# Patent

## Title
Process for the manufacture of (E)-4-N,N-dialkylamino crotonic acid in HX salt form and use thereof for synthesis of EGFR tyrosine kinase inhibitors

## Abstract

The present invention is directed to an efficient process for the manufacture of (E)-4-N,N-dialkylamino crotonic acid in HX salt form of formula I




wherein R1 and R2 independently denote C1-3-alkyl groups and X− denotes an acid anion, such as the chloride, bromide, tosylate, mesylate or trifluoroacetate anion, with high quality, and a process for synthesis of EGFR tyrosine kinase inhibitors with heterocyclic quinazoline, quinoline or pyrimidopyrimidine core structure, using the acid addition salt I and activated derivatives thereof as intermediates.

## Background
BACKGROUND OF THE INVENTION
1. Technical Field
The present invention is directed to an efficient process for the manufacture of (E)-4-N,N-dialkylamino crotonic acid in HX salt form of formula I




wherein R1 and R2 independently denote C1-3-alkyl groups and X− denotes an acid anion, such as the chloride, bromide, tosylate, mesylate or trifluoroacetate anion, with high quality, and a process for synthesis of EGFR tyrosine kinase inhibitors with heterocyclic quinazoline, quinoline or pyrimidopyrimidine core structure, using an acid addition salt I and activated derivatives thereof as intermediates.

2. Background Information
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors have been studied clinically to demonstrate efficacy in treating certain cancers. Compounds which inhibit signal transduction by tyrosine kinases, for example of the human EGF receptor, have been shown to be useful for treating pathophysiological processes caused by hyperfunction of tyrosine kinases. David W. Fry, Pharmacol. Ther. Vol. 82, Nos. 2-3, pp. 207-218, 1999. Several irreversible inhibitors have been shown to have therapeutic advantages such as prolonged tumor suppression compared to reversible inhibitors such as gefitinib. DeBono & Rowinsky, Br. Med. Bull. 64:227-254 (2002).
The compounds of formula I and the salts thereof are suitable as a valuable intermediates in the synthesis of EGFR tyrosine kinase inhibitors based on a quinazoline, quinoline or pyrimidopyrimidine core structure. Examples of such EGFR tyrosinekinase inhibitors are HKI-272 (INN: Neratinib, in phase III clinical development for treatment of breast cancer), BIBW 2992 (INN: Afatinib, approved in the US and Europe for the treatment of non-small cell lung cancer patients with tumors bearing EGFR mutations), EKB-569 (INN: Pelitinib) or HKI 357.
BIBW 2992 is disclosed specifically in WO 02/50043. This compound is a highly selective, potent, irreversible dual inhibitor of erbbl receptor (EGFR) and erbB2 (Her2/neu) receptor tyrosine kinases, suitable for the treatment of e.g. benign or malignant tumours, particularly tumours of epithelial and neuroepithelial origin, metastasis and the abnormal proliferation of vascular endothelial cells (neoangiogenesis), for treating diseases of the airways and lungs which are accompanied by increased or altered production of mucus caused by stimulation by tyrosine kinases, as well as for treating diseases of the gastrointestinal tract and bile duct and gall bladder which are associated with disrupted activity of the tyrosine kinases. Promising effects in treatment of non-small cell lung cancer (NSCLC) patients have been reported already in Drugs of the Future 2008, 33(8): 649-654; and by Li, D. et al, in Oncogene (2008) 27, 4702-4711.
Pharmaceutical formulations of the compound are disclosed in the documents cited hereinbefore and in WO 2009/147238, indications to be treated and combination treatments are disclosed in WO 2007/054550 and WO 2007/054551. Skin toxicity and diarrhea are the most common adverse events in patients with adenocarcinoma of the lung and activating EGFR mutations, treated with this class of compounds (Mukherji, D., et al, Expert Opin. Investig. Drugs (2009) 18(3), 293-300).
Methods for the preparation of BIBW 2992 are described in WO 02/50043, WO 2005/037824 and WO 2007/085638.
WO 2002/50043 discloses a method of production in which aminocrotonylamino-substituted quinazolines are prepared in a one-pot reaction from the corresponding aniline component, bromocrotonic acid, oxalyl chloride and a secondary amine (Scheme 1).




