Manufacturing intermediates

Abstract

A compound represented by formula (Ia) or a salt thereof provided by the present invention can be used as a production intermediate for producing a compound (A) having a BTK-inhibiting effect. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to a novel production intermediate for producing an oxoisoquinoline derivative having BTK inhibitory activity and a method for producing the same. Background Art

[0002] Compounds having Bruton's tyrosine kinase (BTK) inhibitory activity are considered to be useful for treating diseases related to BTK signaling, such as cancer, B-cell lymphoma, and chronic lymphocytic leukemia, and are also useful for treating solid cancers expressing p65BTK. They can also be used for treating allergic diseases, autoimmune diseases, and inflammatory diseases.

[0003] It has been found that oxoisoquinoline derivatives are particularly useful as BTK inhibitors. Patent Document 1 exemplifies 2-(3-{2-amino-6-[1-(oxetan-3-yl)-1,2,3,6-tetrahydropyridin-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-2-(hydroxymethyl)phenyl)-6-cyclopropyl-8-fluoroisoquinolin-1(2H)-one (hereinafter, Compound (A)):

[0004]

[0005] However, the production method of Compound (A) described in Patent Document 1 is difficult to implement on a semi-industrial or industrial scale. Further improvement is required in terms of production operability, purification efficiency, and yield, etc., to find a production method suitable for actual production.

[0006] Prior Art Documents

[0007] Patent Documents

[0008] Patent Document 1: WO2018 / 097234. Summary of the Invention

[0009] Problems to be Solved by the Invention

[0010] In order to industrially produce a high-quality compound as a drug, in addition to developing a novel production intermediate suitable for the actual production level, it is also necessary to solve problems such as reducing the column chromatography purification process, improving the operability or yield of the production process, increasing the purity, or reducing harmful solvents.

[0011] The present invention provides a novel production intermediate and a production method for more economically and highly producing an oxoisoquinoline derivative using the intermediate. Moreover, in the method described in the present application specification, compared with the currently known production method (the method described in Patent Document 1), the economic cost of the production intermediate process can be reduced, and a high yield can be obtained overall.

[0012] Means for solving the problem

[0013] The method for producing compound (A) provided by the present invention is as described below.

[0014] (1) Production method, wherein compound (Ia) is oxetanylated to produce compound (Ib), and then it is reacted with a known compound (B) to obtain the target compound (A).

[0015]

[0016] (2) Production method of compound (A), wherein in the above production method (1), compound (Ia) obtained by chlorinating compound (III) and then deprotecting the trifluoroacetyl group is used.

[0017]

[0018] (3) Production method of compound (A), wherein in the above production method (2), compound (III) obtained by treating compound (IV) with trifluoroacetic anhydride is used.

[0019]

[0020] (4) Production method of compound (A), wherein in the above production method (3), compound (IV) obtained by treating compound (V) with sodium borohydride is used.

[0021]

[0022] (5) Production method of compound (A), wherein in the above production method (4), compound (V) obtained by reacting a brominating agent with compound (VII) and then reacting with compound (VI) is used.

[0023]

[0024] As described below, the present invention also provides compound (Ia) and its production method, which are intermediates for producing compound (A).

[0025] (6) Compound represented by the following formula (Ia) or its salt:

[0026]

[0027] (7) Production method, wherein compound (III) is chlorinated and then treated with ammonia water to produce compound (Ia).

[0028]

[0029] (8) Process for preparing compound (Ia), wherein in the above-mentioned process (7), compound (III) obtained by treating compound (IV) with trifluoroacetic anhydride is used.

[0030]

[0031] (9) Process for preparing compound (Ia), wherein in the above-mentioned process (8), compound (IV) obtained by treating compound (V) with sodium borohydride is used.

[0032]

[0033] (10) Process for preparing compound (Ia), wherein in the above-mentioned process (9), compound (V) obtained by reacting a brominating agent with compound (VII) and then reacting with compound (VI) is used.

