A process for the preparation of (1S,3S)-3-aminocyclopentyl tert-butyl carbamate

Abstract

The application discloses a preparation method of (1S, 3S)-3-aminocyclopentyl carbamic acid tert-butyl ester, which comprises the following steps: protecting the hydroxyl group of compound A by an acid anhydride or an acyl chloride to obtain compound B; substituting reaction of the compound B and potassium phthalimide to obtain compound C; and carrying out an ammonolysis reaction on the phthalimide of the compound C to obtain a target compound D. The preparation method avoids the use of high-risk reagents such as toxic and explosive materials, is high in safety, low in production cost, high in raw material availability, high in yield, and simple in reaction process and post-treatment operation.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of pharmaceutical chemistry, and particularly relates to a preparation method of (1S,3S)-3-aminocyclopentyl tert-butyl carbamate. BACKGROUND

[0002] (1S,3S)-3-aminocyclopentyl tert-butyl carbamate is a key intermediate for the preparation of various drugs, such as NMDA / NR2B antagonists of Merck, which can be used for treating neurological conditions such as, for example, pain, Parkinson's disease, Alzheimer's disease, epilepsy, depression, anxiety, ischemic brain injury including stroke and other conditions; therapeutic agents I of AstraZeneca AB (Sweden) for the treatment of obesity, mental disorders, cognitive disorders, memory disorders, schizophrenia, epilepsy and related conditions, and neurological disorders such as dementia, multiple sclerosis, Parkinson's disease, Huntington's chorea and Alzheimer's disease, and pain-related conditions, and pharmaceutical compositions containing them; MCHIR antagonists of Astrazeneca for the treatment of obesity, psychiatric disorders, cognitive disorders, memory disorders, schizophrenia, epilepsy and related conditions, and neurological disorders such as dementia, multiple sclerosis, Parkinson's disease, Huntington's chorea and Alzheimer's disease, and pain-related conditions.

[0003] The preparation of (1S,3S)-3-aminocyclopentyl tert-butyl carbamate disclosed in the prior art (WO2005066132 A1; WO2005019221 A1; WO2004004726 A1) is to take [(1S,3R)-3-hydroxycyclopentyl] tert-butyl carbamate as the raw material, to protect the hydroxyl group by MsCl, to substitute by sodium azide, and finally to reduce the azide group by palladium-carbon hydrogenation to obtain the target product. However, the synthetic method has the following problems: methylsulfonyl chloride is a strictly controlled chemical reagent belonging to the list of toxic chemicals and cannot be obtained in large quantities, and the reagent is highly toxic and is prone to leakage and other safety accidents during production, processing, transportation, use and post-processing; sodium azide is also a strictly controlled chemical reagent belonging to toxic chemicals and explosives, and cannot be obtained in large quantities at present, and the reagent is prone to leakage and explosion and other safety accidents during production, processing, transportation, use and post-processing; at the same time, the last step uses palladium-carbon, which makes the operation risk great and the cost high. The specific reaction formula is shown in the following formula:

[0004]

[0005] In view of the safety hazards and high cost of the above route, it is necessary to develop a safe and low-cost synthetic route to obtain (1S,3S)-3-aminocyclopentyl tert-butyl carbamate compound. SUMMARY

[0006] The application aims to provide a safe, efficient and low-cost preparation method of (1S, 3S)-3-aminocyclopentyl tert-butyl carbamate.

[0007] The application relates to a preparation method of (1S, 3S)-3-aminocyclopentyl tert-butyl carbamate.

[0008] (1) reacting compound A with a hydroxyl protecting agent in a base and a solvent to obtain compound B

[0009]

[0010] (2) reacting compound B with a phthalimide salt in a solvent to obtain compound C

[0011]

[0012] (3) obtaining compound D, i.e. (1S, 3S)-3-aminocyclopentyl tert-butyl carbamate, from compound C in a base and a solvent

[0013]

[0014] Further, the hydroxyl protecting agent in step (1) is any one or more of methanesulfonic anhydride, methanesulfonyl chloride, p-toluenesulfonic anhydride or p-toluenesulfonyl chloride.

[0015] Further, the solvent in step (1) is any one or more of dichloromethane, pyridine, tetrahydrofuran, acetonitrile, propionitrile, butyronitrile, 1,4-dioxane, chlorobenzene, dichlorobenzene, toluene, N-methylpyrrolidone, N,N-dimethylformamide, dimethyl sulfoxide or N,N-dimethylacetamide.

[0016] Further, the base in step (1) is any one or more of pyridine, N,N-diisopropylethylamine (DIPEA), triethylamine (TEA), N,N,N',N'-tetramethyl ethylenediamine (TMEDA), potassium carbonate, sodium carbonate or cesium carbonate.