The process is not well suited to technical use on an industrial scale, as the yields obtained are at most 50% and as a rule laborious purification by column chromatography is needed. Moreover the educt bromocrotonic acid is not commercially available in large amounts and the corresponding methyl bromocrotonate is only available with a purity of about 80%.
WO 2005/037824 discloses a method of preparation wherein BIBW 2992 is prepared using a Wittig-Horner-Emmons like process wherein the corresponding aminoquinazoline is reacted with diethylphosphonoacetic acid after activation to form a quinazoline substituted in 6-position by a carbamoyl-diethylphosphonate group, which is reacted in a second step with 2-dialkylaminoacetaldehyde or a corresponding aldehyde equivalent such as a corresponding acetale to form the unsaturated side chain in position 6 (Scheme 2).




WO 2007/085638 discloses an improved variant of the Wittig-Horner-Emmons like process described in WO 2005/037824 which uses a hydrogen sulphite adduct of formula




wherein M+ denotes a cation or a proton, instead of the 2-dialkylaminoacetaldehyde or aldehyde equivalent for the reaction with the quinazoline-6-carbamoyl-diethylphosphonate.

WO 2010/048477 discloses methods for manufacturing certain 4-amino-3-quinolinecarbonitrile derivatives, such as HKI-272, using stabilized 4-(amino)-2-butenoyl chloride intermediates (for example, 4-(dimethylamino)-2-butenoyl chloride) for coupling a 4-(amino)-2-butenoyl group to an amino group (—NH2) at the 6- or 7-position of a 4-amino-3-quinolinecarbonitrile. WO 2004/066919 and WO 2006/127207 both disclose preparation of 4-(dialkylamino)-2-butenoyl chloride by reaction of N,N-dialkylamino crotonic acid hydrochloride with oxalylchloride and subsequent amid coupling of 4-(dialkylamino)-2-butenoyl chloride with 4-amino-3-quinolinecarbonitrile.
Different routes to compound I or salts thereof are known in the art, but they all suffer from severe drawbacks from a commercial manufacturing point of view. They also do not allow for the control of the quality of the product in a way that is requested for the production of pharmaceutical intermediates. Therefore it was necessary to develop a novel route to compound I circumventing these problems.
As a very important intermediate in drug synthesis, different synthetic routes were developed to manufacture compound I. Most commonly the substitution between a dialkylamine with (E)-4-bromocrotonate was utilized as the key synthesis strategy.
In WO 2004/066919 two routes are documented employing brominated compounds A and E as key intermediates, as shown in Scheme 3.




Regarding the route starting with compound A, only about 30% total yield was achieved for overall two steps, and the purity of obtained compound I was insufficient (92%) for pharmaceutical production purpose. This is mainly due to the reasons, first, that purity of commerically available compound A is only very moderate, and, second, that hydrolysis occuring under basic conditions easily leads to by-products. Both drawbacks render final purification very difficult and cause low efficiency.
In the alternative route starting with compound C, some severe problems need to be solved before scale-up. These problems are, first, the use of highly toxic solvent CCl4, and, second, the silane reagent which may block the waste gas combustion system by the formation of sand.
WO 2010/131921 (corresponding to US 2012046494 A1) discloses an improved process for preparation of compound I providing better quality compared to the process according to WO 2004/066919. This improvement could be achieved by using compound H in high quality and performing hydrolysis of compound J under acidic conditions (Scheme 4). However, this process suffers from several issues with regard to scale up such as, first, the use of bromine which should be avoided in production scale, second, the use of large amounts of environment-unfriendly solvent dichloromethane, third, extensive work required to obtain pure compound H which needs vacuum distillation, and, fourth, tedious work to distill off great amounts of water during the hydrolysis step, e.g. about 7 ml of water to obtain 1 g of compound H.
All those issues together with the linear synthetic strategy (total yield was around 38%) lead to high expenditure regarding Volume-Time-Output and consequently less competitive.




In the light of the above disadvantages of the known methods of production there was a strong need for a novel or improved process to manufacture the compounds of formula I and the salts thereof. Thus the aim of the present invention is to provide a process which allows the synthesis of the desired product on commercial scale with high quality and in a competitive manner, using highly pure starting materials which are readily available and without any high technical expenditure. Preferably the process according to the invention should be environment friendly and sustainable, avoiding toxic reactants or solvents as well as complex, expensive or time-consuming purification processes and energy consuming reaction steps. As a matter of course, the process of the invention should provide the compounds of formula I and the salts thereof in a quality suitable for use in production of pharmaceuticals according to GMP standards, especially for use in production of EGFR tyrosine kinase inhibitors based on a quinazoline, quinoline or pyrimidopyrimidine core structure.
BRIEF SUMMARY OF THE INVENTION
In a first aspect the present invention is directed to an efficient process for the manufacture of (E)-4-N,N-di-(C1-3)-alkylamino crotonic acid in HX salt form of formula I