[0034]

[0035] Advantages of the Invention

[0036] By using the process for preparing the novel production intermediate according to the present invention, the target compound (A) can be produced more economically in high yields. Moreover, in the process described in the specification of the present application, compared with the currently known production process (the process described in Patent Document 1), the economic cost of the production intermediate process can be reduced, and high yields can be obtained overall. Detailed Embodiments

[0037] The embodiments of the present invention are described as follows.

[0038] The meanings of the abbreviations and symbols used in the following description are as follows.

[0039] Ac: Acetyl

[0040] DCM: Dichloromethane

[0041] DMA: N,N-Dimethylacetamide

[0042] DMSO: Dimethyl sulfoxide

[0043] EtOH: Ethanol

[0044] THF: Tetrahydrofuran

[0045] NBS: N-Bromosuccinimide

[0046] Pd-166: Bis(dicyclohexyl-tert-butylphosphine)palladium(II) dichloride

[0047] TBME: tert-Butyl methyl ether

[0048] (1) The target compound (A) is produced through the steps of oxetanylation of compound (Ia) followed by reaction with a known compound (B).

[0049]

[0050] (1-1) Production of compound (Ib)

[0051] In DMF, 2 equivalents of 3-oxetanone, 0.1 equivalent of zinc chloride are added to compound (Ia), and finally 2.4 equivalents of sodium triacetoxyborohydride are added for reaction. After that, ammonia water is added to quench the reaction, and the precipitated compound (Ib) is obtained.

[0052] (1-2) Production of compound (A)

[0053] In a mixed solvent of DMSO-water, in the presence of 2 equivalents of potassium carbonate and 0.008 equivalent of Pd-166, compound (Ib) is reacted with compound (B) at 90 - 100 °C for 1 - 2 hours. After that, water is added, and the precipitated compound is filtered to obtain the target compound (A).

[0054] (2) Compound (III) is chlorinated, the trifluoroacetyl group is deprotected to produce compound (Ia), and then through the above step (1), the target compound (A) is produced.

[0055]

[0056] (2-1) Production of compound (Ia)

[0057] In acetonitrile, 4 - 8 equivalents, preferably 6 equivalents of phosphoryl chloride are reacted with compound (III) to produce compound (II). The reaction temperature is 50 °C - 80 °C, preferably 55 °C - 65 °C. After that, compound (II) is treated with ammonia water to produce compound (Ia). Alternatively, without separating compound (II), the post-treated solution can be concentrated and treated with ammonia water to produce compound (Ia).

[0058] (2-2) Production of compound (A)

[0059] From the compound (Ia) obtained above, through the said step (1), the target compound (A) is produced.

[0060] (3) Compound (IV) is treated with trifluoroacetic anhydride to produce compound (III),

[0061]

[0062] Subsequently, through the above-mentioned step (2), the target compound (A) is produced.

[0063] (3-1) Production of compound (III)

[0064] In acetonitrile or 1,2-dichloroethane (preferably acetonitrile), in the presence of an amine compound, trifluoroacetic anhydride is reacted with compound (IV). The amine compound is selected from triethylamine, pyridine, 2,6-dimethylpyridine, preferably 2,6-dimethylpyridine. Relative to compound (IV), the amine compound is preferably added in an amount of 6 equivalents or more, and trifluoroacetic anhydride is preferably added in an amount of 5 equivalents or more. The reaction temperature is 30°C to 60°C, preferably 35°C to 45°C.

[0065] Compound (III) can be easily separated, and preferably the separated solid is used in the next step.

[0066] (3-2) Production of compound (A)

[0067] From the compound (III) obtained above, through the above-mentioned step (2), the target compound (A) is produced.

[0068] (4) Treat compound (V) with sodium borohydride to produce compound (IV),

[0069]

[0070] Subsequently, through the above-mentioned step (3), the target compound (A) is produced.

