HK1163670A - Methods of preparing quinoline derivatives - Google Patents

Description

Quinoline derivatives and process for preparing them

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This patent application claims the benefit of united states provisional patent application No. 61/199088 filed on 13/11/2008, the contents of which are incorporated herein by reference in their entirety.

The invention relates to the field

The present patent application describes methods for preparing compounds useful for modulating protein kinase activity. In particular, the present patent application describes methods for preparing compounds useful for modulating cellular activities such as proliferation, differentiation, programmed cell death, migration, and chemical invasion.

Brief description of related Art

Advances made in the specificity of agents used to treat cancer are valuable because their therapeutic effects can be achieved if the side effects produced during the use of these agents can be reduced. Traditionally, great advances in cancer treatment have been accompanied by the discovery of therapeutic agents that act through novel mechanisms.

Protein kinases are enzymes that catalyze the phosphorylation of proteins, particularly the hydroxyl groups on tyrosine, serine, and threonine residues of proteins. The consequences of this seemingly simple activity are surprising; cell differentiation and proliferation, or, in essence, all aspects of cell life, are dependent in some way or another on protein kinase activity. In addition, abnormalities in protein kinase activity are thought to be associated with a number of conditions, ranging from non-fatal diseases such as psoriasis to extremely malignant diseases such as glioblastoma (brain cancer).

Therapeutic applications of kinase modulation may be associated with oncological indications. For example, modulation of protein kinase activity for cancer therapy, by the Food and Drug Administration (FDA) for Gleevec(Gleevec) (imatinib mesylate, manufactured by nova pharmaceuticals, eastern Hanowei, N.J.) has now been successfully validated for the treatment of Chronic Myelogenous Leukemia (CML) and gastrointestinal stromal tumors (GIST). Gleevec is a stem cell factor receptor (c-Kit) and Ab1 kinase inhibitor.

Cell proliferation and angiogenesis are two key cellular processes required for tumor growth and survival (Mat. A, drug development technology 2001, 6 th page 1005-1024), and regulation (especially inhibition) of the cell growth and angiogenesis is an attractive target for small molecule drug development. Anti-angiogenic therapy represents a potentially important approach in the treatment of solid tumors and other diseases associated with vascularization disorders such as ischemic coronary artery disease, diabetic retinopathy, psoriasis and rheumatoid arthritis. Similarly, agents against cellular malignancies are also useful for slowing or arresting tumor growth.

There is a very valuable goal in the regulation of small molecules involved in anti-angiogenic and anti-cell proliferative activities, namely the hepatocyte growth factor receptor (c-Met). The c-Met kinase is a primitive member of a subgroup of heterodimeric Receptor Tyrosine Kinases (RTKs) including methionine, RON, stearic acid, and the like. Expression of c-Met can occur in a wide range of cell types, including epithelial cells, endothelial cells, mesenchymal cells, etc., where activation of the receptor triggers cell migration, invasion, proliferation, and other biological activities associated with "invasive cell growth". In this connection, the signaling by activation of c-Met is responsible for the development of many properties of tumor cells.

The endogenous ligand for c-Met, Hepatocyte Growth Factor (HGF), a very potent inducer of angiogenesis, also known as "spreading factor" (SF). Binding of hepatocyte growth factor to c-Met induces receptor activity by way of receptor autophosphorylation, leading to increased receptor-dependent signaling, which in turn promotes cell growth and invasion. Anti-hepatocyte growth factor antibodies or antagonists to hepatocyte growth factor have been developed for use in inhibiting the in vivo migration of tumor cells (see: Mulick et al, J. Lee., 13 th Ed. 2002, pp. 41-59).

The growth of tumors requires the recruitment of new blood vessels from existing ones, as well as the invasion, adhesion, and proliferation of malignant cells. Accordingly, overexpression of c-Met has been demonstrated in a wide range of tumor types, including breast, colon, kidney, lung, squamous cell myeloid leukemia, hemangioma, melanoma, astrocytoma, and glioblastoma. In addition, activating mutations in the c-Met kinase domain have been found in hereditary and sporadic renal mastoplasia and squamous cell carcinoma (see: Mulick et al, cytokine and growth factor review, 2002, 13 th, pages 41-59; Longgardi et al, contemporary drug targets, 2001, 2 nd, pages 41-55; Bomore Ship et al, Proc. Clin. chem., 2003, pages 1-23). Therefore, the regulation of c-Met is expected to be a method for treating cancer and cancer-related diseases.

Accordingly, it is desirable to develop new methods for making compounds that are modulators of protein kinases.

Summary of The Invention

In one aspect, the present application describes a process for preparing a compound having formula i (1):

or a pharmaceutically acceptable salt thereof, wherein:

R¹、R²and the nitrogen atom to which it is attached, combine to form a 6-membered heterocycloalkyl group;

X¹is H, Br, Cl or F;

X²is H, Br, Cl or F;

s is 2 to 6;

n1 is 1-2; in addition, the first and second substrates are,

n2 is 1-2.

Intermediates useful in the preparation of the above compounds are also disclosed.

Compounds of formula i (1) are useful as modulators of protein kinases and have inhibitory effects on c-Met.

The following patent application describes many different aspects and embodiments, and the various aspects and embodiments are not limiting with respect to the scope of the patent application. The terms "aspects" and "embodiments" should be considered non-limiting regardless of where they appear in the specification. The transitional word "consisting of … …," as used herein, is intended to mean "including," "comprising," or "having … … character," is an inclusive, open-ended word, and does not exclude additional, unrecited elements.

Detailed description of the invention

Aspect (1) described in the present patent application relates to a process for preparing a compound having the formula i (1):

or a pharmaceutically acceptable salt thereof, wherein:

R¹、R²and the nitrogen atom to which it is attached, combine to form a 6-membered heterocycloalkyl group;

X¹can be H, Br, Cl or F;

X²can be H, Br, Cl or F;

s is 2 to 6;

n1 is 1-2; in addition, the first and second substrates are,

n2 is 1-2.

The method comprises the following steps:

contacting a compound having formula h (1) with a reactant z (1) to produce a compound having formula i (1):

the chemical reaction in the aspect (1) described in the present patent application can be conveniently carried out under suitable chemical reaction conditions. As regards the chemical reaction conditions referred to as suitable in the aspect (1), a non-limiting example thereof is the employment of alkaline conditions. With regard to the alkaline conditions which can be used in aspect (1) under the description of the present patent application, non-limiting examples include the use of inorganic bases, such as KOH, NaOH, K in aqueous form₂CO₃、Na₂CO₃、K₃PO₄、Na₃PO₄、K₂HPO₄、Na₂HPO₄And the use of other analogs or related mixtures thereof. Is suitable for use in aspect (1)Other non-limiting examples of chemical reaction conditions also include the use of suitable solvents. Non-limiting examples of suitable solvents that may be used in aspect (1) in the description of this patent application include water-soluble solvents such as Tetrahydrofuran (THF), acetone, alcohols, and the like or related mixtures thereof and the like. Other non-limiting examples of suitable solvents that may be used in aspect (1) under the present patent application specification also include water insoluble solvents such as methyl tert-butyl ether (MTBE), Dichloromethane (DCM), isopropyl acetate (iPAc), toluene, and the like or related mixtures thereof and the like. Other non-limiting examples of suitable chemical reaction conditions in aspect (1) also include the selection of suitable temperatures. The temperature range suitable for the chemical reaction in the aspect (1) may be about 7 ℃ to about 30 ℃, or about 10 ℃ to about 26 ℃, or about 12 ℃ to about 21 ℃. The product produced in aspect (1) is in the form of the free base, and the free base form can be converted into a pharmaceutically acceptable salt thereof by the methods described in the present process. For example, a compound of formula i (1) may be converted to its dimaleate ion salt form by the addition of maleic acid and a suitable solvent. For another example, a compound of formula i (1) may be converted to its bisphosphate salt form by the addition of phosphoric acid and a suitable solvent.