wherein R1 and R2 independently denote C1-3-alkyl groups and X− denotes an acid anion, such as the chloride, bromide, tosylate, mesylate or trifluoroacetate anion, preferably chloride, with high quality, comprising the following synthesis steps:

a) step 1:





wherein R1, R2 and R3 independently denote C1-3-alkyl groups, OBut denotes a tert-butyloxy group, HX denotes an acid selected from HCl, HBr, MeSO3H, p-CH3C6H4SO3H (p-toluenesulfonic acid) and CF3CO2H, preferably HCl, the base preferably denotes a strong base such as alkali hydroxide, e.g. NaOH or KOH or the like, and solvent denotes water, a water miscible organic solvent such as MeOH or EtOH, and the mixtures thereof, preferably pure water or a mixture of water with MeOH or EtOH,

b) step 2:





wherein R1 and R2 independently denote C1-3-alkyl groups, OBut denotes a tert-butyloxy group, HX denotes an acid, preferably an acid selected from HCl, HBr, MeSO3H, p-CH3C6H4SO3H and CF3CO2H, most preferred the acid HCl, and solvent denotes a suitable solvent such as ethyl acetate, i-PrOAc, MTBE (methyl t-butyl ether), 2-MeTHF, MeCN, and dioxane, preferably ethyl acetate.

The second aspect of the invention is directed to the process for the manufacture of (E)-4-N,N-dialkylaminocrotonic acid in HCl salt form of formula I′ using steps 1 and 2 described hereinbefore, wherein HX in both steps denotes HCl, and additional transformation of the hydrochloride salt of formula I′ into the activated derivative (E)-4-N,N-dialkylamino-2-butenoylchloride hydrochloride II by
c) step 3:
subsequent conversion of (E)-4-N,N-dialkylamino crotonic acid hydrochloride salt of compound I′ into the activated derivative II




wherein R1 and R2 independently denote C1-3-alkyl groups, with a chlorinating agent selected from thionylchloride, POCl3, PCl3 or PCl5, preferably with thionylchloride.

Step 3 carried out by reaction of compound I with thionylchloride is of particular advantage since thionylchloride is significantly more stable than the other alternative reagents and provides improved operational safety in production scale. A second significant advantage of this variant is that reaction of compound II prepared with thionylchloride in step 4 described hereinafter leads to a very pure final product of formula III (more that 99%; HPLC) only applying simple purification steps.
In a third aspect the present invention is directed to a process for the manufacture of an EGFR tyrosine kinase inhibitor of general formula




wherein X denotes a methine group substituted by a cyano group or a nitrogen atom,

Ra denotes a 3-chloro-4-fluorophenyl group, a 3-chloro-4-(pyridin-2-yl-methoxy)-phenyl group, or a 3-chloro-4-(3-fluoro-phenylmethoxy)-phenyl group,

Rc denotes a methoxy, ethoxy or tetrahydrofuran-3-yl-oxy group, and

R1 and R2 independently denote C1-3-alkyl groups, comprising the following synthesis steps 1 to 4:

a) step 1:





wherein R1, R2 and R3 independently denote C1-3-alkyl groups, OBut denotes a tert-butyloxy group, and HX denotes an acid selected from HCl, HBr, MeSO3H, p-CH3C6H4SO3H and CF3CO2H, preferably the acid HCl, the base preferably denotes a strong base such as alkali hydroxide, e.g. NaOH, KOH or the like, and solvent denotes water, a water miscible organic solvent such as MeOH or EtOH, and the mixtures thereof, preferably pure water or a mixture of water with MeOH or EtOH,

b) step 2:





wherein R1 and R2 independently denote C1-3-alkyl groups, OBut denotes a tert-butyloxy group, and solvent denotes a suitable solvent such as ethyl acetate, i-PrOAc, MTBE (methyl t-butyl ether), 2-MeTHF, MeCN, and dioxane, preferably ethyl acetate,

c) step 3:

subsequent conversion of (E)-4-N,N-di-(C1-3)-alkylamino crotonic acid hydrochloride salt of compound I′ into the activated derivative II




wherein R1 and R2 independently denote C1-3-alkyl groups, with a chlorinating agent selected from thionylchloride, POCl3, PCl3 or PCl5, preferably with thionylchloride, and
e) step 4:




wherein X denotes a methine group substituted by a cyano group or a nitrogen atom,

Ra denotes a 3-chloro-4-fluorophenyl group, a 3-chloro-4-(pyridin-2-yl-methoxy)-phenyl group, or a 3-chloro-4-(3-fluoro-phenylmethoxy)-phenyl group,

Rc denotes a methoxy, ethoxy or tetrahydrofuran-3-yl-oxy group, and

R1 and R2 independently denote C1-3-alkyl groups.



