Process for preparation exo-tert-butyl n-(3-azabicyclo[3.2.1]octan-8-yl)carbamate

Abstract

To provide a method for synthesizing a compound that is a key intermediate for the synthesis of compounds for the prophylaxis and treatment of diseases associated with the deposition of β-amyloid in the brain, particularly Alzheimer's disease, as well as cerebral amyloid angiopathy and hereditary cerebral hemorrhage with amyloidosis.SOLUTION: The present invention provides a process for the preparation of a compound (I) or a pharmaceutically acceptable salt thereof, using compound (II) as an intermediate.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to compound (I) [ka] Compound (I) or a pharma- ceutically acceptable salt thereof is useful as an important intermediate for synthesizing compounds for the prophylaxis and treatment of diseases associated with the deposition of β-amyloid in the brain, particularly Alzheimer's disease, as well as cerebral amyloid angiopathy, hereditary cerebral hemorrhage with amyloidosis, Dutch type (HCHWA-D), multi-infarct dementia, Pugilus dementia, Down's syndrome, and the like. [Background technology]

[0002] Methods for synthesizing compound (I) are disclosed in WO2018118838 and WO2005021536. However, the current processes have the following problems and are not suitable for large-scale production: (a) Three intermediates require cumbersome column purification: 3-benzyl-3-azabicyclo[3.2.1]octan-8-one oxime; 3-benzyl-3-azabicyclo[3.2.1]octan-8-amine; tert-butyl N-(3-benzyl-3-azabicyclo[3.2.1]octan-8-yl)carbamate; (b) Chiral separation by HPLC or SFC is required, which incurs significant costs; (c) In step d), excess Boc 2 There is no report that the removal of O leads to the formation of a major by-product in step e).

[0003] In view of the above problems, one object of the present invention is to find an efficient synthesis method which overcomes all the above problems and can be applied on a technical scale.

[0004] Another aspect of the present invention relates to a novel process for the preparation of compound (V) and / or compound (Va): [ka] [ka] The acid is selected from D-glutamic acid, (R)-(-)-mandelic acid, 1-hydroxy-2-naphthoic acid, citric acid, 4-aminosalicylic acid, L-tartaric acid, hippuric acid, malonic acid, glutaric acid, oxalic acid, fumaric acid, succinic acid, 4-aminobenzoic acid, 2,5-dihydroxybenzoic acid, L-malic acid, salicylic acid, maleic acid, (1S,3R)-(-)-camphoric acid, pamoic acid, mucic acid, palmitic acid, oleic acid, lactobionic acid; in particular the acid is (R)-(-)-mandelic acid. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0005] definition The term "pharmaceutical acceptable salt" refers to conventional acid or base addition salts that retain the biological effectiveness and properties of the compounds of formula (I) and are formed from suitable non-toxic organic or inorganic acids or organic or inorganic bases. Acid addition salts include, for example, those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and those derived from organic acids such as p-toluenesulfonic acid, salicylic acid, methanesulfonic acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid, and the like. Base addition salts include those derived from ammonium, potassium, sodium, and quaternary ammonium hydroxides, such as tetramethylammonium hydroxide. Chemical modification of pharmaceutical compounds into salts is a technique well known to pharmaceutical scientists to improve the physical and chemical stability, hygroscopicity, flowability, and solubility of the compounds. This is described, for example, in Bastin RJ, et al., Organic Process Research & Development 2000, 4, 427-435; or Ansel, H., et al., In: Pharmaceutical Dosage Forms and Drug Delivery Systems, 6th Edition (1995), pp. 196 and 1456-1457.

[0006] Abbreviation API Active Pharmaceutical Ingredients DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene DCM Dichloromethane DIPEA N,N-Diisopropylethylamine DMF Dimethylformamide eq Equivalent EtOAc or EA Ethyl Acetate IPA Isopropanol IPAc Isopropyl acetate 2-MeTHF 2-Methyltetrahydrofuran MTBE Methyl tert-butyl ether NMM N-Methylmorpholine NMP N-Methyl-2-pyrrolidone Pd / C Palladium Carbon Pd(OH) / C Pearlman catalyst Raney-Ni Raney Nickel TEA Triethylamine TFA Trifluoroacetic acid v / v volume ratio Wt.% Weight percent

[0007] The present invention provides a process for the preparation of compounds of formula (I), as outlined in Scheme 1.