The utility of the compounds of formula I is described in detail in WO 2005/030140A 2.

Embodiment (part a) of aspect (1):

in another specific embodiment of the aspect (1), X¹Is Cl or F.

In another specific embodiment of the aspect (1), X²Is Cl or F.

In another specific embodiment of the aspect (1), X¹Is F.

In another specific embodiment of the aspect (1), X²Is F.

In another specific embodiment of the aspect (1), X¹Is H.

In another specific embodiment of the aspect (1), X²Is H.

In another specific embodiment of aspect (1), n1 is 1.

In another specific embodiment of aspect (1), n2 is 1.

In another specific embodiment of aspect (1), n1 is 2.

In another specific embodiment of aspect (1), n2 is 2.

In another specific embodiment of aspect (1), s is 2.

In another specific embodiment of aspect (1), s is 3.

In another specific embodiment of aspect (1), s is 4.

In another specific embodiment of aspect (1), s is 5.

In another specific embodiment of aspect (1), s is 6.

In another specific embodiment of the aspect (1), R¹、R²And the nitrogen atom to which it is attached together form a piperidinol ester, a piperazinyl group, or a morpholinyl group.

In another specific embodiment of the aspect (1), R¹、R²And the nitrogen atom to which it is attached is combined to form a morpholinyl group.

All compounds of aspect (1) disclosed hereinabove having formula i (1), including any of those disclosed in part A as suitable for each X¹、X²Alternative embodiments of n1, n2 or s are suitable for each X with any of the other embodiments disclosed in part A¹、X²Alternative specific implementations of n1, n2, or sForms of such combinations, and pharmaceutically acceptable salts formed by any such combination.

Embodiment (part B) of aspect (1):

in another specific embodiment of the aspect (1), both n1 and n2 are 1.

In another specific embodiment of the aspect (1), n1 and n2 are both 2.

In another specific embodiment of aspect (1), n1 is 1; n2 is 2.

In another specific embodiment of aspect (1), n1 is 2; n2 is 1.

In another specific embodiment of the aspect (1), X¹Is H; x²Is F.

In another specific embodiment of the aspect (1), X¹Is F; x²Is H.

In another specific embodiment of the aspect (1), X¹And X²Are all H.

In another specific embodiment of the aspect (1), X¹And X²Are all F.

In another specific embodiment of the aspect (1), X¹Is Cl; x²Is H.

In another specific embodiment of the aspect (1), X¹Is H; x²Is Cl.

In another specific embodiment of the aspect (1), X¹And X²Are all Cl.

In another specific embodiment of the aspect (1), X¹Is Cl; x²Is F.

In another specific embodiment of the aspect (1), X¹Is F; x²Is Cl.

In another specific embodiment of aspect (1), s is 3; r¹、R²And the nitrogen atom to which it is attached is combined to form a morpholinyl group.

In embodiment (C) of aspect (1), the compound of formula h (1) may be formed by reduction of a compound of formula g (1):

each R in the same¹、R²、X²The meanings of S and n2 are the same as the corresponding definitions made for any embodiment in aspect (1) or aspect (1) (part a) in the description of the present patent application.

The chemical reaction in the embodiment (C) of the aspect (1) described in the present patent application can be conveniently carried out under suitable chemical reaction conditions. As regards the suitable chemical reaction conditions in the embodiment (C) of aspect (1), a non-limiting example thereof is the reduction of a compound of formula g (1) to a compound of formula h (1) with the addition of a certain catalyst. Non-limiting examples of the above-mentioned catalyst that can be used in embodiment (C) of aspect (1) include platinum group metals and the like. Non-limiting examples of platinum group metal catalysts include palladium, platinum, rhodium, ruthenium, and the like. The reduction of the compounds of formula g (1) can also be non-catalytic, for example using dithionite, ferrite or stannic acid. In another specific embodiment of the specific embodiment (C) of the aspect (1), the chemical reaction is carried out by adding palladium-containing carbon (Pd/C); in another specific embodiment of the specific embodiment (C) of the aspect (1), the chemical reaction is carried out by adding about 5% to about 20% of palladium-containing carbon; in another specific embodiment of the specific embodiment (C) of the aspect (1), the chemical reaction is carried out by adding a wine containing about 7% to about 15% of palladium-containing carbonThe method is carried out in a precise mode; in another specific embodiment of the specific embodiment (C) of the aspect (1), the chemical reaction is carried out by adding an alcohol containing about 10% palladium-containing carbon (Pd/C); in another specific embodiment of the specific embodiment (C) of the aspect (1), the chemical reaction using the aforementioned catalyst is carried out with the addition of a hydrogen transfer agent to produce transfer hydrogenation, where the hydrogen transfer agent includes any hydrogen transfer agent described in the related art that can be recognized by a skilled artisan as being suitable for the chemical reaction; in another specific embodiment of the specific embodiment (C) of the aspect (1), the reduction is a transfer hydrogenation chemical reaction performed after adding formic acid and an aqueous solution of a certain formate salt such as ammonium formate, alkyl ammonium formate or potassium formate. Other non-limiting examples of suitable chemical reaction conditions that may be used in embodiment (C) of aspect (1) also include the selection of suitable solvents in which the chemical reaction is carried out. Non-limiting examples of suitable solvents that may be used in embodiment (C) of aspect (1) include tetrahydrofuran, acetic acid (AcOH), ethanol (EtOH), ethyl acetate, and the like or related mixtures thereof. Other non-limiting examples of suitable chemical reaction conditions that may be used in embodiment (C) of aspect (1) also include the use of hydrogen gas at a suitable pressure that may be used for the chemical reaction. Suitable pressures that may be used in embodiment (C) of aspect (1) include pressure values ranging from about 10 psi to about 50 psi. Other non-limiting examples of suitable chemical reaction conditions that may be used in embodiment (C) of aspect (1) also include the selection of suitable temperatures that may be used for the chemical reaction. The temperature range suitable for the chemical reaction in embodiment (C) of aspect (1) includes the temperature that will be generally selected for the chemical reaction by a person skilled in the art of the process. In another particular embodiment of embodiment (C) of aspect (1), the reduction chemistry may be carried out using about 10% palladium on carbon added to a mixture comprising concentrated hydrochloric acid, ethanol pressurized with about 40 psig hydrogen, and water. The temperature of the chemical reaction may be approximately equal to the ambient temperature. Can be usedAny catalyst can be removed immediately after the reduction chemistry is completed, if desired, by using celiteThe filter bed is used for filtering and sorting the chemical reaction mixture. Alternatively, the chemical reaction mixture may be purified, for example, by adding an alkaline solution such as potassium carbonate, until the pH of the solution reaches a range of about 9 to about 11. The resulting suspension may then be stirred and filtered under standard conditions to collect the resulting solid.

In embodiment (D) of aspect (1), the compound of formula g (1) may be formed by chemically reacting a compound of formula f (1) with reactant y (1):

here, LG represents a leaving group, each R¹、R²、X²S and n2 are as defined in any of the embodiments of aspect (1) or aspect (1) (part A) in the description of the present application. One non-limiting example of a leaving group is a halo group (e.g., Cl, Br, F, or the like). Various compounds of the reagent y (1) are commercially available, such as 2-fluoro-4-nitrophenol and the like. In addition, the reactant y (1) can be modified by modifying the reactant y (1) by using commercially available starting materials and preparing the starting materials by a conventional process to produce various compounds falling within the range of the reactant y (1).

The chemical reaction in the embodiment (D) of the aspect (1) described in the present patent application can be conveniently carried out under suitable chemical reaction conditions. As regards the chemical reaction conditions suitable in the embodiment (D) of the aspect (1), one of its non-limiting examples is the use of basic conditions, such as, for example, the use of 2, 6-lutidine (2, 6-lutidine). Other non-limiting examples of suitable chemical reaction conditions that may be used in embodiment (D) of aspect (1) also include the selection of suitable chemical reaction temperatures after addition of the organic base, which generally ranges from about 120 ℃ to about 180 ℃. In another embodiment, the chemical reaction temperature may range from about 130 ℃ to about 160 ℃; in another embodiment, the chemical reaction temperature may range from about 140 ℃ to about 150 ℃. Once the chemical reaction is complete, a base such as potassium carbonate may be added to the chemical reaction mixture to precipitate a solid, which may be collected by filtration under standard conditions.

