Synthesis method of cis-4-methoxy cyclohexylamine hydrochloride
A three-step synthesis of cis-4-methoxycyclohexylamine hydrochloride was achieved by utilizing a regioselective reaction catalyzed by tetraphenylporphyrin copper and mediated by borate esters, combined with palladium-catalyzed hydrogenation. This method solves the synthesis problems in existing technologies and enables efficient and safe industrial production.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-12-17
- Publication Date
- 2026-04-03
AI Technical Summary
In the existing technology, the synthesis method of cis-4-methoxycyclohexylamine hydrochloride is difficult to achieve efficient, safe and low-cost industrial production, and it is also difficult to separate and purify the cis-trans isomers.
A three-step synthesis method was adopted: first, compound I was generated under the catalysis of tetraphenylporphyrin copper, then compound II was generated under the mediation of borate ester, and cis-4-methoxycyclohexylamine hydrochloride was obtained by reacting it with hydrogen chloride via palladium on carbon catalysis. This method controlled the regio and stereoselectivity and avoided the high temperature and high pressure hydrogenation reaction.
The synthesis of high-purity cis-stereotype products was achieved, with a purity exceeding 98%. The process was simplified, equipment requirements and raw material costs were reduced, making it suitable for industrial production.
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Abstract
Description
Technical fields:
[0001] This invention belongs to the field of organic chemistry technology, specifically relating to a method for synthesizing cis-4-methoxycyclohexylamine hydrochloride. Background technology:
[0002] Amino alcohol backbones are widely found in various natural products and bioactive molecules, especially amino alcohols with stereoconfigurations, which are important structural components of many drugs, peptides, and nucleic acids. Among them, cis-4-methoxy-cyclohexylamine hydrochloride (CAS: 61367-43-9) is an organic intermediate used in the synthesis of DNA polymerase inhibitors for cancer treatment.
[0003] Currently, there are few reported methods for the synthesis of cis-4-methoxycyclohexylamine hydrochloride in the literature. The synthesis of cis-4-methoxycyclohexylamine is basically carried out by reducing the benzene ring of 4-methoxyaniline or 4-methoxyphenol to obtain a cis-trans mixture of 4-methoxycyclohexylamine (refer to Chinese Chemical Letters, 2021, 32, 770-774 and Green Chemistry, 2020, 22, 1884-1893). This type of method yields a cis-trans mixture, which is difficult to separate and purify. In addition, the hydrogenation reduction of the benzene ring under high temperature and high pressure noble metal catalysis requires high equipment requirements, has high raw material costs, and is not suitable for industrial production.
[0004] Therefore, it is necessary to conduct in-depth research on the synthesis process of cis-4-methoxycyclohexylamine hydrochloride to provide a better, safer, more stable synthesis method that is suitable for industrial scale-up production in order to meet market demand. Summary of the Invention:
[0005] To overcome the aforementioned technical deficiencies, this invention discloses a method for synthesizing cis-4-methoxycyclohexylamine hydrochloride. The method comprises three steps: First, N-(benzyloxycarbonyl)hydroxylamine and 1,3-cyclohexadiene react under tetraphenylporphyrin copper catalysis with air to generate compound I; second, compound I reacts with sodium methoxide in the presence of a borate ester to generate compound II; third, compound II undergoes catalytic hydrogenation followed by reaction with hydrogen chloride to obtain cis-4-methoxycyclohexylamine hydrochloride. This method is simple to operate and avoids the dangerous high-temperature, high-pressure hydrogenation reaction conditions used in the reduction of benzene rings. Under the mediation of a borate ester, the regioselectivity and stereoselectivity of the ring-opening reaction between sodium methoxide and compound I are controlled to obtain the cis-structured compound II, which is then catalytically hydrogenated and acidified to form a salt, yielding a high-purity cis-stereomeric product. This provides a new route for the synthesis of cis-4-methoxycyclohexylamine hydrochloride.
[0006] The method for synthesizing cis-4-methoxycyclohexylamine hydrochloride according to the present invention includes the following steps:
[0007] In the first step, N-(benzyloxycarbonyl)hydroxylamine and 1,3-cyclohexadiene react under the catalysis of tetraphenylporphyrin copper with air to generate compound I;
[0008] In the second step, compound I reacts with sodium methoxide in the presence of borate ester to form compound II;
[0009] In the third step, compound II and palladium on carbon are catalytically hydrogenated in an organic solvent, and then salted with hydrogen chloride to prepare cis-4-methoxycyclohexylamine hydrochloride.