[0071] (4-1) Production of compound (IV)

[0072] React 3 equivalents to 6 equivalents, preferably 4 equivalents, of sodium borohydride with compound (V). As the solvent, methanol, ethanol, DMA, pyridine, water can be used, and any one of them can be used alone, or a mixture of multiple ones can be used. Among them, the mixture of methanol and pyridine is the best, and in this case, the ratio of pyridine is preferably 25% to 75%. The reaction temperature is 40°C to 80°C, preferably 50°C to 70°C.

[0073] The resulting compound (IV) can be separated as a free base or a hydrochloride, and preferably separated as a hydrochloride.

[0074] (4-2) Production of compound (A)

[0075] From the compound (IV) obtained above, through the above-mentioned step (3), the target compound (A) is produced.

[0076] (5) React a brominating agent with compound (VII) to form bromide (X), and then

[0077]

[0078] React with diamino pyrimidine (VI) to produce compound (V).

[0079]

[0080] After that, through the above-mentioned step (4), the target compound (A) is produced.

[0081] (5-1) Production of compound (V)

[0082] Brominate compound (VII) with bromine or NBS. When using NBS, add an acetic acid solution of hydrogen bromide. The solvent is selected from acetic acid, dichloromethane, and chloroform, and the reaction temperature is preferably 0°C to 30°C. The resulting bromide (X) can be separated, or the reaction mixture can be directly used in the next reaction.

[0083] The reaction of bromide (X) with diamino pyrimidine (VI) is carried out in acetic acid or a mixture of acetic acid and water. When using a mixture of acetic acid and water, the ratio of water is preferably 1% to 90%. The reaction temperature is 50°C to 90°C, preferably 70°C to 85°C.

[0084] (5-2) Production of compound (A)

[0085] From the compound (V) obtained above, through the said step (4), the target compound (A) is produced.

[0086] It should be noted that, for example, as shown in the following scheme, compound (VII) used as the raw material in the above (5-1) can be produced from anisyl alcohol (IX).

[0087]

[0088] That is, let hydrogen bromide act on anisyl alcohol (IX). After forming 4-methoxybenzyl bromide, react with compound (VIII).

[0089] Regarding the reaction of anisyl alcohol (IX) with hydrogen bromide, in a solvent selected from toluene, dichloromethane, and chloroform, hydrogen bromide is added in the form of an aqueous solution. The reaction temperature is 0°C to 50°C, more preferably 15°C to 30°C. The resulting 4-methoxybenzyl bromide can be used in the next reaction after being temporarily separated, or can be used in the form of a solution dissolved in the reaction solvent. Subsequently, the reaction with compound (VIII) is carried out in a solvent selected from toluene, dichloromethane, and chloroform, and the reaction temperature is 0°C to 50°C, preferably 15°C to 30°C. The resulting compound (VII) can be easily separated as a solid and is preferably used in the next step after separation.

[0090] The compound represented by the following formula (Ia) or its salt is a production intermediate for producing compound (A) and is included in the invention of this application.

[0091]

[0092] The following are embodiments of the invention for manufacturing the manufacturing intermediate.

[0093] (6) After chlorinating compound (III), the trifluoroacetyl group is deprotected to produce the manufacturing intermediate (Ia).

[0094]

[0095] The production of compound (II) and (Ia) is as described in the above-mentioned step (2-1).

[0096] (7) Compound (IV) is treated with trifluoroacetic anhydride to produce compound (III),

[0097]

[0098] Then, through the above-mentioned step (6), the manufacturing intermediate (Ia) is produced.

[0099] The production of compound (III) is as described in the above-mentioned step (3-1).

[0100] (8) Compound (V) is treated with sodium borohydride to produce compound (IV),

[0101]

[0102] Then, through the above-mentioned step (7), the manufacturing intermediate (Ia) is produced.

[0103] The production of compound (IV) is as described in the above-mentioned step (4-1).