[0017] Preferably, the hydroxyl protecting agent in step (1) is methanesulfonic anhydride, the solvent is dichloromethane, and the base is pyridine.

[0018] Further, the phthalimide salt in step (2) is any one or more of phthalimide potassium salt, phthalimide sodium salt, phthalimide magnesium salt or phthalimide lithium salt.

[0019] Further, the solvent in step (2) is any one or more of N,N-dimethylformamide, pyridine, tetrahydrofuran, acetonitrile, propionitrile, butyronitrile, 1,4-dioxane, N-methylpyrrolidone, dimethyl sulfoxide or N,N-dimethylacetamide.

[0020] As a preference, the phthalimide salt in step (2) is potassium phthalimide, and the solvent is N,N-dimethylformamide.

[0021] Further, the solvent in step (3) is any one or more of methanol, ethanol, n-butanol, t-butanol, N,N-dimethylformamide, pyridine, tetrahydrofuran, 1,4-dioxane, N-methylpyrrolidone, dimethyl sulfoxide or N,N-dimethylacetamide.

[0022] Further, the base in step (3) is any one or more of n-butylamine, n-propylamine, methylamine, ethylamine, hydrazine hydrate or ethanolamine.

[0023] As a preference, the solvent in step (3) is methanol, and the base is n-butylamine.

[0024] Further, the reaction temperature in step (1) is 0-5℃, the reaction temperature in step (2) is 60-80℃, and the reaction temperature in step (3) is 70-80℃.

[0025] As a preference, the reaction temperature in step (1) is 5℃, the reaction temperature in step (2) is 70℃, and the reaction temperature in step (3) is 75℃.

[0026] Advantages: Compared with the prior art, the present application has the following remarkable advantages:

[0027] The preparation method disclosed by the present application avoids the use of highly toxic, easily explosive and other high-risk reagents, has high safety, the raw materials are cheap and easy to obtain, the production cost is low, the reaction process and post-treatment operation are simple, and the compound prepared by the specific preparation method of the present application not only has high yield but also high purity. Secondly, the preparation method has strong compatibility, low equipment requirement, does not need to participate in the reaction of ammonia gas, has higher atomic utilization rate, and the last step of post-treatment is simpler. BRIEF DESCRIPTION OF DRAWINGS

[0028] Figure 1 is the H spectrum of compound B;

[0029] Figure 2 is the H spectrum of compound C;

[0030] Figure 3 is the H spectrum of compound D;

[0031] Figure 4LCMS of compound C

[0032] Figure 5 LCMS of compound D. DETAILED DESCRIPTION

[0033] Example 1

[0034] Preparation of compound B:

[0035]

[0036] Compound A (tert-butyl (1 S,3R)-3-hydroxycyclopentyl)carbamate (10 g, 50 mmol, 1 eq) was added into a single-neck flask, dissolved in dichloromethane (100 mL), then pyridine (3 eq) was added, and then the internal temperature was lowered to 5 degrees Celsius, then a solution of methanesulfonic anhydride (Ms20) (13 g, 75 mmol, 1.5 eq) in dichloromethane 20 ml was added dropwise, and after the dropwise addition was completed, stirring was carried out at 5 degrees Celsius for 4 hours. The reaction was monitored by TLC, and when the reaction was completed, the reaction solution was poured into 300 mL of distilled water and stirred for 30 minutes, then 1 N HC1 was added to adjust the pH to 2, and then 50 ml of ethyl acetate was added to extract the product, and then the organic phase was washed once with sodium bicarbonate and sodium chloride, and then dried over sodium sulfate, and then rotary evaporation was carried out to obtain 13.2 g of crude compound B, with a yield of 94%, and the hydrogen spectrum of compound B is shown in Figure 1

[0037] 1 HNMR: (400 MHz, DMSO) δ 6.973 (d, 1H), 5.005 (t, 1H), 3.759 (t, 1H), 3.139 (s, 3H), 2.337 (M, 1H), 1.867 (M, 3H), 1.67 (M, 1H), 1.635 (M, 1H), 1.4 (s, 9H).