[0008] Scheme 1 [ka]

[0009] The synthesis involves the following steps: Step a) Compound (II) [ka] and hydroxylamine hydrochloride, to give compound (III). [ka] and the imine formation of Step b) Compound (VI) obtained by reduction reaction of compound (III) [ka] The formation of Step c) Compound (V) from compound (VI) and an acid [ka] wherein the acid is selected from D-glutamic acid, (R)-(-)-mandelic acid, 1-hydroxy-2-naphthoic acid, citric acid, 4-aminosalicylic acid, L-tartaric acid, hippuric acid, malonic acid, glutaric acid, oxalic acid, fumaric acid, succinic acid, 4-aminobenzoic acid, 2,5-dihydroxybenzoic acid, L-malic acid, salicylic acid, maleic acid, (1S,3R)-(-)-camphoric acid, pamoic acid, mucic acid, palmitic acid, oleic acid, and lactobionic acid, in particular the acid is (R)-(-)-mandelic acid; Step d) Compound (VI) obtained by dissociation of compound (V) and boc protection reaction [ka] The formation of Step e) Compound (I) obtained by deprotection of compound (VI) [ka] and forming a

[0010] A detailed description of the process steps of the present invention is as follows: Step a) Compound (II) [ka] and hydroxylamine hydrochloride, to give compound (III). [ka] Imine formation.

[0011] The compound of formula (III) is synthesized using a suitable base in the presence of a suitable solvent.

[0012] A suitable solvent is selected from MeOH and EtOH; in particular the solvent is EtOH.

[0013] Suitable bases are selected from KOAc and NaOAc; a particularly suitable base is NaOAc.

[0014] The solvent exchange to EtOH after extraction is important for the whole process in terms of technical scale production. Direct removal of EA by concentration gave acceptable yields. However, this process is not suitable for large scale production due to safety concerns. In the present invention, the solvent was exchanged to EtOH, which can be controlled in large scale production.

[0015] Step b) Compound (IV) obtained by reduction reaction of compound (III) [ka] Formation of.

[0016] Compound (IV) is synthesized using a suitable reducing agent in a suitable solvent.

[0017] Suitable solvents are selected from MeOH, EtOH and IPA; in particular the solvent is EtOH.

[0018] Suitable reducing agents are selected from Na, Pd / c and Raney-Ni; in particular the reducing agent is Raney-Ni.

[0019] The reaction is carried out at 0°C to 70°C, particularly 20°C to 30°C.

[0020] Temperature is important for the whole process in terms of endo / exo selectivity. In this invention, steps a) and b) are telescoped without solid separation. High temperature (>50°C) and low temperature (<5°C) during the reduction reaction will reduce the yield of the desired exo product. The temperature system designed in step b) of this invention provides the highest yield and good purging effect on impurities.

[0021] A series of studies was carried out to demonstrate the effect of reaction temperature, and it was found that 20-30°C was the optimal condition for the reduction reaction. [ka] [Table 1]

[0022] Step c) Compound (V) from compound (VI) and an acid [ka] wherein the acid is selected from D-glutamic acid, (R)-(-)-mandelic acid, 1-hydroxy-2-naphthoic acid, citric acid, 4-aminosalicylic acid, L-tartaric acid, hippuric acid, malonic acid, glutaric acid, oxalic acid, fumaric acid, succinic acid, 4-aminobenzoic acid, 2,5-dihydroxybenzoic acid, L-malic acid, salicylic acid, maleic acid, (1S,3R)-(-)-camphoric acid, pamoic acid, mucic acid, palmitic acid, oleic acid, and lactobionic acid, in particular the acid is (R)-(-)-mandelic acid.

[0023] The compound of formula (V) is synthesized in a suitable organic solvent in the presence of a suitable amount of acid.

[0024] The amount of (R)-(-)-mandelic acid used in this step is 0.1-2.0 eq., in particular 0.6 eq.

[0025] Suitable solvents are selected from MeOH, EtOH, n-propanol, IPA, MeCN, acetone, THF and toluene; in particular the solvent is EtOH.

[0026] Step d) Compound (VI) obtained by dissociation of compound (V) and boc protection reaction [ka] Formation of.

[0027] In this step, compound (VI) is synthesized through a dissociation reaction in the presence of a suitable base in a suitable solvent, and then protected with a Boc group. Compound (VI) is purified through recrystallization carried out in a suitable solvent.

[0028] The base used in the dissociation reaction is Na 2 CO 3 , K 2 CO 3 , NaHCO 3 , K.H.C.O. 3 , NaOH, KOH; in particular the base is KOH 2 CO 3 It is.