In certain other alternative embodiments of aspects (1) and (D), the compound of formula h (1) may be produced by chemically reacting a compound of formula f (1) with a reactant u; where each R is¹、R²、X²S and n2 are as defined in any of the embodiments of aspect (1) or aspect (1) (part A) in the description of the present application.

Here, LG represents a leaving group. One non-limiting example of a leaving group is a halo group (e.g., Cl, Br, F, or the like). The optional steps of embodiments (C) and (D) in aspect 1 above may be conveniently carried out under suitable chemical reaction conditions. Regarding suitable chemical reaction conditions in the optional steps of aspects (1) to embody forms (C) and (D), non-limiting examples thereof are selection of suitable solvents. With regard to suitable solvents for use in the alternative steps of embodiments (C) and (D) in aspect 1, non-limiting examples thereof include polar solvents such as Dimethylacetamide (DMA), Dimethylsulfoxide (DMSO), Dimethylformamide (DMF), ethyl acetate, N-methylpyrrolidone (NMP), propylene carbonate and the like or related mixtures thereof and the like. Other non-limiting examples of suitable chemical reaction conditions in the optional steps of aspects (1) and (C) include the selection of suitable bases, such as non-nucleophilic bases and the like. Non-limiting examples of useful non-nucleophilic bases include lithium diisopropylamine, lithium tetramethylpiperidine, alkali metal alkoxides such as sodium tert-butoxide and potassium tert-butoxide, and the like or related mixtures. Other non-limiting examples of suitable chemical reaction conditions also include chemical reaction temperatures in the range of about 75 to about 120 deg.C, or about 85 to about 110 deg.C, or 95 to about 100 deg.C. The temperature of the chemical reaction can then be lowered to below 50 ℃ for the additional addition of alkali and reactant u, and then the temperature of the chemical reaction can be raised again to the suitable chemical reaction temperature described above, so that additional product can be obtained by flooding and leaching the educts.

In embodiment (E) of aspect (1), the compound of formula f (1) may be produced by a process of converting a compound of formula E (1) to a compound of formula f (1):

here, LG represents a leaving group; each of s and R¹And R²The meaning of (A) is the same as the corresponding definition made for any specific implementation form of the aspect (1) or the aspect (1) (part A) in the specification of the patent application. One non-limiting example of a leaving group suitable for use in embodiment (E) of aspect (1) is a halo group (e.g., Cl, Br, or F, etc.) that can be added by a halogenating agent. Non-limiting examples of the halogenating agent suitable for use in embodiment (E) of aspect (1) include₂、SO₂Cl₂、COCl₂、PCl₅、POCl₃And the like.

The chemical reaction in the embodiment (E) of the aspect (1) described in the present patent application can be conveniently carried out under suitable chemical reaction conditions. The chemical reaction conditions suitable in embodiment (E) of aspect (1) are, as a non-limiting example, the selection of a suitable solvent. With respect to suitable solvents that may be used in embodiment (E) of aspect (1) during halogenation of the compound of formula E (1), non-limiting examples include polar, aprotic solvents such as Acrylonitrile (ACN), dimethylformamide, the like or related mixtures thereof, and the like. In certain other embodiments, the polymer can be prepared by using a composition containing POCl₃Acetonitrile of (4) and (2) containing COCl₂Of dimethylformamide or containing SOCl₂The chlorinating agent is conveniently added at a temperature ranging from about 35 ℃ to about 75 ℃; in other certain embodiments, the addition of the chlorinating agent may be conveniently carried out at a temperature ranging from about 45 ℃ to about 65 ℃; in certain other embodiments, the addition of the chlorinating agent may be conveniently carried out at a temperature ranging from about 50 ℃ to about 60 ℃. After the chlorination chemical reaction is complete, the mixture may be heated to reflux until the chemical reaction is complete. The mixture of chemical reactions may be filtered to remove solids; the product in the filtrate can be extracted using standard techniques.

In embodiment (F) of aspect (1), the compound of formula e (1) may be prepared by a method of converting a compound of formula d (1) into a compound of formula e (1) using an alkyl formic acid, such as methyl formate, ethyl formate, n-propyl formate, i-propyl formate, or the like:

here, each of s and R¹And R²The meaning of (1) is identical to that of this patent applicationThe corresponding definitions made for aspect (1) or any specific implementation form of aspect (1) (part a) in the specification are hereby made.

The chemical reaction in the embodiment (F) of the aspect (1) described in the present patent application can be conveniently carried out under suitable chemical reaction conditions. The chemical reaction conditions suitable in embodiment (F) of aspect (1) are, by way of non-limiting example, the selection of a suitable base. With respect to suitable bases which may be used in embodiment (F) of aspect (1), non-limiting examples thereof include strong bases such as sodium alkoxides (e.g., sodium ethoxide). Other non-limiting examples of suitable chemical reaction conditions in embodiment (F) of aspect (1) also include the selection of suitable solvents. With respect to suitable solvents that may be used in embodiment (F) of aspect (1), non-limiting examples thereof include alcohols that are combined with esters, such as ethyl formate, and the like or related mixtures thereof. Other non-limiting examples of suitable chemical reaction conditions in embodiment (F) of aspect (1) also include the selection of suitable temperatures. The chemical reaction may be conveniently carried out at a suitable temperature ranging from about 30 ℃ to about 60 ℃. In certain other embodiments, the chemical reaction may be carried out at a temperature ranging from about 40 ℃ to about 50 ℃. In certain other embodiments, the chemical reaction may be carried out at a temperature of about 44 ℃. After the chemical reaction is complete, the product may be precipitated by the addition of any solvent that will precipitate the product, such as methyl tert-butyl ether (MTBE). The production may be collected by filtration and optionally purified by standard techniques.

In embodiment (G) of aspect (1), the compound of formula d (1) may be produced by a process of reducing a compound of formula c (1):

here, each of s and R¹And R²The meaning of (A) is the same as the corresponding definition made for any specific implementation form of the aspect (1) or the aspect (1) (part A) in the specification of the patent application.

The chemical reaction in the embodiment (G) of the aspect (1) described in the present patent application can be conveniently carried out under suitable chemical reaction conditions. Non-limiting examples of suitable chemical reaction conditions in embodiment (G) of aspect (1) include reduction of a compound of formula c (1) to a compound of formula d (1) with the addition of a catalyst. Non-limiting examples of the above-mentioned catalyst that can be used in embodiment (G) of aspect (1) include platinum group metals and the like. Non-limiting examples of catalysts belonging to the platinum group metals include palladium, platinum, rhodium, ruthenium, and the like. The reduction of the compounds of formula c (1) can also be non-catalytic, for example using dithionite, ferrite or stannic acid. In another specific embodiment of the specific embodiment (G) of the aspect (1), the chemical reaction is carried out by adding palladium-containing carbon (Pd/C). In another specific embodiment of the specific embodiment (G) of the aspect (1), the chemical reaction is carried out by adding about 5% to about 20% palladium-containing carbon (Pd/C); in another specific embodiment of the specific embodiment (G) of the aspect (1), the chemical reaction is carried out by adding an alcohol containing about 7% to about 15% palladium-containing carbon (Pd/C); in another specific embodiment of the embodiment (G) of the aspect (1), the chemical reaction is carried out by adding an alcohol containing about 10% palladium-containing carbon (Pd/C); in another embodiment of embodiment (G) of aspect (1), the reduction reaction is carried out with the addition of a hydrogen transfer reagent to produce transfer hydrogenation, where the hydrogen transfer reagent comprises any hydrogen transfer reagent described in the relevant art that would be recognized by the skilled artisan as suitable for the chemical reaction; in another specific embodiment of the embodiment (G) of the aspect (1), the reduction is a transfer hydrogenation chemical reaction performed after adding formic acid, an aqueous solution of potassium formate. Other non-limiting examples of suitable chemical reaction conditions that may be used in embodiment (G) of aspect (1) also include the selection of suitable solvents in which the chemical reaction is carried out. Non-limiting examples of suitable solvents that may be used in embodiment (G) of aspect (1) include Tetrahydrofuran (THF), acetic acid (AcOH), ethanol (EtOH), ethyl acetate (EtOAc), isopropyl alcohol (IPA), and analogs or related mixtures thereof. Other non-limiting examples of suitable chemical reaction conditions that may be used in embodiment (G) of aspect (1) also include the selection of suitable pressures that may be used for the chemical reaction. Suitable pressures that may be used in embodiment (G) of aspect (1) include pressure values ranging from about 10 psi to about 50 psi.