DETAILED DESCRIPTION OF THE INVENTION
In a first aspect this invention describes an efficient process for the manufacture of (E)-4-N,N-di-(C1-3)-alkylamino crotonic acid in HX acid addition salt form, such as the hydrochloride, hydrobromide, the methanesulfonate salt, p-toluolsulfonate salt and trifluoroacetate, preferably the hydrochloride, and as an activated derivative (E)-4-N,N-di-(C1-3)-alkylamino-2-butenoylchloride hydrochloride, using commercially available starting material in a convergent manner, providing the desired product with very high quality. Key step 1 takes advantage of a highly stereoselective olefination reaction so that a convergent synthetic strategy could be implemented and consequently secures high efficiency. Thus compound I wherein R1 and R2 independently denote C1-3-alkyl groups) could be obtained through 3 linear steps in overall more than 71% yield, starting from commercially available educts (Scheme 5):




Preferred Embodiments of the First Aspect of the Invention
In a preferred embodiment the first aspect of the invention is directed to an efficient process for the manufacture of (E)-4-N,N-di-(C1-3)-alkylamino crotonic acid in HX salt form of formula I




wherein R1 and R2 independently denote methyl or ethyl groups, preferably methyl groups, and X− denotes an acid anion, such as the chloride, bromide, tosylate, mesylate or trifluoroacetate anion, preferably the chloride anion, with high quality, comprising the following synthesis steps:

a) step 1:





wherein R1 and R2 independently denote methyl or ethyl groups, preferably methyl groups, R3 independently denote C1-3-alkyl groups, OBut denotes a tert-butyloxy group, HX denotes an acid selected from HCl, HBr, MeSO3H, p-CH3C6H4SO3H (p-toluenesulfonic acid) and CF3CO2H, preferably HCl, the base preferably denotes an alkali hydroxide selected from NaOH and KOH, preferably NaOH, and solvent denotes water, a water miscible organic solvent such as MeOH or EtOH, and the mixtures thereof, preferably pure water or a mixture of water with MeOH or EtOH,

b) step 2:





wherein R1 and R2 independently denote methyl or ethyl groups, preferably methyl groups, OBut denotes a tert-butyloxy group, HX denotes an acid selected from HCl, HBr, MeSO3H, p-CH3C6H4SO3H and CF3CO2H, preferably HCl, and solvent denotes a suitable solvent such as ethyl acetate, i-PrOAc, MTBE (methyl t-butyl ether), 2-MeTHF, MeCN, and dioxane, preferably ethyl acetate.
Preferred Embodiments of the Second Aspect of the Invention
In a preferred embodiment the second aspect of the invention is directed to the process for the manufacture of (E)-4-N,N-dialkylaminocrotonic acid in HCl salt form of formula I′ using steps 1 and 2 described under the preferred embodiment of the first aspect of the invention and additional transformation of the hydrochloride salt of formula I′ into the activated derivative (E)-4-N,N-di-(C1-3)-alkylamino-2-butenoylchloride hydrochloride II by
c) step 3:
subsequent conversion of (E)-4-N,N-dialkylamino crotonic acid hydrochloride salt of compound I′ into the activated derivative II




wherein R1 and R2 independently denote methyl or ethyl groups, preferably methyl groups, with thionylchloride as the chlorinating agent.

The reaction of step 3 may be carried out by dropwise addition of thionylchloride at 10 to −10° C., preferably at 0 to −5° C., into a solution of (E)-4-N,N-dialkylamino crotonic acid hydrochloride in a polar aprotic solvent such as N-methylpyrrolidone (NMP), acetone, N,N-Dimethylformamide (DMF), Acetonitrile or dimethyl sulfoxide (DMSO), preferably NMP.
Preferred Embodiments of the Third Aspect of the Invention
In a preferred embodiment the third aspect of the invention is directed to a process for the manufacture of an EGFR tyrosine kinase inhibitor of general formula




wherein X denotes a nitrogen atom,

Ra denotes a 3-chloro-4-fluorophenyl group,

Rc denotes a tetrahydrofuran-3-yl-oxy group, and

R1 and R2 both denote methyl groups,

comprising the following synthesis steps:

a) step 1:





wherein R1 and R2 both denote methyl groups, R3 independently denote C1-3-alkyl groups, OBut denotes a tert-butyloxy group, HX denotes an acid selected from HCl, HBr, MeSO3H, p-CH3C6H4SO3H (p-toluenesulfonic acid) and CF3CO2H, preferably HCl, the base preferably denotes an alkali hydroxide selected from NaOH and KOH, preferably NaOH, and solvent denotes water, a water miscible organic solvent such as MeOH or EtOH, and the mixtures thereof, preferably pure water or a mixture of water with MeOH or EtOH,

b) step 2:





wherein R1 and R2 both denote methyl groups, OBut denotes a tert-butyloxy group, and solvent denotes a suitable solvent such as ethyl acetate, i-PrOAc, MTBE (methyl t-butyl ether), 2-MeTHF, MeCN, and dioxane, preferably ethyl acetate,

c) step 3:

subsequent conversion of (E)-4-N,N-dimethylamino crotonic acid hydrochloride salt I′ into the activated derivative II





wherein R1 and R2 both denote methyl groups, with thionylchloride as the chlorinating agent, and

e) step 4:





wherein X denotes a nitrogen atom,

Ra denotes the 3-chloro-4-fluorophenyl group,

Rc denotes a tetrahydrofuran-3-yl-oxy group, and

R1 and R2 both denote methyl groups.

The reaction of step 3 may be carried out by dropwise addition of thionylchloride at 10 to −10° C., preferably at 0 to −5° C., into a solution of (E)-4-N,N-dialkylamino crotonic acid hydrochloride in a polar aprotic solvent such as N-methylpyrrolidone (NMP), acetone, N,N-Dimethylformamide (DMF), Acetonitrile or dimethyl sulfoxide (DMSO), preferably NMP,
The amid formation of step 4 may be carried out by dropwise addition of the (E)-4-N,N-dialkylamino crotonic acid chloride solution prepared according to step 3 into a solution of the compound of formula IV in a polar aprotic solvent such as N-methylpyrrolidone (NMP), acetone, N,N-Dimethylformamide (DMF), Acetonitrile or dimethyl sulfoxide (DMSO), preferably NMP at 10 to −10° C., preferably at 0 to −5° C.
This invention describes an efficient process for preparation of (E)-4-N,N-dialkylamino crotonic acid addition salts such as preferably the hydrochloride, which is a suitable starting compound for the preparation of activated derivatives such as (E)-4-N,N-dialkylamino crotonic acid chloride, suitable as a valuable intermediates in the synthesis of EGFR tyrosine kinase inhibitors based on a quinazoline, quinoline or pyrimidopyrimidine core structure. Specific reaction conditions and advantages of the process according to the invention are
(1) Key step 1 uses a highly stereoselective olefination reaction designed to assemble the target compound, which employs dialkylamino group functionalized starting material directly and thus avoids the possibility of the formation of 3,4-bis(dialkylamino)butanoic acid derivatives byproduct as reported in WO 2010/131921.

(2) Preferred solvent for step 1 is water, MeOH, EtOH, or a mixture thereof, the preferred solvent is Water. Step 1 can be performed preferably by adding aqueous base solution into the mixture of compounds 1 and 2 in water or, in the alternative, by adding aqueous solution of compound 1 into the mixture of compound 2 and base in water. The base employed in Step 1 may be, for example, NaOH, KOH, and LiOH, NaOH is preferred in this invention considering the lower costs. Temperature range for Step 1 is −10° C. to 30° C., preferably 0° C. to 20° C. Molar ratio of NaOH to 1 to 2 is in the range of about 3.5-10 to 1.05-1.5 to 1.0, preferably 3.5-4.0 to 1.05-1.2 to 1.0.

(3) Compound 3 with a t-butyl ester moiety is a key intermediate, which is stable under basic condition employed in Step 1 without the formation of potential byproduct 4-dialkylamino-3-hydroxybutanoic acid or derivatives thereof observed according to WO 2004/066919 and WO 2010/131921. Advantageously, compound 3 can be easily isolated by simple extraction with an organic solvent, and can be used directly in the next reaction step without further purification. Suitable organic solvents include but are not limited to MTBE (methyl t-butyl ether), 2-MeTHF, and i-PrOAc.