[0029] The solvent used for the dissociation reaction is selected from IPAc, EtOAc, MTBE, toluene, THF, 2-MeTHF; in particular the solvent is THF.

[0030] The recrystallization is carried out in a suitable solvent at 20° C. to 70° C., particularly 20° C. to 30° C., for 2 to 48 hours, particularly 16 hours, where the suitable solvent is selected from n-heptane, hexane and petroleum ether; in particular the solvent is n-heptane.

[0031] Recrystallization in n-heptane improved the yield and removed excess Boc 2 It is important in the whole process to remove O and avoid di-Boc by-products after deprotection of the benzyl group in step e). In the present invention, the removal and protection by Boc group are telescoping without separation. The recrystallization system designed in this step of the present invention has high yield and high purging effect of impurities. Furthermore, the excess Boc remaining in step d) can be easily removed. 2 The main by-product in step e) after the deprotection reaction with O [ka] Prevent the generation of

[0032] Step e) Compound (I) obtained by deprotection of compound (VI) [ka] Formation of.

[0033] Compounds of formula (I) are deprotected and elaborated using a suitable reducing agent in the presence of a suitable solvent.

[0034] A suitable solvent is selected from MeOH and EtOH; in particular the solvent is EtOH.

[0035] The reducing agent is selected from hydrogenation with Pd / C and Pd(OH) / C; in particular the reducing agent is Pd(OH) / C.

[0036] The reaction temperature is 20°C to 100°C, particularly 65°C to 75°C. EXAMPLES

[0037] The present invention will be more fully understood by reference to the following examples, which should not, however, be construed as limiting the scope of the invention.

[0038] Example 1 3-Benzyl-3-azabicyclo[3.2.1]octan-8-one oxime (compound III) [ka] N 2In a 500 L glass-lined reactor under protection, EtOH (150.00 kg) and 3-benzyl-3-azabicyclo[3.2.1]octan-8-one (Xinlong Pharmaceutical Co., Ltd. compound (II), 27 kg, 125.41 mol, 1.00 eq) were charged at 15°C-25°C. After stirring for 30 min, hydroxylamine hydrochloride (15.7 kg, 225.93 mol, 1.80 eq), sodium acetate (15.4 kg, 187.74 mol, 1.5 eq) were slowly charged in small portions at 15°C-20°C to the reaction mixture. The resulting reaction mixture was heated to 40°C-50°C and stirred for 20 h, after which it was concentrated to remove a portion of the solvent to approximately 60 L-80 L. The residual solution was cooled to 0°C-5°C, followed by the addition of ice water (108 kg) over 20 min at the same temperature range. Then, NaHCO 3 (32.4 kg) was added in small portions to the mixture over 2 h at 0° C. to 20° C. The resulting reaction mixture was stirred for another 1 h at 20° C. to 25° C., and then extracted three times with EA (80 kg). The combined organic layers were washed with water (54 kg) and 20% wt aqueous NaCl solution (40.5 kg), followed by extraction with Na 2 SO 4 The mixture was filtered through a pad of (20 kg) and concentrated to remove some of the solvent to 40-50 L. EtOH (108 kg) was added to the mixture and concentrated to 40-50 L, after which EtOH (108 kg) was added to the residue again and concentrated to 50-60 L to give the crude product, which was used directly in the next step.

[0039] Example 2 3-Benzyl-3-azabicyclo[3.2.1]octan-8-amine (compound (IV)) [ka] A 1000 L glass-lined reactor was charged with EtOH (270 kg) and 3-benzyl-3-azabicyclo[3.2.1]octan-8-one (compound (III), from Example 1). The formed suspension was degassed under vacuum and then purified with N 2After purging three times with 500 cc, Raney-Ni (32 kg, 0.8 wt%) was added at 15°C to 25°C. The resulting suspension was degassed under vacuum and then purified with H 2 The reaction mixture was purged three times with H2 at 0.2 MPa to 0.3 MPa. 2 After heating to 25-30°C under stirring for an additional 14 hours under the above conditions, the mixture was filtered through a pad of MCC (microcrystalline cellulose) and subsequently washed with EtOH (160 kg) to remove the catalyst. The mother liquor was concentrated to about 180 L to obtain crude compound (IV). This crude compound was used in the next step reaction without further purification.