In another embodiment of embodiment (G) of aspect (1), the reduction reaction is carried out with the addition of a hydrogen transfer reagent to produce transfer hydrogenation, where the hydrogen transfer reagent comprises any hydrogen transfer reagent described in the relevant art that would be recognized by the skilled artisan as suitable for the chemical reaction; in another specific embodiment of the embodiment (G) of the aspect (1), the reduction is a transfer hydrogenation chemical reaction performed after adding formic acid and an aqueous solution of a certain formate salt such as potassium formate, ammonium formate or alkyl ammonium formate. Other non-limiting examples of suitable chemical reaction conditions that may be used in embodiment (G) of aspect (1) also include the selection of suitable temperatures that may be used for the chemical reaction. The temperature range suitable for the chemical reaction in embodiment (G) of aspect (1) includes the temperature that will be generally selected for the chemical reaction by a person skilled in the art of the process. In another particular embodiment of embodiment (G) of aspect (1), the reduction chemistry may be carried out using about 10% palladium on carbon added to a mixture comprising concentrated hydrochloric acid, ethanol pressurized with about 40 psig hydrogen, and water. The temperature of the chemical reaction may be approximately equal to the ambient temperature. After the chemical reaction is completed, the catalyst can be removed, and the compound can be extracted by using the existing process.

In embodiment (H) of aspect (1), the compound of formula c (1) may be prepared by reacting compounds of formulae b (1) andthe compound of (1) is produced by a method of reducing:

xb here is Br or Cl; each of s, R1 and R²The meaning of (A) is the same as the corresponding definition made for any specific implementation form of the aspect (1) or the aspect (1) (part A) in the specification of the patent application.

The chemical reaction in the embodiment (H) of the aspect (1) described in the present patent application can be conveniently carried out under suitable chemical reaction conditions. Non-limiting examples of suitable chemical reaction conditions in embodiment (H) of aspect (1) include the selection of a phase transfer catalyst that facilitates the chemical reaction to occur. Non-limiting examples of the phase transfer catalyst which can be used in embodiment (H) of aspect (1) include methyltributylammonium chloride, methyltriethylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium chloride hydrate, tetrabutylammonium bromide (Bu)₄NBr), tetrabutylammonium hydrogen sulfate, tetrabutylammonium hydroxide, tetraethylammonium bromide, tetramethylammonium hydroxide, and the like. In another specific embodiment, the phase transfer catalyst used in embodiment (H) of aspect (1) is tetrabutylammonium bromide (Bu)₄NBr). Other non-limiting examples of suitable chemical reaction conditions in embodiment (H) of aspect (1) also include the selection of alkaline conditions for the chemical reaction to be carried out therein. Non-limiting examples of the base which can be used in embodiment (H) of aspect (1) include Cs₂CO₃、K₂CO₃、Na₂CO₃And analogs or related mixtures thereof. In another specific embodiment, forThe base of the embodiment (H) of the aspect (1) is K₂CO₃. Other non-limiting examples of suitable chemical reaction conditions in embodiment (H) of aspect (1) also include the selection of suitable solvents to facilitate the chemical reaction. Non-limiting examples of solvents that can be used in embodiment (H) of aspect (1) include Dimethoxymethane (DME), tetrahydrofuran, toluene, dichloromethane, and the like or related mixtures thereof. In another specific embodiment, the solvent used in embodiment (H) of aspect (1) is toluene. In another specific embodiment of the embodiment (H) of the aspect (1), the phase transfer catalyst is tetrabutylammonium bromide (Bu)₄NBr), toluene as solvent and K as base₂CO₃(Potassium carbonate). The product can be extracted by the existing extraction process in the process.

In embodiment form (I) of aspect (1), the compound of formula b (1) may be prepared by reacting a compound of formula a (1) with HNO₃The compound of (1) is produced by a method of reducing:

xb here is Br or Cl; each of s and R¹And R²The meaning of (A) is the same as the corresponding definition made for any specific implementation form of the aspect (1) or the aspect (1) (part A) in the specification of the patent application.

The chemical reaction in the embodiment (I) of the aspect (1) described in the present patent application can be conveniently carried out under suitable chemical reaction conditions. Non-limiting examples of suitable chemical reaction conditions in embodiment (I) of aspect (1) include those that will have formula a (1) with HNO₃And a compound of the same formula as H₂SO₄To carry out a chemical reaction. Other non-limiting examples of suitable chemical reaction conditions that may be used in relation to embodiment (I) of aspect (1) also include those at temperatures in the range of about 0 ℃ to about 15 ℃Alternatively, the chemical reaction may be carried out at a temperature in the range of about 3 ℃ to about 10 ℃ or in the range of about 5 ℃ to about 10 ℃. The product b (1) can be extracted by techniques known in the art, such as extraction with dichloromethane, water and some aqueous solution of potassium bicarbonate.

In the embodiment (J) of the aspect (1) described in the present patent application, the reactant z (1) can be produced by chemically reacting the reactant z (1a) with a chlorinating agent:

x herein¹Br or Cl; n1 is 1-2. The compounds of the reagent z (1a) can be prepared according to the method described in "example 25" of WO 2005/030140A 2. the skilled worker can also carry out any necessary substitution operations using commercially available starting materials in order to be able to prepare a variety of related compounds falling within the scope of the reagent z (1 a). "example 25" in WO 2005/030140A2 is incorporated herein by reference.

The chemical reaction in the embodiment (J) of the aspect (1) described in the present patent application can be conveniently carried out under suitable chemical reaction conditions. Non-limiting examples of suitable chemical reaction conditions in embodiment (J) of aspect (1) include for example POCl₃The use of chlorinating agents such as oxalyl chloride and the like. In another specific embodiment of the embodiment (J) of the aspect (1), the chlorinating agent used is oxalyl chloride. Other non-limiting examples of suitable chemical reaction conditions in embodiment (J) of aspect (1) also include conducting the chemical reaction at a temperature in the range of about 0 ℃ to about 15 ℃, or in the range of about 3 ℃ to about 10 ℃, or in the range of about 5 ℃ to about 10 ℃. Other non-limiting examples of suitable chemical reaction conditions in embodiment (J) of aspect (1) further include the selection of suitable solvents for carrying out the chemical reaction. About tools applicable to aspect (1)Suitable solvents in embodiment (J) include, by way of non-limiting example, polar aprotic solvents such as halogenated hydrocarbons, i.e., dichloromethane or chloroform; or ethers, i.e. Et₂O, dioxane, Tetrahydrofuran (THF) with Dimethylformamide (DMF) as a catalyst, and the like or related mixtures. The resulting solvent containing the reactant z (1) can be used without further processing for the production of the compound of formula i (1) described in aspect (1) of the present patent application.

In another particular embodiment of aspect (1) of the present patent application, the compound of formula i (1) is a compound of formula i (2):

or a pharmaceutically acceptable salt thereof, wherein:

X¹is H, Cl, Br or F; in addition, the first and second substrates are,

X²is H, Cl, Br or F. As mentioned above, for compounds of formula i (1), the compounds of formula i (2) may be in the form of the free base or may be converted into a pharmaceutically acceptable salt thereof. Accordingly, a compound of formula i (2) may be converted to its dimaleate form by the addition of maleic acid and a suitable solvent; the compound of formula i (2) may also be converted into its diphosphate form by the addition of phosphoric acid and a suitable solvent.