[0038] Preparation of compound C

[0039]

[0040] ​Compound B (50 g, 181.22 mmol, 1 eq) was taken in 2000 ml single neck flask, dissolved in N,N-dimethylformamide (906 ml), purged with N2for 3 times, then added potassium phthalimide salt (50.35 g, 271.83 mmol, 1.5 eq), purged with N2for 3 times. Heated to 70 °C and stirred for 6 h. TLC monitored the end of the reaction, poured the reaction liquid into 3 L distilled water, extracted with ethyl acetate (500 ml) twice, combined the organic phase and washed with saturated NaCl solution (500 ml) once, dried over anhydrous sodium sulfate, rotary evaporation to get compound C crude product 77.4 g, yield 130%. To the compound C crude product, added ethyl acetate (100 ml), heated to 75 °C to reflux dissolution, then added n-heptane 400 ml, cooled to precipitate solid, suction filtration and rotary evaporation to get product 47 g, yield 81%, HPLC purity 97%, the hydrogen spectrum of compound C is shown in Figure 2 , and the mass spectrum is shown in Figure 4 .

[0041] 1 H NMR: (400 MHz, DMSO) δ 7.857 (s, 4H), 6.973 (s, 1H), 4.69 (M, 1H), 4.139 ((s, 1H), 2.229 (M, 1H), 2.112 (M, 1H), 2.082 (M, 2H), 1.8 (M, 1H), 1.5 (M, 1H), 1.39 (s, 9H). LCMS: ESI: [M- t Bu+H] + = 275

[0042] Preparation of compound D

[0043]

[0044] Compound C prepared in this example (20 g, 60.6 mmol, 1 eq) was taken in 250 ml single neck flask, dissolved in methanol (85 ml), added n-butylamine (65 g, 900 mmol, 15 eq) at room temperature. Heated to 75 °C and stirred for 24 h. TLC monitored the end of the reaction, rotary evaporation of methanol and most of the n-butylamine, the rotary evaporation of the crude product 10% methanol / dichloromethane, 200-300 mesh silica gel column to get product 10 g, yield 85%, HPLC purity 98%, the hydrogen spectrum of compound D is shown in Figure 3 , and the mass spectrum of compound D is shown in Figure 5 .

[0045] 1HNMR: (400 MHz, DMSO) δ 6.752 (s, 1H), 3.907 (M, 1H), 3.325 (M, 2H), 1.926 (M, 1H), 1.815 (M, 1H), 1.534 (M, 2H), 1.435 (M, 9H), 1.277 (M, 1H), 1.124 (M, 1H). LCMS: ESI: [M- t Bu+H] + = 145

[0046] Comparative Example 1

[0047]

[0048] Synthesis of Compound B

[0049] Compound A (10 g, 50 mmol, 1 eq) was added to a single-neck flask, pyridine (60 mL) was added to dissolve, then methanesulfonic anhydride (13 g, 75 mmol, 1.5 eq) was added, and a slight exothermic heat of about 25°C was observed, and the reaction was stirred at room temperature for 4 h. TLC monitoring showed that the reaction was complete, the reaction solution was poured into 300 mL of water and stirred for 30 min, 2N HCl was added to adjust the solution pH to 3, and the product was extracted with ethyl acetate, the organic phase was washed once with sodium chloride, dried over sodium sulfate, and rotary evaporated to obtain 12.5 g of crude product Compound B, with a yield of 89%.

[0050] Synthesis of Compound E

[0051] Compound B (10 g, 36 mmol, 1 eq) was added to a single-neck flask, acetonitrile (70 mL) was added to dissolve, then benzylamine (4.2 g, 39.6 mmol, 1.1 eq) was added, and then potassium carbonate (5 g, 36 mmol, 1 eq) was added and heated to 85°C to reflux, and stirred for 14 h. TLC monitoring showed that Compound B disappeared, indicating that the reaction was complete, the reaction solution was cooled to room temperature, the salt was removed by suction filtration on filter paper, and the filtrate was rotary evaporated to obtain 13 g of crude product Compound E, with a yield of 130%. It was directly used in the next step.

[0052] Synthesis of Compound D

[0053] Compound E (10 g, 36 mmol, 1 eq) was added to a single-neck flask, methanol (20 mL) was added to dissolve, then palladium on carbon (10 g, 100% W) was added, and then vacuum injection of hydrogen was performed, and stirred for 20 h. TLC monitoring showed that Compound E disappeared, indicating that the reaction was complete, the palladium on carbon was removed by suction filtration on filter paper, and the filtrate was rotary evaporated to obtain 9 g of crude product Compound D, which was rotary evaporated to a sticky solid, 36 ml of tert-butyl methyl ether was added, stirred for 30 min, suction filtered, and rotary evaporated to obtain 5 g of pure product, with a yield of 71% and an HPLC purity of 82%.

