-pyrrolidin-2-one / 1 h / 0 - 10 °C View Scheme

trans-4-dimethylaminocrotonic acid hydrochloride (98548-81-3) → 4-(N,N-dimethylamino)-2-ene-butyryl chloride (774534-34-8)

Conditions	Yield
With oxalyl dichloride In tetrahydrofuran; N,N-dimethyl-formamide at 0 - 20℃; for 2h;
With oxalyl dichloride; N,N-dimethyl-formamide In tetrahydrofuran at 0 - 20℃; for 1.5h;	130 mg

trans-4-dimethylaminocrotonic acid hydrochloride (98548-81-3) → C27H29N3O5

Conditions	Yield
Multi-step reaction with 2 steps 1: oxalyl dichloride / N,N-dimethyl-formamide; tetrahydrofuran / 2 h / 0 - 20 °C 2: triethylamine / dichloromethane / 12 h / 20 °C View Scheme

trans-4-dimethylaminocrotonic acid hydrochloride (98548-81-3) + 2-(4-phenoxyphenyl)-5,6,7,8-tetrahydro-4H-pyrazolo[5',1':2,3]imidazo[4,5-c]pyridine-3-carboxamide trifluoroacetate → 7-(4-(dimethylamino)but-2-enoyl)-2-(4-phenoxyphenyl)-5,6,7,8-tetrahydro-4H-pyrazolo[5',1':2,3]imidazo[4,5-c]pyridine-3-carboxamide

Conditions

Yield

Stage #1: trans-4-dimethylaminocrotonic acid hydrochloride; 2-(4-phenoxyphenyl)-5,6,7,8-tetrahydro-4H-pyrazolo[5',1':2,3]imidazo[4,5-c]pyridine-3-carboxamide trifluoroacetate With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane at 20℃; for 2h; Inert atmosphere; Stage #2: In dichloromethane at 20℃; Inert atmosphere;

trans-4-dimethylaminocrotonic acid hydrochloride (98548-81-3) + 3-(1H-indazol-3-yl)aniline → C19H20N4O

Conditions	Yield
Stage #1: trans-4-dimethylaminocrotonic acid hydrochloride With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide; acetonitrile for 0.0833333h; Stage #2: 3-(1H-indazol-3-yl)aniline In N,N-dimethyl-formamide; acetonitrile at 20℃; for 48h; pH=8 - 9;

trans-4-dimethylaminocrotonic acid hydrochloride (98548-81-3) + phenethylamine (64-04-0) → N-ethyl-N,N-dimethyl-4-oxo-4-(phenethylamino)but-2-en-1-aminium

Conditions	Yield
Multi-step reaction with 2 steps 1.1: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / -20 - 20 °C / Inert atmosphere 2.1: triethylamine; trimethylsilyl bromide / acetonitrile / 24 h / 36 °C / Inert atmosphere 2.2: 0.08 h / Inert atmosphere View Scheme

Upstream product

• 1413945-87-5 dimethylaminoacetaldehyde-hydrogen sulphite adduct 
• 88738-78-7 bis-(2,2,2-trifluoroethyl)(methoxycarbonylmethyl)phosphonate 
• 1259519-60-2 4-dimethylaminocrotonic acid methyl ester hydrochloride 
• 98552-51-3 ethyl 4-(dimethylamino)crotonate 
• 13991-36-1 4-bromocrotonic acid 
• 124-40-3 dimethyl amine 

Downstream Products

• 1055943-40-2 trans-4-dimethylamino crotonic acid chloride hydrochloride salt 
• 1202755-89-2 (E)-4-(dimethylamino)-N-(3-(5-fluoro-4-(m-tolylamino)pyrimidin-2-ylamino)phenyl)but-2-enamide 
• 1144561-29-4 (E)-N-[6-(3-chloro-4-fluorophenylamino)pyrimidin-4-ylaminopyridin-2-yl]-4-(dimethylamino)but-2-enamide 

Relevant academic research and scientific papers

Synthetic method for (2Z)-4-(dimethylamino)but-2-enoic acid hydrochloride

The invention discloses a synthetic method for (2Z)-4-(dimethylamino)but-2-enoic acid hydrochloride. The synthetic method comprises the following steps: under an inert gas atmosphere, dissolving [bi(2,2,2-trifluoroethoxy)-phosphinyl]methyl acetate in organic solvent, adding lithium reagent, adding alkali solution, controlling the temperature to 0-30 DEG C, adding 2-(dimethylamino)acetaldehyde sulfite, and carrying out stirring reaction, carrying out acidification, extraction and column purification after reaction to obtain the (2Z)-4-(dimethylamino)but-2-enoic acid hydrochloride. The syntheticmethod has the advantages of convenience in operation and high yield, and industrial production can be realized.

QUINAZOLINE DERIVATIVE, PREPARATION METHOD THEREFOR, AND PHARMACEUTICAL COMPOSITION AND APPLICATION THEREOF

Disclosed are a quinazoline derivative, a preparation method therefor, and a pharmaceutical composition and an application thereof. The present invention provides a compound represented by general formula I, a stereoisomer thereof and a pharmaceutical acceptable salt or a solvate thereof. The quinazoline derivative of the present invention has a unique chemical structure, is characterized by irreversibly inhibiting EGFR tyrosine kinase, has high biological activity, apparently improves the inhibiting effect on the EGFR tyrosine kinase, has quite strong tumor inhibiting effect on tumor cells and a transplantation tumor pathological model of animal tumors, and has good market developing prospects.

A steps Hua Tini chemical synthesis method (by machine translation)

The present invention provides a convenient steps Hua Tini chemical synthesis method, using the synthesis method adopted in the process of preparing steps Hua Tini cheap raw materials, is easy to obtain, and saves the production cost, and the adoption of the synthesis method of the high yield of the product, the whole in the preparation process of mild reaction conditions, the atom economy is high. (by machine translation)

PROCESS FOR THE PREPARATION OF 4-DIMETHYLAMINOCROTONIC ACID

The present invention provides a process for the preparation of 4- dimethylaminocrotonic acid of Formula (II) or its salts, which is used as an intermediate for the preparation of afatinib or its salts.

Antineoplastic combinations

This invention provides the use of a combination of CCI-779 and EKB-569 in the treatment of neoplasms.