In another particular embodiment of aspect (1) of the present patent application, the compound is a compound having formula i (2), wherein X¹Is F; x²Is F.

In another embodiment of embodiment (I) of aspect (1) of the present patent application, the compound of formula a (1) is a compound of formula a (2):

wherein Xb is Br or Cl; in addition, the method can be used for producing a composite material

The compound of formula b (1) is a compound of formula b (2):

wherein Xb is Br or Cl.

In another embodiment of embodiment (H) of aspect (1) of the present patent application, the compound of formula b (1) is a compound of formula b (2):

wherein Xb is Br or Cl;

the compound of formula c (1) is a compound of formula c (2):

wherein Xb is Br or Cl; in addition, the method can be used for producing a composite material

Is morpholine.

In another embodiment of embodiment (G) of aspect (1) of the present patent application, the compound of formula c (1) is a compound of formula c (2):

and the compound of formula d (1) is a compound of formula d (2):

in another embodiment of embodiment (F) of aspect (1) of the present patent application, the compound of formula d (1) is a compound of formula d (2):

and, the compound having the formula e (1) is a compound having the formula e (2):

in another embodiment of embodiment (E) of aspect (1) of the present patent application, the compound of formula E (1) is a compound of formula E (2):

and the compound of formula f (1) is a compound of formula f (2):

in another embodiment of embodiment (D) of aspect (1) of the present patent application, the compound of formula f (1) is a compound of formula f (2):

reactant y (1) is reactant (y) (2):

wherein X²Is chlorine or fluorine; in addition, the method can be used for producing a composite material

A compound having the formula g (1) is a compound having the formula g (2):

in another embodiment of embodiment (C) of aspect (1) of the present patent application, the compound of formula g (1) is a compound of formula g (2):

wherein X²Is chlorine or fluorine; in addition, the method can be used for producing a composite material

The compound of formula h (1) is a compound of formula h (2):

in another certain alternative embodiment of embodiments (C) and (D) of aspect 1, the compound having formula f (1) is a compound having formula f (3):

the compound of formula h (1) is a compound of formula h (3):

and reactant u is reactant u 2:

in another specific embodiment of aspect (1) of the present patent application, the compound of formula h (1) is a compound of formula h (2).

Wherein X²Is F;

reactant z (1) is reactant (z) (2):

wherein X¹Is F; in addition, the method can be used for producing a composite material

The compound of formula i (1) is a compound of formula i (2):

in another specific embodiment of aspect (1) of the present patent application, the compound having formulae h (2), i (2), and each X in reactant z (2)¹And X²Are both Cl or F. In another specific embodiment of aspect (1) of the present patent application, the compound having formulae h (2), i (2), and each X in reactant z (2)¹And X2 are both F.

Aspect (2) of the present patent application relates to a process for preparing a compound having the formula b (2):

or a pharmaceutically acceptable salt thereof; the method comprises the following specific contents:

subjecting a compound having the formula:

wherein HNO should be added₃And a suitable solvent to produce a compound having the formula b (2):

wherein Xa is Cl or Br; xb is Cl or Br. The compound of formula b (2) may be in its free base form. Any of the chemical reaction conditions described in embodiment (I) of aspect (1) can be selected as the chemical reaction conditions in the present aspect.

Aspect (3) of the present patent application relates to a process for preparing a compound having the formula c (1):

or a pharmaceutically acceptable salt thereof; the method specifically comprises the following steps:

adding a compound of formula b (2) under basic conditions to a phase transfer catalyst (e.g., tetrabutylammonium bromide (Bu)₄NBr)) and a suitable solvent, to form a compound having the formula c (2):

the compounds of formula c (2) may be in their free base form or may be converted into their pharmaceutically acceptable salts. Any of the chemical reaction conditions described in embodiment (H) of aspect (1) can be selected as the chemical reaction conditions in the present aspect.

Aspect (4) of the present patent application relates to a process for preparing a compound having the formula d (2):

or a pharmaceutically acceptable salt thereof; the method specifically comprises the following steps:

subjecting a compound of formula c (2) to a hydrogenation reaction with the addition of a catalyst to produce a compound of formula d (2):

the compounds of formula d (2) may be in their free base form or may be converted into their pharmaceutically acceptable salts. Any of the chemical reaction conditions described in embodiment (G) of aspect (1) can be selected as the chemical reaction conditions in the present aspect.

Aspect (5) of the present patent application relates to a process for preparing a compound having the formula e (2):

or a pharmaceutically acceptable salt thereof, by converting a compound of formula d (2) to a compound of formula e (2) with the addition of sodium ethoxide and an alkyl formic acid such as ethyl formate, using a suitable solvent.

The compounds of formula e (2) may be in their free base form or may be converted into their pharmaceutically acceptable salts. Any of the chemical reaction conditions described in embodiment (F) of aspect (1) can be selected as the chemical reaction conditions in the present aspect.

Aspect (6) of the present patent application relates to a process for preparing a compound of formula f (2):

or a pharmaceutically acceptable salt thereof, by converting a compound of formula e (2) to a compound of formula f (2) with the addition of a chlorinating agent and the use of a suitable solvent.

The compounds of formula f (2) may be in their free base form or may be converted into their pharmaceutically acceptable salts. Any of the chemical reaction conditions described in embodiment (E) of aspect (1) can be selected as the chemical reaction conditions in the present aspect.

Aspect (7) of the present patent application relates to a process for preparing a compound having the formula g (2):

or a pharmaceutically acceptable salt thereof, by chemically reacting a compound of formula f (2) with a reagent y (2) in a suitable solvent (2, 6-lutidine, a sterically hindered organic weak base) under basic conditions to form a compound of formula g (2):

here X²Is H, Br, Cl or F. Compounds of formula g (2) may be converted into related salts of pharmaceutical value. Any of the chemical reaction conditions described in embodiment (D) of aspect (1) can be selected as the chemical reaction conditions in the present aspect.

Aspect (8) of the present patent application relates to a process for preparing a compound having the formula h (2):

or a pharmaceutically acceptable salt thereof, by hydrogenation of a compound of formula g (2) with a catalyst in a suitable solvent to form a compound corresponding to formula h (2):

here X²Is H, Br, Cl or F. The compounds of formula h (2) may be in their free base form or may be converted into their pharmaceutically relevant salts. Any of the chemical reaction conditions described in embodiment (C) of aspect (1) can be selected as the chemical reaction conditions in the present aspect.

Aspect (9) of the present patent document relates to a process for the preparation of a compound of formula h (3) by chemically reacting a compound of formula f (3) with a reactant u 2.

Any of the chemical reaction conditions described in the optional embodiments of the aspects (1), (C) and (D) can be selected as the chemical reaction conditions in the present aspect.

Definition of

The following words and phrases used in this specification shall generally have the meanings as set forth below, except to the extent that the context dictates otherwise, or the terms and phrases are expressly defined to have different meanings.

The word "may" is used in its non-limiting sense, having a completely opposite sense to the word "must". Thus, for example, in various aspects of the invention, a particular element described as "capable of" has a particular property is intended to convey the meaning that the subject element is permitted, but not required, to have that property in accordance with the teachings of the invention.

If a certain group "R" is described as "suspended" on a ring system, that substituent "R" may, unless otherwise defined, reside on any atom in that ring system, provided that the resulting structure is stable, then a described, implied or otherwise defined hydrogen atom may be replaced by an atom in the ring.

If the number of "suspending" groups mentioned above is more than one, as is the case in the formulae: if two groups are present, i.e., there is an "R" and a chemical bond indicating its connectivity to the parent structure, then each "pendent" group may, unless otherwise defined, reside on any atom of the ring system, and it is likewise contemplated herein that each atom may be substituted for a hydrogen atom on the ring as described, implied or explicitly defined.