[0040] Example 3 exo-3-benzyl-3-azabicyclo[3.2.1]octan-8-amine; (R)-(-)-mandelic acid (compound (Va)) [ka] To a 300 L glass-lined reactor containing a solution (180 L) of 3-benzyl-3-azabicyclo[3.2.1]octan-8-amine from compound (IV), (R)-(-)-mandelic acid (12 kg, 78.87 mol, 0.60 eq) was charged at 60°C-70°C. After addition, the reaction mixture was stirred at this temperature for an additional 3 h, cooled to 20°C-25°C over 4 h, and stirred at this temperature for an additional 7 h. The solids were separated by centrifuge. The wet cake was washed with EtOH (10 kg) to obtain the crude product, compound (Va), as a wet cake.

[0041] The wet cake and EtOH (126 kg) were charged into a 300 L glass-lined reactor at 15°C-25°C and heated to 80°C-85°C for 6 h with stirring. The solution was cooled to 20°C-30°C over 4 h and stirred at this temperature for an additional 16 h. The solid was separated by centrifuge, washed with EtOH (10 kg), and then dried in a vacuum oven (30 mmHg, 40°C) for 32 h to obtain compound (Va) (16 kg, 34.6% yield (3 steps from compound II), 99.65% chiral purity).

[0042] Compound (Va): 1 H NMR (400 MHz, DMSO-d6) δ=7.37-7.12(m, 11H), 4.51(s, 1H), 2.99(s, 1H), 2.60(dd, J=4.0, 10.7 Hz, 2H), 2.16-2.03(m, 4H), 1.78-1.70(m, 2H), 1.70-1.60(m, 2H)

[0043] Example 4 Exo-tert-butyl N-(3-benzyl-3-azabicyclo[3.2.1]octan-8-yl)carbamate (Compound (VI)) [ka] A 100 L glass-lined reactor was charged with 3-benzyl-3-azabicyclo[3.2.1]octan-8-amine-(R)-(-)-mandelate (compound (V)) (7 kg, 19.0 mol, 1.00 eq.), water (32 kg) and K 2 CO 3 (9.17 kg, 66.35 mol, 3.49 eq.) solution was slowly added at 20°C to 30°C. The resulting reaction mixture was stirred at 20°C to 30°C for 0.5 h, diluted with THF (35 kg), and then Boc 2 O (4.97 kg, 22.77 mol, 1.2 eq) was added dropwise over 1.5 h at 20°C-30°C. After stirring for an additional 16 h at 20°C-30°C, the reaction mixture was extracted three times with EtOAc (25 L). The combined organic layers were washed three times with water (10 kg) and diluted with Na 2 SO 4(3.00 kg) for 0.5 h and then concentrated to remove almost all EtOAc to give 16 kg of crude solid. The crude residue was suspended in n-heptane (10.00 L) and heated with stirring at 50°C-60°C for 3 h. After cooling to 5°C-10°C, it was stirred for an additional 5 h and filtered. The collected solid was washed twice with n-heptane (5 L) and dried under vacuum at 45°C-50°C for 20 h to give tert-butyl N-(3-benzyl-3-azabicyclo[3.2.1]octan-8-yl)carbamate (compound (VI), 5.60 kg, 1.26 mol, 93.5% yield, 99.68% purity) as an off-white solid.

[0044] Compound (VI): 1 HNMR: (400MHz, CDCl 3 )δppm:7.22-7.32(m, 5H), 4.43(s, 1H), 3.49-3.54(d, 1H), 2.66-2.71(dd, 2H), 2.1 9-2.23(d, 2H), 2.12(s, 2H), 1.77-1.84(dd, 2H), 1.64-1.72(dd, 2H), 1.46(s, 9H).

[0045] Example 5 Exo-tert-butyl N-(benzyl-3-azabicyclo[3.2.1]octan-8-yl)carbamate (Compound (I)) [ka] A 100 L autoclave reactor was charged with EtOH (35.00 L), Pd(OH) / C (350.00 g, 10% wt), and tert-butyl N-(3-benzyl-3-azabicyclo[3.2.1]octan-8-yl)carbamate (compound VI, 3.50 kg, 11.06 mol, 1.00 eq) at 10° C.-20° C. The resulting suspension was degassed under vacuum and purified with H. 2 After purging three times with H 2The mixture was heated at 50°C-55°C with stirring under (0.3Mpa-0.4Mpa) atmosphere for 16 hours. The same batch size was repeated three times and combined and then filtered through an MCC pad to remove the catalyst. The filtrate was concentrated twice by azeotroping with n-heptane (10.00L) and mixed with n-heptane (10.00L). The mixture was heated at 50°C-55°C with stirring for 16 hours and then cooled to 20°C-30°C to form a suspension. The solid was collected by vacuum filtration and washed twice with n-heptane (5L). The resulting wet cake was washed twice with n-heptane (5 L) and dried under vacuum at 45°C-50°C for 20 hours to give tert-butyl N-(benzyl-3-azabicyclo[3.2.1]octan-8-yl)carbamate (Compound (I), 6.00 kg, 26.51 mol, 80% yield, 99.38% purity) as an off-white solid.

