CN108409639B - Preparation and structure confirmation method of (S) -3-Boc-aminomethyl piperidine - Google Patents
Preparation and structure confirmation method of (S) -3-Boc-aminomethyl piperidine Download PDFInfo
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- CN108409639B CN108409639B CN201810368264.0A CN201810368264A CN108409639B CN 108409639 B CN108409639 B CN 108409639B CN 201810368264 A CN201810368264 A CN 201810368264A CN 108409639 B CN108409639 B CN 108409639B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Abstract
The invention discloses preparation and structure confirmation of (S) -3-Boc-aminomethyl piperidine, wherein a compound 5 is obtained by benzylating a compound 1, reducing carbonyl, protecting amino and carrying out catalytic hydrogenation; and deriving the compound 5 to obtain a crystal, and performing diffraction test and analysis on the crystal to obtain the compound 5, namely (S) -3-Boc-aminomethyl piperidine with the optical rotation of-8.98, thereby further verifying that the method for preparing the compound 5 is feasible. The preparation method uses the cheap and easily-obtained chiral raw material compound 1, does not need a resolving agent, and has advantages in yield and cost; the product is tested in a derivation and diffraction mode to determine the correct configuration, and the preparation and confirmation method forms a system, is beneficial to industrial production and has wide application prospect.
Description
Technical Field
The invention belongs to the field of chemistry, and particularly relates to a novel preparation and structure confirmation method of (S) -3-Boc-aminomethyl piperidine.
Background
(S) -3-Boc-aminomethyl piperidine as a white or off-white crystalline powder which is highly effective in cardiovascular disease, and is a fragment of this class of drugs having the following formula:
at present, in the prior art, (S) -3-Boc-aminomethyl piperidine is prepared by splitting 3-Boc-aminomethyl piperidine, a resolving agent used for preparation is L-DTTA (L- (-) -di-p-methylbenzoyl tartaric acid, the yield is below 33%, the yield is lower, the material cost for synthesizing the 3-Boc-aminomethyl piperidine is higher, and three wastes are discharged in the production process.
Disclosure of Invention
The invention aims to: in view of the above problems, a novel method for preparing (S) -3-Boc-aminomethyl piperidine and for confirming the structure thereof is provided. By using cheap and easily-obtained chiral raw materials, a product with chirality is directly synthesized without using a resolving agent, and the method has certain advantages in yield and cost; and the crystal is cultured after derivation, and a single crystal diffraction test is carried out to determine that the product is S configuration, thereby further proving the feasibility of the preparation method.
The technical scheme adopted by the invention is as follows: the new preparation method of (S) -3-Boc-aminomethyl piperidine comprises the following synthetic route:
wherein the benzyl halide comprises one of benzyl bromide, benzyl chloride and benzyl iodide; the reducing agent comprises one of lithium aluminum hydride, diborane, sodium borohydride, aluminum hydride, lithium amino borohydride and sodium borohydride-titanium chloride; the weak base comprises one of triethylamine and potassium carbonate; the catalyst comprises one of palladium/carbon, platinum/carbon, rhodium/carbon, and ruthenium/carbon.
The specific preparation steps of the compound 2 are as follows: at room temperature, dissolving the compound 1 in N, N-dimethylformamide, adding potassium carbonate in batches, cooling to 8-12 ℃, dropwise adding benzyl halide, controlling the temperature to be 10-20 ℃, and reacting the system for 18-22 h; pouring the reaction solution into ice water, stirring and centrifuging to obtain a crude product; extracting, concentrating, purifying and drying the crude product to obtain the compound 2.
Further, in the specific preparation step of the compound 2, the molar ratio of the compound 1 to the benzyl halide is 1: 1.0-1: 1.1; the molar ratio of the compound 1 to the potassium carbonate is 1: 2.5-1: 3.0; the mass ratio of the compound 1 to the N, N-dimethylformamide is 1: 10.6-1: 10.8.
the specific preparation steps of the compound 3 are as follows: adding a reducing agent into tetrahydrofuran in batches at room temperature, and heating the system to 40 ℃ after the addition is finished; 50-55 percent of compound 2 dissolved in tetrahydrofuran is added into the reaction system for reaction under the temperature of 40-55 ℃; after the reaction is finished, adding 500-520 mass percent tetrahydrofuran aqueous solution into the reaction system, filtering with diatomite, washing, concentrating and drying to obtain yellow oily compound 3.
Further, the molar ratio of the compound 2 to the reducing agent in the specific preparation step of the compound 3 is 1: 1.4-1: 1.6; the mass ratio of the tetrahydrofuran to the reducing agent is 20: 1-21: 1.
the specific preparation steps of the compound 4 are as follows: adding potassium carbonate into water in batches at room temperature, adding a compound 3 after dissolving, and cooling to 15 ℃; 62-67% of Boc by mass2Slowly dripping O-ethanol solution, controlling the temperature to be 10-20 ℃ for reaction; after the reaction is finished, filtering and purifying to obtain the compound 4.