(4) The mild reaction condition and using organic solvent for the hydrolysis of compound 3 (Step 2) could effectively suppress the formation byproducts and simplify the work-up. The hydrolysis is performed at a temperature from −10° C. to 30° C., preferably at 5° C. to 25° C. Organic solvents could be EtOAc, MTBE, 2-MeTHF, MeCN, and dioxane, preferably EtOAc. And 2.5-10 equiv. of hydrochloric acid in organic solvent with concentration ranging from 1.0-8.0 mol/L is used.

(5) Following the synthetic route developed in this invention, last purification of the (E)-4-N,N-dialkylamino crotonic acid in HX salt form of formula I could be easily realized by simple operation like re-slurry instead of recrystallization. And it was found that a recrystallization in i-PrOH as documented in WO 2010/131921 could lead to the formation of corresponding i-propyl ester (up to 3.5 area-%, HPLC) when performed on large scale. Suitable solvents to perform re-slurry include MeCN, acetone, and MIBK, preferably MeCN.

(6) The preparation of the (E)-4-N,N-dialkylamino-2-butenoylchloride hydrochloride II of in step 3, especially of the dimethylamino crotonic acid chloride, is advantageously carried out using thionylcloride as the chlorinating agent, added dropwise with cooling at preferably at 0 to −5° C., into a solution of (E)-4-N,N-dialkylamino crotonic acid hydrochloride in a polar aprotic solvent such as N-methylpyrrolidone (NMP), acetone, N,N-Dimethylformamide (DMF), Acetonitrile or dimethyl sulfoxide (DMSO), preferably NMP. Thionylchloride is by far preferred in this step compared to other chlorinating agents which may be considered suitable for this purpose such as oxalic acid chloride, oxalic acid ethylester chloride, POCl3, PCl3 or PCl5, regarding operational safety. Furthermore, the chlorinated product can be directly used in the amid formation step 4 without intermediate purification step and allows to obtain a very pure final product of formula III (more that 99%; HPLC) only applying simple purification steps.

(7) In its most preferred embodiment the amid formation of step 4 is carried out by dropwise addition of (E)-4-N,N-dialkylamino-2-butenoylchloride hydrochloride II solution in a polar aprotic solvent such as N-methylpyrrolidone (NMP), N,N-Dimethylformamide (DMF) or Acetonitrile, preferably NMP, prepared according to step 3, into a solution of 6-amino-4-[(3-chloro-4-fluorophenyl)amino]-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline in the same a polar aprotic solvent at 10 to −10° C., preferably at 0 to −5° C. Purification is carried out by addition of water, adjusting pH >9 and extraction with an ester such as ethyl acetate or, preferably, butyl acetate. The polar aprotic solvent is removed by extraction with water and the remaining organic phase is concentrated by evaporation. After addition of small amounts of water and methylcyclohexane crystallization of the product may be induced by inoculation.