[0104] (9) A brominating agent is reacted with compound (VII), and then with diaminopyrimidine (VI) to produce compound (V),

[0105]

[0106] Then, through the above-mentioned step (8), the manufacturing intermediate (Ia) is produced.

[0107] The production of compound (V) is as described in the above-mentioned step (5-1).

[0108] Examples and reference examples are described below to specifically illustrate the present invention, and these examples and reference examples do not limit the scope of the present invention.

[0109] In addition, compound (A) produced from the manufacturing intermediate of the present invention is currently in clinical development. The production method of compound (A) is described as a reference example.

[0110] Example

[0111] Example 1

[0112] Preparation of 4-chloro-6-(1,2,3,6-tetrahydropyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine (Ia)

[0113]

[0114] (Step 1) 4-acetyl-1-(4-methoxybenzyl)pyridin-1-ium bromide (VII)

[0115]

[0116] Using a stirrer, stir anisyl alcohol (IX) (400 g, 1 Eq, 2.89 mol) in 2 L of toluene, and add 48% aqueous hydrobromic acid solution (987 mL, 8.8 molar, 3 Eq, 8.68 mol). After stirring for 1 hour, separate the two layers, and extract the aqueous layer twice with toluene (500 mL). Combine the organic layers, dry over sodium sulfate, filter, and wash the solid with toluene (400 mL). Add 1-(pyridin-4-yl)ethan-1-one (VIII) (351 g, 1 Eq, 2.89 mol) all at once, and heat the reaction mixture at 60 °C for 23 hours. Filter the solid by suction, wash with toluene, and dry under reduced pressure to obtain 133.13 g of the product. Take out the large pieces adhering to the bottom of the container, crush them into small pieces, and obtain 730.5 g of the second batch of crystals. The total yield is 863.63 g (93%).

[0117] 1 H NMR (400 MHz, DMSO-d6) δ 9.44 - 9.36 (m, 2H), 8.48 (d, J = 6.1 Hz, 2H), 7.62 - 7.50 (m, 2H), 7.07 - 6.96 (m, 2H), 5.89 (d, J = 5.4 Hz, 2H), 3.75 (s, 3H), 2.72 (s, 3H). LCMS (m / z): 242.4 [M] +

[0118] (Step 2) 4-(2-amino-4-hydroxy-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-1-(4-methoxybenzyl)pyridin-1-ium bromide (V)

[0119]

[0120] In a 20 L flask, 4-acetyl-1-(4-methoxybenzyl)pyridin-1-ium bromide (VII) (617 g, 1.0 Eq, 1.91 mol) was dissolved in acetic acid (1.25 L). A solution of bromine (306 g, 98.7 mL, 1.0 Eq, 1.91 mol) in acetic acid (625 mL) was added dropwise over 10 minutes using a dropping funnel. After stirring for 55 minutes, 2,6-diaminopyrimidin-4-ol (VI) (242 g, 1.0 Eq, 1.91 mol) was added all at once, followed by an aqueous solution of sodium acetate trihydrate (521 g, 2.0 Eq, 3.83 mol).

[0121] The mixture was stirred at room temperature for 1 hour and 45 minutes, further stirred at 80 °C for 3 hours and 30 minutes, then heating was stopped and the mixture was stirred at room temperature overnight. The reaction mixture was suction filtered using a P2 glass filter to obtain a pale orange wet solid and an orange filtrate. The orange solid on the glass filter was washed with water (3 x 500 mL) and then dried under reduced pressure to obtain the orange title compound. The yield was 637.42 g (78%).