[0046] Compound (I): 1 HNMR: (400MHz, DMSO) δppm: 6.49(s, 1H), 3.284-3.293(d, 1H), 2.48-2.57(m, 5H), 1.89(s, 2H), 1.66-1.68(m, 2H), 1.40-1.42(d, 2H), 1.34(s, 9H).

Claims

1. Compound (I), 【Chemistry 24】 or a pharma- ceutically acceptable salt thereof, comprising: Step a) Compound (II) 【Chemistry 25】 and hydroxylamine hydrochloride to give compound (III). 【Chemistry 26】 and the imine formation of Step b) Compound (VI) obtained by reduction reaction of compound (III) 【Chemical 27】 The formation of Step c) Compound (V) from compound (VI) and an acid 【Chemistry 28】 wherein the acid is selected from D-glutamic acid, (R)-(-)-mandelic acid, 1-hydroxy-2-naphthoic acid, citric acid, 4-aminosalicylic acid, L-tartaric acid, hippuric acid, malonic acid, glutaric acid, oxalic acid, fumaric acid, succinic acid, 4-aminobenzoic acid, 2,5-dihydroxybenzoic acid, L-malic acid, salicylic acid, maleic acid, (1S,3R)-(-)-camphoric acid, pamoic acid, mucic acid, palmitic acid, oleic acid, and lactobionic acid, in particular wherein the acid is (R)-(-)-mandelic acid; Step d) Compound (VI) obtained by dissociation of compound (V) and boc protection reaction 【Chemical 29】 The formation of Step e) Compound (I) obtained by deprotection of compound (VI) 【Chemistry 30】 and the formation of.

2. 2. The process according to claim 1, characterized in that the formation of compound (IV) in step b) is carried out in the presence of a reducing agent at 0° C. to 70° C., said reducing agent being selected from Na, Pd / c and Raney-Ni, in particular the reaction is carried out in the presence of Raney-Ni at 20° C. to 30° C.

3. 3. The process according to claim 1 or 2, characterized in that the amount of (R)-(-)-mandelic acid used in step c) is 0.1 to 2.0 eq., in particular 0.6 eq.

4. 4. The process according to any one of claims 1 to 3, characterized in that compound (VI) synthesized in step d) is purified through a recrystallization carried out in a solvent, said solvent being selected from n-heptane, hexane and petroleum ether, in particular said solvent being n-heptane.

5. 5. The process according to any one of claims 1 to 4, characterized in that the reduction reaction of step d) is carried out at a temperature between 20°C and 100°C, in particular between 65°C and 75°C.

6. Compound (I) 【Chemistry 31】 or a pharma- ceutically acceptable salt thereof, comprising: Step c) Compound (VI) 【Chemistry 32】 and an acid, 【Chemical 33】 wherein the acid is selected from D-glutamic acid, (R)-(-)-mandelic acid, 1-hydroxy-2-naphthoic acid, citric acid, 4-aminosalicylic acid, L-tartaric acid, hippuric acid, malonic acid, glutaric acid, oxalic acid, fumaric acid, succinic acid, 4-aminobenzoic acid, 2,5-dihydroxybenzoic acid, L-malic acid, salicylic acid, maleic acid, (1S,3R)-(-)-camphoric acid, pamoic acid, mucic acid, palmitic acid, oleic acid, lactobionic acid, in particular wherein the acid is (R)-(-)-mandelic acid, The process includes:

7. Compound (V) 【Chemical 34】 And, A compound wherein the acid is selected from D-glutamic acid, (R)-(-)-mandelic acid, 1-hydroxy-2-naphthoic acid, citric acid, 4-aminosalicylic acid, L-tartaric acid, hippuric acid, malonic acid, glutaric acid, oxalic acid, fumaric acid, succinic acid, 4-aminobenzoic acid, 2,5-dihydroxybenzoic acid, L-malic acid, salicylic acid, maleic acid, (1S,3R)-(-)-camphoric acid, pamoic acid, mucic acid, palmitic acid, oleic acid, and lactobionic acid.

8. exo-3-benzyl-3-azabicyclo[3.2.1]octan-8-amine; (R)-(-)-mandelic acid, 【Chemistry 35】 A compound.

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