[0010] The reaction route is represented by the following equation:
[0011]
[0012] The structural formula of the tetraphenylporphyrin copper (TPP-Cu) is as follows:
[0013]
[0014] Furthermore, in the first step, the reaction solvent is selected from toluene, tetrahydrofuran, or 2-methyltetrahydrofuran.
[0015] Furthermore, in the first step, the molar ratio of N-(benzyloxycarbonyl)hydroxylamine, 1,3-cyclohexadiene, and tetraphenylporphyrin copper is 1.0:1.0-1.2:0.01-0.02.
[0016] Furthermore, in the first step, the reaction temperature is selected from 20-50℃, preferably 30-40℃.
[0017] Furthermore, in the second step, the molar ratio of compound I, borate ester, and sodium methoxide is 1.0:0.1-0.2:2.0-3.0.
[0018] Further, in the second step, the borate ester is selected from trimethyl borate or tri(2,2,2-trifluoroethyl) borate, preferably tri(2,2,2-trifluoroethyl) borate.
[0019] Furthermore, in the second step, the reaction solvent is selected from 1,4-dioxane; the reaction temperature is selected from 20-30℃.
[0020] Furthermore, in the third step, the reaction solvent is selected from ethanol or isopropanol; the hydrogen chloride is selected from an ethyl acetate solution of hydrogen chloride.
[0021] Furthermore, in the third step, the molar ratio of compound II to hydrogen chloride is 1:1.0-1.5.
[0022] Furthermore, in the third step, the weight ratio of compound II to palladium on carbon is 1:0.03-0.05.
[0023] Beneficial effects of the invention:
[0024] 1. In this invention, under the catalysis of tetraphenylporphyrin copper, N-(benzyloxycarbonyl)hydroxylamine and 1,3-cyclohexadiene are efficiently and rapidly converted into nitroso compound I in air. Under the mediation of borate ester, the regioselectivity and stereoselectivity of the ring-opening reaction between sodium methoxide and compound I are controlled, ensuring the cis stereoconfiguration of the product and the purity of the product >98%, avoiding the separation and purification of cis-trans isomers. Finally, the reduction and deprotection of the carbon-carbon double bond and isohydroxamic acid of compound II are efficiently completed in one step by palladium-catalyzed hydrogenation. The raw material can be completely converted into cis-4-methoxycyclohexylamine in 12 hours.
[0025] 2. It avoids the reaction conditions of reducing benzene rings with precious metals under high temperature and high pressure, and is safe, stable and easy to operate, providing a new route for the synthesis of cis-4-methoxycyclohexylamine hydrochloride. Attached Figure Description
[0026] Figure 1 The NMR spectrum of cis-4-methoxycyclohexylamine hydrochloride in Example 5 is shown. Detailed Implementation
[0027] Example 1: Synthesis of Compound I
[0028] Under nitrogen protection, 50.1 g (0.30 mol) of N-(benzyloxycarbonyl)hydroxylamine, 28.9 g (0.36 mol) of 1,3-cyclohexadiene, 4.06 g (6 mmol) of tetraphenylporphyrin copper, and 500 mL of toluene were added to the reaction flask. Air was then introduced at 30-40°C (40 cm⁻¹). 3 The reaction was carried out at a rate of 100 g / min for 2 hours. HPLC analysis showed that the remaining N-(benzyloxycarbonyl)hydroxylamine was <0.2%, indicating the reaction was complete. The solvent was concentrated under reduced pressure, and 150 mL of anhydrous ethanol and 4.0 g of activated carbon were added. The mixture was stirred at room temperature for 1 hour, filtered, and the filtrate was concentrated under reduced pressure to obtain 90-100 mL of anhydrous ethanol. Distillation was stopped, and 500 mL of n-heptane was added. The mixture was stirred at -10 to 0 °C for 1 hour, filtered, and 70.9 g of a white solid (I) was obtained, with a yield of 96.3% and an HPLC purity of 98.5%. 1H-NMR (400MHz, CDCl3): 1.43-1.31(m,1H).1.52(tt,J=12.2,2.9Hz,1H),2.16(ddt,J=12.4,9.0,3.1Hz,1H),2.26-2.17(m,1H),4.79(dd d,J=5.5,3.8,1.9Hz,1H),4.96(td,J=5.4,2.8Hz,1H),5.19(dd,J=29.2,12.3Hz,2H),6.61-6.49(m,2H),7.41-7.30(m,5H).