[0122] 1 H NMR (400 MHz, DMSO-d6) δ 12.19 (s, 1H), 10.73 (s, 1H), 8.81 (d, J = 6.9 Hz, 2H), 8.14 (d, J = 6.8 Hz, 2H), 7.68 (s, 1H), 7.56 - 7.45 (m, 2H), 7.03 - 6.94 (m, 2H), 6.74 (s, 2H), 5.52 (s, 2H), 3.75 (s, 3H). LCMS (m / z): 348.4 [M] +

[0123] (Step 3) 2-Amino-6-(1-(4-methoxybenzyl)-1,2,3,6-tetrahydropyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ol (IV)

[0124]

[0125] 4-(2-Amino-4-hydroxy-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-1-(4-methoxybenzyl)pyridin-1-ium bromide (V) (843.46 g, 1.0 Eq, 1.96 mol) was suspended in a mixed solvent of methanol (1.675 L) and pyridine (5.025 L), and sodium borohydride (223.5 g, 3.0 Eq, 5.9081 mol) was added portionwise in small amounts with stirring at room temperature. The mixture was heated for 4 hours and 15 minutes while maintaining the internal temperature at around 40 °C, and then the reaction mixture was cooled in an ice bath. After adding water (5 L), concentrated hydrochloric acid (1 L) was slowly added while controlling the temperature below 28 °C. Two pieces of filter paper were overlapped, and the solid was suction filtered through a Buchner funnel. The yellow solid was washed with water (2 x 2 L), acetonitrile (1 L), and then with TBME (2 x 1 L). It was dried overnight under a nitrogen stream and then dried under reduced pressure at 50 °C to obtain the title compound. The yield was 628.4 g (91%).

[0126] 1 H NMR (400 MHz, DMSO-d6) δ 11.31 (d, J = 2.4 Hz, 1H), 10.37 (d, J = 12.3 Hz, 1H), 7.53 (td, J = 8.5, 2.6 Hz, 2H), 7.02 (dd, J = 8.8, 2.5 Hz, 2H), 6.33 - 6.23 (m, 3H), 6.02 (d, J = 4.4 Hz, 1H), 4.37 - 4.24 (m, 2H), 3.79 (d, J = 0.8 Hz, 3H), 3.70 (s, 2H), 3.51 (s, 1H), 3.12 (d, J = 10.1 Hz, 1H), 2.70 (s, 2H).

[0127] LCMS (m / z): 352.0 [M+H] +

[0128] (Step 4) 2,2,2-Trifluoro-N-(4-hydroxy-6-(1-(2,2,2-trifluoroacetyl)-1,2,3,6-tetrahydropyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)acetamide (III)

[0129]

[0130] To acetonitrile (1.0 L) was added 2,6-dimethylpyridine (467 g, 505 mL, 7.66 Eq, 4.36 mol), and 2-amino-6-[1-(4-methoxybenzyl)-1,2,3,6-tetrahydropyridin-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-ol (IV) (200 g, 1.0 Eq, 569 mmol) was suspended. While maintaining the internal temperature below 35 °C, trifluoroacetic anhydride (598 g, 402 mL, 5 Eq, 2.85 mol) was slowly added using a dropping funnel. After 35 minutes, the addition was complete and the ice bath was removed. After further stirring for 3 hours, the reaction mixture was poured into water (2.5 L) containing ice (6 L). The red / orange solid was separated by suction filtration using a Buchner funnel and filter paper. The separated compound was transferred to a round bottom flask, heated to 70 °C in acetonitrile (ca. 400 mL), cooled in an ice bath, filtered using a Buchner funnel and filter paper, and washed with acetonitrile and TBME. The resulting solid was dried under reduced pressure (20 mbar) at 50 °C to give the title compound. The yield was 163.37 g (68%).

[0131] 1 H NMR (400 MHz, DMSO-d6) δ 12.41 (s, 1H), 12.05 (s, 1H), 11.64 (s, 1H), 6.51 (d, J = 0.6 Hz, 1H), 6.29 (s, 1H), 4.26 (d, J = 10.5 Hz, 2H), 3.75 (s, 2H), 2.57 (s, 2H).