[0054] Comparative Example 1, although the excipient is easy to obtain, and the post-treatment does not require the use of water, spin-drying, stirring or recrystallization. However, Comparative Example 1 uses too much palladium-carbon in the preparation of compound D, and the palladium-carbon itself is a kind of active metal, which can self-ignite in the air. The reaction requires the participation of hydrogen, which is a dangerous flammable gas. The combination of hydrogen and palladium-carbon with self-ignition risk makes the operation extremely risky. Moreover, palladium-carbon is a noble metal, which is expensive to sell, increasing the cost of use, and is not suitable for large-scale industrial production. Moreover, the yield and purity of product D prepared by the method of Comparative Example 1 are obviously inferior to those of Example 1 of the present application.

[0055] Comparative Example 2

[0056]

[0057] Synthesis of Compound B

[0058] Compound A (10 g, 50 mmol, 1 eq) was added to a single-neck flask, pyridine (60 mL) was added to dissolve the solution, then methyl sulfonic anhydride (13 g, 75 mmol, 1.5 eq) was added, which was slightly exothermic at about 25°C, and stirred at room temperature for 4 h. TLC monitoring showed that the reaction was completed. The reaction liquid was poured into 300 mL of water and stirred for 30 minutes. 2N HCl was used to adjust the pH to 3-4. The product was extracted with ethyl acetate. The organic phase was washed once with sodium chloride. Sodium sulfate was used for drying. The rotary evaporation gave 11.9 g of crude product B with a yield of 84%. It was directly used for the next step.

[0059] Synthesis of Compound D

[0060] Compound B (5 g, 17.9 mmol, 1 eq) was added to a muffle, tetrahydrofuran (36 mL) was added to dissolve the solution, then ammonia was introduced for 5 minutes to saturate the tetrahydrofuran, and it was heated at 55°C for 24 h. After cooling and pressure relief, TLC monitoring showed that the reaction was completed. The tetrahydrofuran and most of the ammonia were rotary evaporated. The rotary-evaporated crude product was passed through a column with 10% methanol / dichloromethane and 200-300 mesh silica gel to obtain 2.8 g of product with a yield of 78% and a HPLC purity of 94%.

[0061] Comparative Example 2 has a shorter synthesis route and lower cost than Example 1. However, Comparative Example 2 requires the introduction of ammonia in the second step (synthesis of compound D), which involves pressure equipment, has high requirements for equipment, is highly corrosive, and has a higher risk coefficient for operators. Moreover, the yield of product D prepared by the method of Comparative Example 2 is obviously inferior to that of Example 1 of the present application.

Claims

1. A process for the preparation of (1S,3S)-tert-butyl 3-aminocyclopentylcarbamate, characterized in that, Specifically comprising the following steps: (1) Compound A is reacted with a hydroxyl protecting agent in the presence of a base and a solvent to obtain compound B (2) Compound B is reacted with a phthalimide salt in a solvent to obtain compound C (3) Compound C is reacted in the presence of a base and a solvent to obtain compound D, i.e. tert-butyl (1S,3S)-3-aminocyclopentylcarbamate The hydroxyl protecting agent in step (1) is selected from any one or more of methanesulfonic anhydride, p-toluenesulfonic anhydride or p-toluenesulfonyl chloride; The base in step (1) is selected from any one or more of pyridine, N,N-diisopropylethylamine, N,N,N',N'-tetramethyl ethylenediamine, potassium carbonate, sodium carbonate or cesium carbonate; The base in step (3) is selected from any one or more of n-butylamine, n-propylamine, methylamine, ethylamine or ethanolamine; The reaction temperature in step (1) is 0-5 degrees Celsius, the reaction temperature in step (2) is 60-80 degrees Celsius, and the reaction temperature in step (3) is 70-80 degrees Celsius.

2. The production method according to claim 1, characterized by, The solvent in step (1) is selected from any one or more of dichloromethane, pyridine, tetrahydrofuran, acetonitrile, propionitrile, butyronitrile, 1,4-dioxane, chlorobenzene, dichlorobenzene, toluene, N-methylpyrrolidone, N,N-dimethylformamide, dimethyl sulfoxide or N,N-dimethylacetamide.

3. The preparation method according to claim 1, characterized in that, The phthalimide salt in step (2) is any one or more of potassium phthalimide, sodium phthalimide, magnesium phthalimide or lithium phthalimide.

4. The method of claim 1, wherein, The solvent in step (2) is any one or more of N,N-dimethylformamide, pyridine, tetrahydrofuran, acetonitrile, propionitrile, butyronitrile, 1,4-dioxane, N-methylpyrrolidone, dimethyl sulfoxide or N,N-dimethylacetamide.

5. The preparation method according to claim 1, characterized in that, The solvent in step (3) is selected from any one or more of methanol, ethanol, n-butanol, tert-butanol, N,N-dimethylformamide, pyridine, tetrahydrofuran, 1,4-dioxane, N-methylpyrrolidone, dimethyl sulfoxide or N,N-dimethylacetamide.

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