The following Examples are intended to illustrate the invention in more detail:
Example 1
Preparation of Compound 1 (R1═R2=Me)
Sodium 2-Dimethylamino-1-hydroxy-ethanesulfonate
To a 5 L jacket reactor, (Dimethylamino)acetaldehyde diethyl acetal (400 g) and Water (200 mL) is charged at room temperature. Start agitation and cool the system down to 0° C., then Conc. HCl aqueous solution (37 wt %, 480 g) is added within 1 h, followed by stirring at 40° C. for 4 h. At this point, a solution of sodium metasulphite (424 g) in water (720 mL) is added into the above system within 40 min, and keep stirring at 40° C. for 2 h. The ethanol (2 L) is added and cool the mixture to 0° C., followed by filteration and washing with ethanol to get a white cake, which is dried in vacuo at 45° C. for 6 h to give desired compound 1 in 84% yield (474 g) and >98% NMR purity.
Example 2
Preparation of Compound 2 (R3=Et)
(Diethoxy-phosphoryl)-acetic acid tert-butyl ester
Triethyl phosphite (485 g) is warmed up to 90° C. under N2 atmosphere in a three-necked round-bottomed flask, and t-butyl bromoacetate (541 g) is added dropwise into the system within 2 h. Then the mixture is kept stirring at 90° C. for around 4 h, and then cooled to room temperature. The obtained mixture is distilled under vacuo to remove compounds with low boiling point, and the residue is collected as a colorless liquid compound 5 in 97% yield (680 g) and >98% GC purity.
Example 3
Preparation of Compound 3 (R1═R2=Me)
(E)-4-Dimethylamino-but-2-enoic acid tert-butyl ester
Charge tert-Butyl diethyl phosphonoacetate (3, 252 g), sulphite adduct (2, 240 g) and water (720 mL) to a 5 L jacket reactor, and cool the mixture down to 0° C. A solution of NaOH aqueous solution (2.5 mol/L, 1.5 L) is added dropwise into the system within 1 h, and keep stirring at this temperature until process monitoring indicates less than 5 area % compound 3 remains. The mixture is extracted with MTBE (1 L×3), followed by distillation under vacuo to give compound 3 as a pale-yellow liquid in 100% yield (185 g) and 92% GC purity, which is used directly for the next step without further purification.
Example 4
Preparation of Compound I (R1═R2=Me)
(E)-4-Dimethylamino-crotonic acid hydrochloride
Synthesis Step:
Crude compound 3 (105 g) and EtOAc (80 mL) are charged to a 2 L jacket reactor and cool down to 10° C. under N2 atmosphere. To this system, hydrochloric acid solution in EtOAc (5 mol/L, 750 mL) is added dropwise at temperature in the range of 10 ̃25° C., and keep stirring at 20 ̃25° C. until process monitoring indicates less than 1 area % compound 3 remains. Cool the system down to 0° C. and perform filtration, washing with EtOAc (1 L) to get a wet cake, which is dried under vacuo at 45° C. to deliver (E)-4-N,N-dimethylamino crotonic acid hydrochloride as a white solid in 92% yield (79 g) and 97.5% HPLC purity.
Purification Step:
The (E)-4-N,N-dimethylamino crotonic acid hydrochloride obtained above (60 g) and MeCN (480 mL) are charged to a 750 mL jacket reactor. Heat the mixture up to 85° C. and keep stirring at this temperature for 1.5 h. Perform filtration after cooling the system down to room temperature, the white cake is then dried under vacuo to deliver (E)-4-N,N-dimethylamino crotonic acid hydrochloride as a white solid in 93% yield (56 g) and 99.5% HPLC purity.
Example 5
Preparation of Compound II (R1═R2=Me)
(E)-4-N,N-dialkylamino-2-butenoylchloride hydrochloride
Synthesis Step:
9.66 g of (E)-4-Dimethylamino-crotonic acid hydrochloride (0.055 Mol) in 90 ml of NMP are cooled down to 0 to −5° C. 6.6 g (0.055 Mol) of thionyl chloride are added dropwise into this solution within 5 to 10 minutes, thereafter purging with 3 ml of NMP. The reaction mixture is kept stirring for about 20 minutes at 0 to −5° C.
Purification Step:
The product solution can be used without further purification.
Example 6
Preparation of Compound III (X═N, Ra=3-chloro-4-fluorophenyl, Rc=tetrahydrofuran-3-yl-oxy, R1═R2=Me)
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline
Synthesis Step:
12.46 g of 6-amino-4-[(3-chloro-4-fluorophenyl)amino]-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline (0.033 Mol) with a water content of at max 0.15% in 60 ml of NMP are added dropwise within 15 to 30 minutes at 0 to −5° C. into the product solution prepared according to Example 5. The reaction mixture is kept stirring for about 15 minutes. Reaction control by HPLC shows a content <1% of the educt amine.
Purification Step:
100 ml of water are added dropwise under control of heat evolution at 15° C. max. About 23 g 50% NaOH solution are added at 25° C. at max to adjust to pH >9. The alcaline water phase is extracted 3 times by stirring with 400 ml of butyl acetate. Afterwards the organic phase is extracted 3 times by stirring with 100 ml of water in order to remove NMP. The organic phase is evaporated at 60° C. max and 100-300 mbar and concentrated to a volume of about 80 ml, then 12.2 ml of methylcyclohexane and 2 ml of water are added and crystallization of the product is induced by inoculation, slowly cooling down to ambient temperature. The product is filtered with suction, washed with 60 ml of methylcyclohexane and dried at reduced pressure at 40° C.
Yield: 14.1 g (87%), purity: 99.64% (HPLC).

## Claims

1. A process for the manufacture of (E)-4-N,N-di-(C1-3)-alkylamino crotonic acid in HX salt form of formula I



wherein R1 and R2 independently denote C1-3-alkyl groups and X− denotes an acid anion, comprising the following synthesis steps:
a) step 1:




wherein R1, R2 and R3 independently denote C1-3-alkyl groups, OBut denotes a tert-butyloxy group, HX denotes an acid selected from HCl, HBr, MeSO3H, p-CH3C6H4SO3H (p-toluenesulfonic acid) and CF3CO2H, the base denotes a strong base, and solvent denotes water, a water miscible organic solvent, and the mixtures thereof, and
b) step 2:




wherein R1 and R2 independently denote C1-3-alkyl groups, OBut denotes a tert-butyloxy group, HX denotes an acid, and solvent denotes a suitable solvent.