[0029] Example 2 Synthesis of Compound I
[0030] Under nitrogen protection, 100.3 g (0.60 mol) of N-(benzyloxycarbonyl)hydroxylamine, 52.9 g (0.66 mol) of 1,3-cyclohexadiene, 4.06 g (6 mmol) of tetraphenylporphyrin copper, and 1 L of 2-methyltetrahydrofuran were added to the reaction flask. Air was then introduced at 30-40°C (80 cm⁻¹). 3 The reaction was carried out at a rate of 100 g / min for 2 hours. HPLC analysis showed that the remaining N-(benzyloxycarbonyl)hydroxylamine was <0.2%, indicating the reaction was complete. The solvent was concentrated under reduced pressure, and 300 mL of anhydrous ethanol and 4.0 g of activated carbon were added. The mixture was stirred at room temperature for 1 hour, filtered, and the filtrate was concentrated under reduced pressure to obtain 180-200 mL of anhydrous ethanol. Distillation was stopped, and 1 L of n-heptane was added. The mixture was stirred at -10 to 0 °C for 1 hour, filtered, and 142.7 g of a white solid (I) was obtained, with a yield of 97.0% and an HPLC purity of 98.8%.
[0031] Example 3 Synthesis of Compound II
[0032] 600 mL of 1,4-dioxane, 70.9 g (0.29 mol) of compound I obtained in Example 1, 47.0 g (0.87 mol) of sodium methoxide, and 6.0 g (0.058 mol) of trimethyl borate were added to the reaction flask. The mixture was stirred at room temperature for 8 hours. The concentration of compound I was controlled to be <0.3% by HPLC. The pH was adjusted to 6-7 by slowly adding 1N dilute hydrochloric acid at 0-10 °C. The mixture was extracted three times with 200 mL of ethyl acetate each time. The organic layers were combined, washed once with saturated brine, and concentrated under reduced pressure to obtain a crude product. The crude product was slurried with 200 mL of n-heptane and filtered to obtain 46.8 g of white solid compound II, with a yield of 58.4%. 11H-NMR (400MHz, DMSO-d6): 1.67-1.77 (m, 2H), 2.06-2.43 (m, 2H), 3.26 (s, 3H), 3.73 (s, 2H), 4.31 (bs, 1H), 5.34 (bs, 1H), 5.75 (d, J = 4.8Hz, 1H), 6.07 (d, J = 5.4Hz, 1H), 7.28 (m, 5H), 9.62 (s, 1H); A small amount of the trans-ring-opening product compound III was visible in the 1H NMR spectrum, and the ratio of compound II to compound III was 76 / 1.
[0033]
[0034] Example 4 Synthesis of Compound II
[0035] 1.2 L of 1,4-dioxane, 142.7 g (0.58 mol) of compound I obtained in Example 2, 62.9 g (1.16 mol) of sodium methoxide, and 17.9 g (0.058 mol) of tris(2,2,2-trifluoroethyl) borate were added to the reaction flask. The mixture was stirred at room temperature for 8 hours. The concentration of compound I was controlled to be <0.3% in HPLC. The pH was adjusted to 6-7 by slowly adding 1N dilute hydrochloric acid at 0-10°C. The mixture was extracted three times with 400 mL of ethyl acetate each time. The organic layers were combined, washed once with saturated brine, and concentrated under reduced pressure to obtain a crude product. The crude product was slurried in 400 mL of n-heptane and filtered to obtain 134.9 g of white solid compound II, with a yield of 83.9% and an HPLC purity of 98.9%. 1 No trans-ring-opening product compound III was observed in H-NMR.
[0036] Example 5: Synthesis of cis-4-methoxycyclohexylamine hydrochloride
[0037] Compound II (62.8 g, 0.226 mol) obtained in Example 3, 10% palladium on carbon (3.15 g), and 500 mL isopropanol were added to a hydrogenation reactor. The reactor was purged with nitrogen three times, and hydrogen was introduced to a pressure of 1.0 MPa. The mixture was stirred at 40-50°C for 12 hours. After cooling to room temperature and purging the nitrogen atmosphere, the mixture was filtered. The filtrate was concentrated under reduced pressure to obtain approximately 450 mL of solvent. 120 mL of ethyl acetate was added, and 85 mL of 4M ethyl hydrochloride solution was added dropwise at 20-30°C. The mixture was stirred at room temperature for 2 hours, then slowly cooled to 0°C and stirred for 1 hour. After filtration and drying, 33.9 g of a white solid, cis-4-methoxycyclohexylamine hydrochloride, was obtained with a purity of 98.9% and a yield of 90.6%. 1 HNMR characterization spectra as follows Figure 1 As shown.