Pharmaceutically acceptable salts include acid addition salts.

"pharmaceutically-valuable acid addition salts" refers to salts which retain the biological potency of the free base but which are free of undesirable biological or other components, including inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, and the like or related mixtures thereof, and organic acids such as acetic, trifluoroacetic, propionic, glycolic, pyruvic, oxalic, maleic, malonic, succinic, fumaric, tartaric, citric, benzoic, cinnamic, phenylglycolic, methanesulfonic, ethanesulfonic, p-toluenesulfonic, salicylic, and the like or related mixtures thereof.

The following examples further illustrate the present patent application and are not to be construed as limiting the scope or spirit of the present patent application to the particular procedures described therein.

Unless otherwise specified, each starting material and each intermediate is available from a variety of commercial sources and can be prepared from commercially available organic compounds or using a variety of well-known synthetic methods.

Experimental procedure

The present invention has been further illustrated by the examples in figure 1 and their associated descriptions, but should not be construed as limited to the particular flow set forth herein to limit the scope or spirit of the invention. One skilled in the art of this process will recognize that the starting materials may be of different types, as shown in the following examples, and that additional steps may be required to make the compounds encompassed by the present invention. One skilled in the art of the process will also recognize that it may be necessary to use different solvents or reactants to be able to perform some of the above conversions.

All reactants and solvents, unless otherwise specified, should be of standard commercial grade and used without further purification. Suitable atmospheric environments for carrying out the reaction therein, such as air, nitrogen, hydrogen, argon and the like, will be readily apparent to those skilled in the art of carrying out the process.

FIG. 1 is a schematic representation of

Xb in the above-mentioned scheme 1 is Br or Cl. As to the names of the intermediates mentioned in the description related to scheme 1 below, Xb means halogen, and the halogen group of the related intermediate means either Br or Cl. This definition of halogen shall only apply to the intermediates described in the relevant description of scheme 1 below, and does not alter the relevant definitions made in the definitions section herein.

1- [5 methoxy-4 (3-halopropoxy) -2-nitro-phenyl]Preparation of ethanones

Water (70 l) was taken up in a solution of 1- [4- (3-halopropoxy) -3-methoxyphenyl ] ethanone (both brominated and chlorinated compounds are commercially available). The solution was cooled to about 4 ℃. Concentrated sulfuric acid (129.5 kg) was added at a rate such that the batch reached a temperature not exceeding about 18 ℃. The resulting solution was cooled to about 5 c and 70% nitric acid (75.8 kg) was added at a rate such that the batch did not reach a temperature above about 10 c. Methylene chloride, water and ice were added to a separate reactor. The aforementioned acidic reaction mixture is then added to the mixture. The dichloromethane layer was separated and the aqueous layer was back-extracted with dichloromethane. The dichloromethane layer was washed with aqueous potassium bicarbonate solution and concentrated using vacuum distillation. 1-butanol was added and the mixture was again concentrated by vacuum distillation. The resultant solution was stirred at about 20 ℃ while the resultant was crystallized. The solid was collected by filtration and washed with 1-butanol, and the resulting compound, the title compound, was isolated as a wet cake of solvent which was used directly in the next step.

¹Nuclear magnetic resonance hydrogen spectroscopy (400MHz, dimethylated inkstone-d 6); δ. 7.69(s, 1H), 7.24(s, 1H); 4.23(m, 2H), 3.94(s, 3H), 3.78(t) -3.65(t) (2H), 2.51(s, 3H), 2.30-2.08(m, 2H) liquid chromatography/Mass Spectrometry [ M (Cl) + H]⁺Calculated 288.1, experimental 288.0; [ M (Br) + H]⁺Calculated values 332.0, 334.0, experimental values 331.9, 334.0.

1- [ 5-methoxy-4- (3-morpholin-4-yl-propoxy) -2-nitro-phenyl]Preparation of ethanones

The wet cake of solvent isolated in the previous step was dissolved in toluene. A solution of sodium iodide (67.9 kg) and potassium carbonate (83.4 kg) was added to the solution, followed by tetrabutylammonium bromide (9.92 kg) and morpholine (83.4 kg). The resulting 2-phase mixture is heated for about 9 hours to about 85 ℃. The mixture was then cooled to room temperature. The organic layer thereof is removed. The aqueous layer was back-extracted with toluene. The toluene layer was washed with saturated water twice and water twice in this order. The resulting solution of the title compound is used in the next step without further processing.

¹Nuclear magnetic resonance hydrogen spectrum (400MHz, dimethylated inkstone-d 6): δ. 7.64(s, 1H), 7.22(s, 1H), 4.15(t, 2H), 3.93(s, 3H), 3.57(t, 4H), 2.52(s, 3H), 2.44-2.30(m, 6H), 1.90(quin, 2H); liquid chromatography/Mass Spectrometry [ M + H]⁺Calculated 339.2 and experimental 339.2.

1- [ 2-amino-5-methoxy-4- (3-morpholin-4-yl-propoxy) -phenyl]Preparation of ethanones

The solution obtained from the previous step was concentrated under reduced pressure to an amount of about half of the original amount. Ethanol and 10% palladium on carbon (50% hydrophilic, 5.02 kg) were added; the resulting suspension was heated to about 48 ℃ and an aqueous solution of formic acid (22.0 kg) and potassium formate (37.0 kg) was added. After the addition was complete and the chemical reaction was confirmed by Thin Layer Chromatography (TLC), water was added to dissolve the byproduct salt. The mixture was filtered to remove insoluble catalyst. The filtrate was concentrated under reduced pressure, and toluene was further added. After addition of aqueous potassium carbonate, the mixture will be basic (pH about 10). The toluene layer was separated and the aqueous layer was back-extracted with toluene. The combined toluene phases were dried over anhydrous sodium sulfate. The drying agent is removed by filtration and the resulting solution is used in the next step without further processing.

¹Nuclear magnetic resonance hydrogen spectrum (400MHz, dimethylated inkstone-d 6): δ. 7.11(s, 1H), 7.01(br s, 2H), 6.31(s, 1H), 3.97(t, 2H), 3.69(s, 3H), 3.57(t, 4H), 2.42(s, 3H), 2.44-2.30(m, 6H), 1.91(quin, 2H); liquid chromatography/Mass Spectrometry [ M + H]⁺Calculated 309.2, experimental 309.1.

Preparation of 6-methoxy-7- (3-morpholin-4-yl-propoxy) -quinoline-4-ethanol sodium salt

A solution of sodium ethoxide (85.0 kg) in ethanol and ethyl formate (70.0 kg) was added to the solution obtained from the previous step. The resulting 2-phase mixture is heated for about 3 hours to about 44 ℃. The chemical reaction mixture was cooled to about 25 ℃. Methyl tert-butyl ether (MTBE) was added to precipitate the product. The resultant was collected by filtration, and the filter cake was washed with methyl t-butyl ether and dried under reduced pressure at room temperature. The dried product was milled using a mesh screen to give 60.2 kg of the title compound.

¹Nuclear magnetic resonance hydrogen spectrum (400MHz, dimethylated inkstone-d 6): δ. 11.22(br s, 1H), 8.61(d, 1H), 7.55(s, 1H)H) 7.54(s, 1H), 7.17(d, 1H), 4.29(t, 2H), 3.99(M, 2H), 3.96(s, 3H), 3.84(t, 2H), 3.50(d, 2H), 3.30(M, 2H), 3.11(M, 2H), 2.35(M, 2H), liquid chromatography/mass spectrometry [ M + H]⁺Calculated 319.2, experimental 319.1.