2. The process of claim 1 for the manufacture of (E)-4-N,N-dimethylamino crotonic acid in HX salt form wherein
R1 and R2 denote methyl groups,
R3 independently denote C1-3-alkyl groups,
in step 1 HX denotes HCl, the base denotes NaOH, and the solvent denotes pure water or a mixture of water with MeOH or EtOH, and
in step 2 HX denotes HCl and the solvent denotes ethyl acetate.

3. The process of claim 1, wherein HX in both steps denotes HCl, and further comprising converting (E)-4-N,N-di-(C1-3)-alkylamino crotonic acid hydrochloride salt of compound I′ according to
c) step 3:




wherein R1 and R2 independently denote C1-3-alkyl groups, with a chlorinating agent selected from thionylchloride, POCl3, PCl.

4. The process according to claim 3, wherein R1 and R2 denote methyl groups, and the chlorinating agent is thionyl chloride.

5. A process for the manufacture of formula (III)



wherein X denotes a methine group substituted by a cyano group or a nitrogen atom,
Ra denotes a 3-chloro-4-fluorophenyl group, a 3-chloro-4-(pyridin-2-yl-methoxy)-phenyl group, or a 3-chloro-4-(3-fluoro-phenylmethoxy)-phenyl group,
Rc denotes a methoxy, ethoxy or tetrahydrofuran-3-yl-oxy group, and
R1 and R2 independently denote C1-3-alkyl groups,
comprising:
a) step 1:




wherein R1, R2 and R3 independently denote C1-3-alkyl groups, OBut denotes a tert-butyloxy group, and HX denotes an acid selected from HCl, HBr, MeSO3H, p-CH3C6H4SO3H and CF3CO2H, the base denotes a strong base, and solvent denotes water, a water miscible organic solvent, and the mixtures thereof,
b) step 2:




wherein R1 and R2 independently denote C1-3-alkyl groups, OBut denotes a tert-butyloxy group, and solvent denotes selected from ethyl acetate, i-PrOAc, MTBE (methyl t-butyl ether), 2-MeTHF, MeCN, and dioxane,
c) step 3:
subsequent conversion of (E)-4-N,N-dialkylamino crotonic acid hydrochloride salt of compound I′ into the activated derivative II




wherein R1 and R2 independently denote C1-3-alkyl groups, with a chlorinating agent selected from thionylchloride, POCl3, PCl5, and
e) step 4:




wherein X denotes a methine group substituted by a cyano group or a nitrogen atom,
Ra denotes a 3-chloro-4-fluorophenyl group, a 3-chloro-4-(pyridin-2-yl-methoxy)-phenyl group, or a 3-chloro-4-(3-fluoro-phenylmethoxy)-phenyl group,
Rc denotes a methoxy, ethoxy or tetrahydrofuran-3-yl-oxy group, and
R1 and R2 independently denote C1-3-alkyl groups.

6. The process of claim 5, wherein
wherein X denotes a nitrogen atom,
Ra denotes a 3-chloro-4-fluorophenyl group,
Rc denotes a tetrahydrofuran-3-yl-oxy group, and
R1 and R2 both denote methyl groups,
comprising the following synthesis steps:
a) step 1:




wherein R1 and R2 both denote methyl groups, R3 independently denote C1-3-alkyl groups, OBut denotes a tert-butyloxy group, HX denotes HCl, the base denotes an alkali hydroxide, and solvent denotes water, a water miscible organic solvent,
b) step 2:




wherein R1 and R2 both denote methyl groups, OBut denotes a tert-butyloxy group, and solvent denotes a solvent selected from such as ethyl acetate, i-PrOAc, MTBE (methyl t-butyl ether), 2-MeTHF, MeCN, and dioxane,
c) step 3:
subsequent conversion of (E)-4-N,N-dimethylamino crotonic acid hydrochloride salt I′ into the activated derivative II




wherein R1 and R2 both denote methyl groups, with thionylchloride as the chlorinating agent,
and
e) step 4:




wherein X denotes a nitrogen atom,
Ra denotes the 3-chloro-4-fluorophenyl group,
Rc denotes a tetrahydrofuran-3-yl-oxy group, and R1 and R2 both denote methyl groups.