[0132] LCMS (m / z): 424.2 [M+H] +

[0133] (Step 5) N-(4-Chloro-6-(1-(2,2,2-trifluoroacetyl)-1,2,3,6-tetrahydropyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-2,2,2-trifluoroacetamide (II)

[0134]

[0135] Into a three-necked round-bottom flask equipped with a stirrer and a reflux concentrator, add 2,2,2-trifluoro-N-{4-hydroxy-6-[1-(2,2,2-trifluoroacetyl)-1,2,3,6-tetrahydropyridin-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-2-yl}acetamide (III) (163.3 g, 1 Eq, 385.8 mmol), acetonitrile (500 mL) and phosphorus oxychloride (354.9 g, 215.7 mL, 6 Eq, 2.315 mol), and heat under reflux. After heating overnight, cool the brown solution in an ice bath. Pour the reaction mixture directly into water (1.8 L) containing ice (3.0 L), and stir vigorously by hand for 5 minutes. Then stir with a stirrer for 30 minutes. Suction filter the solid with a Buchner funnel and wash with water (3 x 250 mL). Add acetonitrile (3 x 250 mL) to the yellow solid, azeotropically remove water under reduced pressure, and further dry under reduced pressure at 50 °C. The yield is 87.9 g (52%).

[0136] 1 1H NMR (400 MHz, DMSO-d6) δ 12.88 (d, J = 4.1 Hz, 1H), 12.19 (s, 1H), 6.62 (s, 1H), 6.59 (d, J = 1.2 Hz, 1H), 4.30 (m, 2H), 3.80 (m, 2H), 2.66 (m, 2H).

[0137] LCMS (m / z): 442.2 [M+H] +

[0138] (Step 6) 4-Chloro-6-(1,2,3,6-tetrahydropyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine (Ia)

[0139]

[0140] Suspend N-{4-chloro-6-[1-(2,2,2-trifluoroacetyl)-1,2,3,6-tetrahydropyridin-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-2-yl}-2,2,2-trifluoroacetamide (II) (50.0 g, 1 Eq, 113 mmol) in 2-propanol (200 mL) and stir at room temperature. After almost all the solid has dissolved, add ammonia water (154 g, 196 mL, 25.0% Wt, 20 Eq, 2.26 mol). After stirring at room temperature overnight, suction filter with a P3 filter, separate the white solid, wash with acetonitrile and then with diethyl ether, and transfer to a 250 ml round-bottom flask with acetonitrile. Concentrate the mixture under reduced pressure at 40 - 50 °C. The yield is 26.89 g (yield 95%).

[0141] 11H NMR (400 MHz, DMSO-d6) δ 11.76 (s, 1H), 6.60 (s, 2H), 6.35 (s, 1H), 6.28 (s, 1H), 3.68 (s, 2H), 3.20 (s, 2H), 2.60 (s, 2H).

[0142] LCMS (m / z): 250.2 [M+H] +

[0143] Reference Example 1

[0144] Preparation of 2-(3-{2-amino-6-[1-(oxetan-3-yl)-1,2,3,6-tetrahydropyridin-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-2-(hydroxymethyl)phenyl)-6-cyclopropyl-8-fluoroisoquinolin-1(2H)-one (Compound A)

[0145] (1) Preparation of 4-chloro-6-[1-(oxetan-3-yl)-1,2,3,6-tetrahydropyridin-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-2-amine (Ib)

[0146]