Further, the weak acid, the compound 3 and the Boc in the specific preparation step of the compound 42The molar ratio of O is 1.30-1.35: 1.01-1.06: 1.00-1.05; the mass ratio of the water to the weak acid is 11: 1-13: 1.
The specific preparation steps of the compound 5 are as follows: dissolving the compound 4, 5-8% of catalyst in methanol, reacting at 20-25 ℃ for 3-5 h, filtering with diatomite, concentrating, purifying and drying to obtain the compound 5; the mass ratio of the methanol, the compound 4 and the catalyst is 65-68: 9.60-10.00: 1.00-1.05.
Further, the extracting agent used in the extraction in the specific preparation step is one of dichloromethane, methyl tert-butyl ether and ethyl tert-butyl ether, preferably dichloromethane; the solvent used for purification is one of petroleum ether, n-heptane and diethyl ether, preferably petroleum ether; the drying agent is at least one of anhydrous sodium sulfate, anhydrous magnesium sulfate, activated carbon, anhydrous calcium chloride and the like, and preferably the anhydrous sodium sulfate.
Specifically, the (S) -3-Boc-aminomethyl piperidine is prepared through the process without using a resolving agent, the preparation method is simple, and the reaction conditions are mild.
The novel structure confirmation method of (S) -3-Boc-aminomethyl piperidine comprises the following specific derivation reaction formula:
the specific operation method of the reaction is as follows: dissolving N-benzyloxycarbonyl-L-proline and N-methylmorpholine in tetrahydrofuran, cooling the ice salt to-5-0 ℃, dropwise adding ethyl chloroformate, and stirring for reaction after dropwise adding; after the reaction is finished, dropwise adding the compound 5, and naturally returning the temperature to react for 12-15 h after the dropwise adding is finished; quenching the reaction by ice water, extracting, washing, drying, filtering, concentrating, and passing through a silica gel column to obtain a white solid, namely the compound 5.
Further, the mass ratio of the N-benzyloxycarbonyl-L-proline, N-methylmorpholine to ethyl chloroformate was 2.2-2.5: 1.3-1.5: 0.8-1.0; the mass ratio of the compound 5 to the N-benzyloxycarbonyl-L-proline is 1: 1.15-1: 1.18; the extractant used for extraction is at least one of ethyl acetate, butyl acetate and butanone, preferably ethyl acetate; the drying agent is at least one of anhydrous sodium sulfate, anhydrous magnesium sulfate, activated carbon, anhydrous calcium chloride and the like, and preferably the anhydrous sodium sulfate.
Specifically, the feasibility of the novel method for preparing (S) -3-Boc-aminomethyl piperidine is further verified by culturing the derivative of compound 5 and measuring the corresponding configuration of the crystal by using a single crystal diffraction method to estimate the configuration of compound 5.
In summary, due to the adoption of the technical scheme, the invention has the beneficial effects that: by adopting the novel preparation and structure confirmation method of the (S) -3-Boc-aminomethyl piperidine, the chiral raw materials which are cheap and easy to obtain are used for directly synthesizing the product with chirality, and a resolving agent is not used, so that the method has the advantages of yield and cost; the obtained product is subjected to derivation culture crystal and single crystal diffraction test, and the configuration of the product produced by the synthesis method is (S) -3-Boc-aminomethyl piperidine, the optical purity is more than 99%, and the optical rotation value is-8.98, so that the synthesis method is further proved to be feasible; the synthesis method and the confirmation means form a production and detection system, are suitable for industrial production and have wide application prospect.
Drawings
FIG. 1 is a synthetic route for Compound 5;
FIG. 2 is a scheme of derivatization of Compound 5;
FIG. 3 is the structural formula of Compound 5;
figure 4 is a single crystal diffractogram of compound 6.
Detailed Description
Example 1
Preparation of Compound 2
Introducing nitrogen into a 50L double-layer glass reaction kettle at room temperature, adding N, N-dimethylformamide (32.0 kg) and a compound 1(3.0kg, 18.22mol), and adding potassium carbonate (6.23kg, 45.08mol) in batches after the compound 1 is dissolved; after the system was cooled to 10 ℃ benzyl bromide (3.12kg,18.24 mol) was initially added dropwise and, after the addition was complete, the reaction was carried out at 10-20 ℃ for 18 h.
Pouring the reaction solution into ice water (75.0kg), stirring for 1h, and filtering by a centrifugal machine to obtain a crude product of a white solid; the crude product was extracted with dichloromethane (12.0kg) and the organic phase was dried over anhydrous sodium sulphate (2.0kg) for 1 h; desolventizing under reduced pressure until no solvent is distilled out, slowly pouring the concentrated solution into petroleum ether (5.0kg), and stirring for 1 h; filtration gave a wet white solid which was oven dried at 50 ℃ under reduced pressure to give compound 2 as an off-white solid in 53.2% yield and 96.5% HPLC.