[0038] Example 6: Synthesis of cis-4-methoxycyclohexylamine hydrochloride
[0039] 134.9 g (0.486 mol) of compound II obtained by the method in Example 4, 6.7 g of 10% palladium on carbon, and 1 L of anhydrous ethanol were added to a hydrogenation reactor. The reactor was purged with nitrogen three times, and hydrogen was introduced to a pressure of 1.0 MPa. The mixture was stirred at 40-50 °C for 12 hours. After cooling to room temperature and purging the nitrogen atmosphere, the mixture was filtered. The filtrate was concentrated under reduced pressure to obtain approximately 900 mL of solvent. 260 mL of ethyl acetate was added, and 146 mL of a 4M hydrogen chloride solution in ethyl acetate was added dropwise at 20-30 °C. The mixture was stirred at room temperature for 2 hours, and then slowly cooled to 0 °C and stirred for 1 hour. After filtration and drying, 71.3 g of a white solid, cis-4-methoxycyclohexylamine hydrochloride, with a purity of 99.5% and a yield of 88.5% was obtained.
[0040] The foregoing has shown and described the basic principles, main features, and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited to the above embodiments. The embodiments and descriptions in the specification are merely illustrative of the principles of the invention. Various changes and modifications can be made to the invention without departing from its spirit and scope, and all such changes and modifications fall within the scope of the present invention as claimed. The scope of protection of this invention is defined by the appended claims and their equivalents.
Claims
1. A method for synthesizing cis-4-methoxycyclohexylamine hydrochloride, characterized in that, Includes the following steps: In the first step, N-(benzyloxycarbonyl)hydroxylamine and 1,3-cyclohexadiene react under the catalysis of tetraphenylporphyrin copper with air to generate compound I; In the second step, compound I reacts with sodium methoxide in the presence of borate ester to form compound II; In the third step, compound II and palladium on carbon are catalytically hydrogenated in an organic solvent, and then salted with hydrogen chloride to prepare cis-4-methoxycyclohexylamine hydrochloride.
2. The method for synthesizing cis-4-methoxycyclohexylamine hydrochloride according to claim 1, characterized in that: In the first step, the reaction solvent is selected from toluene, tetrahydrofuran, or 2-methyltetrahydrofuran.
3. The method for synthesizing cis-4-methoxycyclohexylamine hydrochloride according to claim 1, characterized in that: In the first step, the molar ratio of N-(benzyloxycarbonyl)hydroxylamine, 1,3-cyclohexadiene and tetraphenylporphyrin copper is 1.0:1.0-1.2:0.01-0.
02.
4. The method for synthesizing cis-4-methoxycyclohexylamine hydrochloride according to claim 1, characterized in that: In the first step, the reaction temperature is selected from 20-50℃.
5. The method for synthesizing cis-4-methoxycyclohexylamine hydrochloride according to claim 1, characterized in that: In the second step, the molar ratio of compound I, borate ester, and sodium methoxide is 1.0:0.1-0.2:2.0-3.
0.
6. The method for synthesizing cis-4-methoxycyclohexylamine hydrochloride according to claim 1, characterized in that: In the second step, the borate ester is selected from trimethyl borate or tri(2,2,2-trifluoroethyl) borate.
7. The method for synthesizing cis-4-methoxycyclohexylamine hydrochloride according to claim 1, characterized in that: In the second step, the reaction solvent is selected from 1,4-dioxane, and the reaction temperature is selected from 20-30℃.
8. The method for synthesizing cis-4-methoxycyclohexylamine hydrochloride according to claim 1, characterized in that: In the third step, the organic solvent is selected from ethanol or isopropanol; the hydrogen chloride is selected from an ethyl acetate solution of hydrogen chloride.
9. The method for synthesizing cis-4-methoxycyclohexylamine hydrochloride according to claim 1, characterized in that: In the third step, the molar ratio of compound II to hydrogen chloride is 1:1.0-1.
5.
10. The method for synthesizing cis-4-methoxycyclohexylamine hydrochloride according to claim 1, characterized in that: In the third step, the weight ratio of compound II to palladium on carbon is 1:0.03-0.05.