[0147] Compound (Ia) (15.00 g, 1.0 eq) was stirred in DMF (128 mL, 8.5 vol.), 3-oxetanone (8.66 g, 2.0 eq) was added under a nitrogen atmosphere, and then zinc chloride (0.82 g, 0.10 eq) was added. The mixture was stirred at 20 °C for 1 hour. Sodium triacetoxyborohydride (30.56 g, 2.4 eq) was added in three portions over 90 minutes, and then the mixture was stirred at 20 °C for 1 hour. Water (75 mL, 5 vol.) and 20% aqueous ammonia (30 mL, 2 vol.) were added while maintaining the internal temperature below 10 °C, and further water (118 mL, 7.9 vol.) was added. After temporarily raising the temperature to 20 °C and then cooling to 5 °C, the precipitated product was filtered off. The filter cake was washed with water (45 mL x 3 times) and 2-propanol (45 mL, 3 vol.), and dried overnight at 55 °C to obtain compound (Ib). When cooled to 5 °C (internal temperature), heat was generated and gas was evolved when water was added, but the internal temperature was maintained below 10 °C. Further water was added below 10 °C, and the pH was confirmed to be 11 - 12. After stirring at 5 - 20 °C for 14 - 15 hours, the product was filtered off. The solid was washed with water until the mother liquor became neutral, and then washed with 2-propanol. Drying overnight at 55 °C gave compound (Ib) as a crude product. The yield was 14.7 g (80% yield).

[0148] 11H NMR (400 MHz, DMSO-d6) δ 11.58 (s, 1H), 6.53 (s, 2H), 6.33 (s, 1H), 6.18 (s, 1H), 4.53 (dt, J = 12.2, 6.3 Hz, 4H), 3.53 (p, J = 6.3 Hz, 1H), 2.99 (s, 2H), 2.46 (d, J = 3.8 Hz, 4H).

[0149] LCMS (m / z): 306.8 [M+H] +

[0150] (2) Preparation of Compound A

[0151]

[0152] To a solvent of DMSO-water (8:3), add Compound (Ib) (15.0 g, 1.0 eq), Compound (B) (25.76 g, 1.1 eq), and potassium carbonate (13.56 g, 2.0 eq). Under a nitrogen atmosphere, add Pd-166 (0.27 g, 0.8% mol). Heat the reaction mixture at 100 °C (internal temperature) for about 40 minutes, then stir at the same temperature for more than 3 hours. Cool the mixture to 90 °C over more than 15 minutes, and add water equal to the amount of DMSO over more than 1.5 hours. Stir the mixture at 90 °C for at least 1 hour, then stir at 20 °C (internal temperature) for more than 2 hours. Filter the product, wash it with DMSO-water (1.5:3), and then wash it with water. Under reduced pressure, conduct vacuum drying at 60 °C to obtain the target product. The yield is 29.5 g (yield 97%).

[0153] 1 1H NMR (400 MHz, DMSO-d6) δ 11.52 (s, 1H), 7.72 (dd, J = 7.7, 1.1 Hz,

[0154] 1H), 7.59 (t, J = 7.8 Hz, 1H), 7.46 (dd, J = 7.8, 1.1 Hz, 1H), 7.36 (d, J = 7.4 Hz, 1H), 7.27 (d, J = 1.3 Hz, 1H), 6.99 (dd, J = 13.2, 1.3 Hz, 1H), 6.62 (dd, J = 7.5, 2.0 Hz, 1H), 6.41 (s, 2H), 6.35 (s, 1H), 6.21 (s, 1H), 5.18 (dd, J = 8.8, 4.5 Hz, 1H), 4.53 (dt, J = 30.5, 6.3 Hz, 4H), 4.25 (dd, J = 12.0, 4.4 Hz, 1H), 4.05 (dd, J = 11.9, 9.0 Hz, 1H), 3.54 (m, 4H), 3.01 (s, 2H), 2.46 (d, J = 4.0 Hz, 4H), 2.20 - 2.14 (m, 1H), 1.14 - 1.05 (m, 2H), 0.93 - 0.80 (m, 2H).

[0155] Industrial applicability

[0156] The compound of the present invention can be used as an intermediate for the production of compound (A) having BTK inhibitory activity.

[0157] By using this intermediate, compound (A) can be produced more economically in high yields.

Claims

1. A compound represented by the following formula (Ia) or a salt thereof:

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