Preparation of 4-chloro-6-methoxy-7- (3 morpholin-4-yl) -quinoline

To a solution of 6-methoxy-7- (3-morpholin-4-yl-propoxy) -quinolin-4-ol (5.00 kg) in acetonitrile heated to 50-55 c was added phosphorus oxychloride (26.32 kg). After the addition was complete, the mixture was heated to reflux (about 82 ℃) and held at that temperature, while it was sampled for in-process High Performance Liquid Chromatography (HPLC) analysis, it was stirred for about 18 hours. If 5% of starting material remains under Net Mass Transfer (NMT) conditions, the chemical reaction can be considered complete. The chemical reaction mixture was then cooled to 20-25 ℃ and filtered to remove solids. The filtrate was concentrated to yield a residue. Acetonitrile was added and the resulting solution was concentrated to yield a residue. Dichloromethane is added to the filter residue and the resulting solution is quenched with a mixture of dichloromethane and aqueous ammonium hydroxide. The resulting 2-phase mixture was isolated and the aqueous layer was back-extracted with dichloromethane. The mixed dichloromethane solution was dried over anhydrous sodium sulfate, filtered and concentrated to a solid. The solid was dried under reduced pressure at 30-40 ℃ to give the title compound (1.480 kg).

¹Nuclear magnetic resonance hydrogen spectrum (400MHz, dimethylated inkstone-d 6): δ. 8.61(d, 1H), 7.56(d, 1H), 7.45(s, 1H), 7.38(s, 1H), 4.21(t, 2H), 3.97(s, 3H), 3.58(M, 2H), 2.50-2.30(M, 6H), 1.97(quin, 2H) liquid chromatography/mass spectrometry [ M + H ] mass spectrometry]⁺Calculated 458.2, experimental 458.0.

Preparation of 4- (2-fluoro-4-nitro-phenoxy) -6-methoxy-7- (3-morpholin-4-ylpropoxy) quinoline

A solution of 2, 6-lutidine containing 4-chloro-6-methoxy-7- (3 morpholin-4-yl) -quinoline (2.005 kg, 5.95 mol), 2 chloro-4-nitrophenol (1.169 kg, 7.44 mol) was heated to 140 ℃ and 145 ℃ and stirred for about 2 hours while it was sampled for in-process High Performance Liquid Chromatography (HPLC) analysis. If less than 5% of the starting material remains, the chemical reaction can be considered complete. The chemical reaction mixture was then cooled to about 75 ℃ and water was added. Potassium carbonate was added to the mixture, which was then stirred at room temperature overnight. The precipitated solid was collected by filtration, washed with aqueous potassium carbonate, and dried under reduced pressure at 55-60 ℃ to give the title compound (1.7 kg).

¹Nuclear magnetic resonance hydrogen spectrum (400MHz, dimethylated inkstone-d 6): δ 8.54(d, 1H), 8.44(dd, 1H), 8.18(m, 1H), 7.60(m, 1H), 7.43(s, 1H), 7.42(s, 1H), 6.75(d, 1H), 4.19(t, 2H), 3.90(s, 3H), 3.56(t, 4H), 2.44(t, 2H), 2.36(m, 4H), 1.96(m, 2H). Liquid chromatography/Mass Spectrometry [ M + H]+ calculated 337.1, 339.1, experimental 337.0, 339.0.

3-fluoro-4- [ 6-methoxy-7- (3-morpholin-4-yl-propoxy) -quinolin-4-yloxy]Preparation of anilines

A reactor containing 4- (2-fluoro-4-nitro-phenoxy) -6-methoxy-7- (3-morpholin-4-ylpropoxy) quinoline (2.5 kg) and 10% palladium on carbon (50% hydrophilic, 250 g) was pressurized with hydrogen (about 40 psig) in a mixture of ethanol and water containing concentrated hydrochloric acid (1.5 l). The mixture was stirred at room temperature. After in-process High Performance Liquid Chromatography (HPLC) analysis confirmed that the chemical reaction was complete (typically 2 hours), hydrogen was vented and argon was added to make the reactor inert. Using a compound of the formulaThe filter bed filters the chemical reaction mixture to remove the catalyst. Adding potassium carbonate to the filtrate until the pH of the solutionUntil the value reaches about 10. The resulting suspension was stirred at 20-25 ℃ for about 1 hour. The precipitated solid was collected by filtration, washed with water, and dried under reduced pressure at 50-60 ℃ to give the title compound (1.164 kg).

¹Nuclear magnetic resonance hydrogen spectrum (400MHz, dimethylated inkstone-d 6): δ 8.45(d, 1H), 7.51(s, 1H), 7.38(s, 1H), 7.08(t, 1H), 6.55(dd, 1H), 6.46(dd, 1H), 6.39(dd, 1H), 5.51(br.s, 2H), 4.19(t, 2H), 3.94(s, 3H), 3.59(t, 4H), 2.47(t, 2H), 2.39(m, 4H), 1.98(m, 2H). Liquid chromatography/Mass Spectrometry [ M + H]⁺Calculated 428.2, experimental 428.1.

Preparation of 1- (4-fluoro-phenylaminocarbonyl) -cyclopropanecarboxylic acid

Triethylamine (7.78 kg) was added to a cooled (about 4 ℃ C.) solution of tetrahydrofuran containing cyclopropane 1, 1-dicarboxylic acid (9.95 kg) which is commercially available at a rate such that the batch reached a temperature not exceeding 10 ℃. The solution was stirred for about 30 minutes, and thionyl chloride (9.14 kg) was added thereto to keep the temperature of the batch at 10 ℃ or lower. After the addition was complete, a solution of 4-fluoroaniline (9.4 kg) in tetrahydrofuran was added at a rate such that the batch reached a temperature not exceeding 10 ℃. The mixture was stirred for about 4 hours and then diluted with isopropyl acetate. The diluted solution was washed with aqueous sodium hydroxide, water and aqueous sodium chloride in that order. The organic solution was concentrated by vacuum distillation. Heptane was added to the concentrate. The resulting suspension was filtered by centrifugation and the solid was dried under vacuum at about 35 c to yield the title compound (10.2 kg).

¹H NMR (400MHz, DMSO-d 6): 13.06(br s, 1H), 10.58(s, 1H), 7.65-7.60(M, 2H), 7.18-7.12(M, 2H), 1.41(s, 4H), liquid chromatography/mass spectrometry [ M + H ]]+ calculated 224.1, experimental 224.0.

Preparation of 1- (4-fluoro-phenylaminocarbonyl) -cyclopropylcarbonyl chloride

Oxalyl chloride (291 ml) was slowly added to a cooled (about 5 ℃) solution of 1- (4-chloro-phenylaminocarbonyl) -cyclopropanecarboxylic acid in tetrahydrofuran at a rate such that the temperature of the batch did not exceed 10 ℃. After the addition is complete, the batch may be heated to room temperature and stirred for about 2 hours while the chemical reaction is complete as confirmed by High Performance Liquid Chromatography (HPLC) analysis. The resulting solution can be used in the next step without further processing.

Cyclopropane-1, 1-dicarboxylic acid { 3-fluoro-4- [ 6-methoxy-7- (3-morpholin-4-yl-propoxy) -quinolin-4-ylamino]Phenyl } -amide- (4) Preparation of fluorophenyl) -amides

Adding the solution obtained from the previous step to a 3-fluoro-4- [ 6-methoxy-7- (3-morpholin-4-yl-propoxy) -quinolin-4-yloxy group]Aniline (1160 kg), tetrahydrofuran containing potassium carbonate (412.25 g) and water, at such a rate that the temperature of the batch is maintained between about 15-21 ℃. After the addition is complete, the batch may be heated to room temperature and stirred for about 1 hour while the chemical reaction is complete as confirmed by High Performance Liquid Chromatography (HPLC) analysis. Aqueous potassium carbonate solution and isopropyl acetate were added to the work-up. The resulting 2-phase mixture was stirred and the phases were separated. The aqueous phase was back-extracted with isopropyl acetate. The mixed isopropyl acetate layer was washed with water and then with aqueous sodium chloride, and then mixed with a mixture of magnesium sulfate and activated carbon to form a slurry. Using a compound of the formulaThe resulting slurry was filtered through a filter bed and the filtrate was concentrated under vacuum at a temperature of about 30 c to an oil to yield the title compound which was used in the next step without further processingIn the step (c).

¹Nuclear magnetic resonance hydrogen spectrum (400MHz, dimethylated inkstone-d 6): δ 10.41(s, 1H), 10.03(s, 1H), 8.47(d, 1H), 7.91(dd, 1H), 7.65(m, 2H), 7.53(m, 2H), 7.42(m, 2H), 7.16(t, 2H), 6.41(d, 1H), 4.20(t, 2H), 3.95(s, 3H), 3.59(t, 4H), 2.47(t, 2H), 2.39(m, 4H), 1.98(m, 2H), 1.47(m, 4H). Liquid chromatography/Mass Spectrometry [ M + H]⁺Calculated 633.2, experimental 633.1.

Cyclopropane-1, 1-dicarboxylic acid { 3-fluoro-4- [ 6-methoxy-7- (3-morpholin-4-yl-propoxy) -morpholin-4-ylamino]Phenyl } -amino group Preparation of (4-fluoro-phenyl) -aminodiphosphate

Cyclopropane-1, 1-dicarboxylic acid { 3-fluoro-4- [ 6-methoxy-7- (3-morpholin-4-yl-propoxy) -morpholin-4-ylamino ] obtained in the preceding step]Phenyl } -amino (4-fluoro-phenyl) -amino is dissolved in acetone and water. Phosphoric acid (85% strength, 372.48 g) was added at a rate such that the batch did not exceed a temperature of 30 ℃. The batch was kept at a temperature of about 15-30 c and stirred for 1 hour while the product precipitated. The solid was collected by filtration, washed with acetone, and dried under vacuum at about 60 ℃ to give the title compound (1.533 kg). c-Met IC of the title named Compound₅₀Values were less than 50 nM. The diphosphate is not contained in scheme 1.

¹Nuclear magnetic resonance hydrogen spectrum (400MHz, dimethylated inkstone-d 6): (diphosphonic acid) 10.41(s, 1H), 10.02(s, 1H), 8.48(d, 1H), 7.93(dd, 1H), 7.65(m, 2H), 7.53(d, 2H), 7.42(m, 2H), 7.17(m, 2H), 6.48(d, 1H), 5.6(br s, 6H), 4.24(t, 2H), 3.95(s, 3H), 3.69(bs, 4H), 2.73(bs, 6H), 2.09(t, 2H), 1.48(d, 4H).

Direct coupling procedure

To a suspension of chloroquinoline (3.37 g; 10 mmol) in dimethylacetamide (35 ml) was added solid sodium tert-butoxide (1.20 g; 12.5 mmol) and solid 2-fluoro-4-hydroxyaniline was added. The dark green reaction mixture was heated at 95-100 deg.C for 18 hours and HPLC analysis showed about 18% starting material remaining and about 79% product remaining. The chemical reaction mixture was cooled to below 50 ℃ and then sodium tert-butoxide (300 mg; 3.125 mmol) and aniline (300 mg; 2.36 mmol) were added separately and heating continued at 95-100 ℃. Analysis by high performance liquid chromatography after 18 hours showed that less than 3% of the starting material remained. The chemical reaction was cooled to below 30 ℃ and ice water (50 ml) was added while maintaining the temperature below 30 ℃. After stirring at room temperature for 1 hour, the product was collected by filtration, washed with water (2X 10 mL), and dried in a filter funnel under vacuum to give 4.11 g of a tan solid conjugated product (yield 96%; 89% after removal of water content).

¹Hydrogen and mass nuclear magnetic resonance spectroscopy: in line with the production: 97.8% liquid crystalline aromatic high molecular polymer (LCAP); the weight percent of water to potassium fluoride is 7.

The foregoing patent application has been described in some detail by way of illustration and example for purposes of clarity and understanding. The present invention has been described in relation to particular embodiments and techniques, which are intended to be employed. It will be understood, however, that various modifications and changes may be made without departing from the spirit and scope of the invention. It will be apparent to those skilled in the art that various changes and modifications may be made without departing from the scope of the appended claims. Accordingly, it is to be understood that the above description is intended to be illustrative only and not restrictive. The scope of the invention should, therefore, be determined not with reference to the above description, but instead should be determined with reference to the following appended claims, along with the full scope of equivalents to which such claims are entitled.

Claims (15)

1. A process for preparing a compound having the formula i (1):

or a pharmaceutically acceptable salt thereof, wherein:

R¹、R²and the nitrogen atom to which it is attached combine to form a 6-membered heterocycloalkyl group;

X¹is H, Br, Cl or F;

X²is H, Br, Cl or F;

s is 2 to 6;

n1 is 1-2; in addition, the method can be used for producing a composite material

n2 is 1-2;

the method comprises the following steps:

contacting a compound having formula h (1) with a reactant z (1) to produce a compound having formula i (1):

2. the method of claim 1, wherein s is 3; r¹、R²And the nitrogen atom to which it is attached is combined to form a morpholinyl group.

3. The method of claim 1, wherein the compound of formula h (1) is formed by reducing a compound of formula g (1) to a compound of formula h (1):

where R is¹、R²、X²S and n2 are as defined in claim 1.

4. The method of claim 1, wherein the compound of formula h (1) is formed by chemically reacting a compound of formula f (1) with a reactant u:

wherein LG represents a leaving group.

5. The method of claim 3, wherein the compound of formula g (1) is formed by chemically reacting a compound of formula f (1) with reactant y (1):

reactant

LG here represents a leaving group, R¹、R²、X²S and n2 are as defined in claim 1.

6. The method of claim 5, wherein the compound of formula f (1) is formed by converting a compound of formula e (1) to a compound of formula f (1):

LG here represents a leaving group, s, R¹And R²The definitions of (A) and (B) are the same as in claim 1.

7. The method of claim 6, wherein the compound of formula e (1) is formed by converting a compound of formula d (1) to a compound of formula e (1) with the addition of an alkyl formic acid:

where s, R¹And R²The definitions of (A) and (B) are the same as in claim 1.

8. The method of claim 7, wherein the compound of formula d (1) is formed by reducing a compound of formula c (1) to a compound of formula d (1):

where s, R¹And R²The definitions of (A) and (B) are the same as in claim 1.

9. The method of claim 8, wherein the compound of formula c (1) is prepared by reacting a compound of formula b (1) withCarrying out a chemical reaction to produce:

here Xb is Br or Cl; s, R¹And R²The definitions of (A) and (B) are the same as in claim 1.

10. The method of claim 9, wherein the compound of formula b (1) is prepared by reacting a compound of formula a (1) with HNO₃Carrying out a chemical reaction to produce:

here Xb is Br or Cl; s, R¹And R²The definitions of (A) and (B) are the same as in claim 1.

11. The process according to claim 1, wherein the reagent z (1) is formed by chemically reacting the reagent z (1a) with a chlorinating agent:

x herein¹Br or Cl; n1 is 1-2.

12. The method of claim 1, wherein the compound of formula i (1) is a compound of formula i (2):

or a pharmaceutically acceptable salt thereof, wherein:

X¹is H, Br, Cl or F; in addition, the method can be used for producing a composite material

X²Is H, Br, Cl or F.

13. The method of claim 5, wherein the compound of formula f (1) is a compound of formula f (2):

reactant y (1), i.e., reactant (y) (2):

here X²Is chloro or fluoro; in addition, the method can be used for producing a composite material

A compound having the formula g (1), i.e. a compound having the formula g (2):

14. the method of claim 3, wherein the compound having the formula g (1) is a compound having the formula g (2):

here X²Is chloro or fluoro; in addition, the method can be used for producing a composite material

A compound having the formula h (1), i.e. a compound having the formula h (2):

15. the method of claim 1, wherein the compound having the formula h (1) is a compound having the formula h (2):

wherein X²Is F;

reactant z (1), i.e., reactant (z) (2):

wherein X¹Is F; in addition, the method can be used for producing a composite material

A compound having formula i (1), i.e. a compound having formula i (2):