Preparation of Compound 3
Introducing nitrogen into a 50L double-layer glass reaction kettle, adding tetrahydrofuran (10.7kg), adding lithium aluminum hydride (0.52kg, 13.6mol) in batches, and heating to 40 ℃ after the addition is finished; compound 2(2.0kg, 9.16mol) dissolved in tetrahydrofuran (3.6kg) was slowly dropped into the reaction system while controlling the temperature at 40-55 ℃. The HPLC detection control raw material is less than 0.2 percent, and the reaction is finished; tetrahydrofuran (2.7kg) was added to water (0.52kg) and slowly dropped into the reaction kettle, the mixture was filtered through celite, the filtrate was washed twice with tetrahydrofuran, and the filtrate was concentrated under reduced pressure to obtain compound 3 as a yellow oil in a yield of 80% and an HPLC of 94.3%.
Preparation of Compound 4
Water (15.0kg) was poured into a 50L double-glazed reaction vessel at room temperature, potassium carbonate (1.31 kg, 9.48mol) and compound 3(1.5kg, 7.34mol) were added in portions, the temperature was lowered to 15 ℃ and di-tert-butyldicarbonate (1.59kg, 7.28mol) was dissolved in ethanol (2.5kg) and slowly dropped into the reaction vessel, and the temperature was controlled at 10-20 ℃ for reaction. The HPLC detection control raw material is less than 0.2%; after the completion of the reaction, the reaction mixture was directly filtered to obtain a wet product, which was purified with petroleum ether (7.0kg) to obtain a white solid compound 4 with a yield of 86% and an HPLC of 99.1%.
Preparation of Compound 5
A20L autoclave was purged with nitrogen, charged with methanol (13.0kg), starting material (1.92kg) and 5% palladium on carbon (0.2kg), and closed with a lid. Reaction at 20-25 deg.C under 0.5MPa for 4-6 h until the central control material disappears. Filtering with celite, and concentrating the filtrate; slowly pouring the concentrated solution into petroleum ether (1.4kg), crystallizing at 10 deg.C to obtain white solid wet product, and oven drying to obtain white solid compound 5 with yield of 74%, GC 97.9%, and ee% 99.9%.
Example 2
Preparation of Compound 2
Introducing nitrogen into a 50L double-layer glass reaction kettle at room temperature, adding N, N-dimethylformamide (32.0 kg) and a compound 1(3.0kg, 18.22mol), and adding potassium carbonate (6.23kg, 45.08mol) in batches after the compound 1 is dissolved; after the system had been cooled to 10 ℃ the dropwise addition of benzyl chloride (2.31kg,18.24 mol) was started and, after the dropwise addition was complete, the reaction was carried out for 18h at 10-20 ℃.
Pouring the reaction solution into ice water (75.0kg), stirring for 1h, and filtering by a centrifugal machine to obtain a crude product of a white solid; the crude product was extracted with dichloromethane (12.0kg) and the organic phase was dried over anhydrous sodium sulphate (2.0kg) for 1 h; desolventizing under reduced pressure until no solvent is distilled out, slowly pouring the concentrated solution into petroleum ether (5.0kg), and stirring for 1 h; filtration gave a wet white solid which was oven dried at 50 ℃ under reduced pressure to give compound 2 as an off-white solid in 51.0% yield and 95.5% HPLC.
Preparation of Compound 3
Introducing nitrogen into a 50L double-layer glass reaction kettle, adding tetrahydrofuran (10.7kg), adding sodium borohydride (0.51kg, 13.6mol) in batches, and heating to 40 ℃ after the addition is finished; compound 2(2.0kg, 9.16mol) dissolved in tetrahydrofuran (3.6kg) was slowly dropped into the reaction system while controlling the temperature at 40-55 ℃. The HPLC detection control raw material is less than 0.2 percent, and the reaction is finished; tetrahydrofuran (2.7kg) was added to water (0.52kg) and slowly dropped into the reaction kettle, the mixture was filtered through celite, the filtrate was washed twice with tetrahydrofuran, and the filtrate was concentrated under reduced pressure to obtain compound 3 as a yellow oil in a yield of 70% and an HPLC of 93.3%.
Preparation of Compound 4
Water (15.0kg) was poured into a 50L double-glazed reaction vessel at room temperature, triethylamine (0.959, 9.48mol) and the compound 3(1.5kg, 7.34mol) were added in portions, the temperature was lowered to 15 ℃ and di-tert-butyldicarbonate (1.59kg, 7.28mol) was dissolved in ethanol (2.5kg) and slowly dropped into the reaction vessel, and the temperature was controlled at 10-20 ℃ to react the system. The HPLC detection control raw material is less than 0.2%; after the completion of the reaction, the reaction mixture was directly filtered to obtain a wet product, which was purified with petroleum ether (7.0kg) to obtain a white solid compound 4 with a yield of 60% and an HPLC of 90.2%.
Preparation of Compound 5
A20L autoclave was purged with nitrogen, charged with methanol (13.0kg), starting material (1.92kg) and 5% palladium on carbon (0.2kg), and closed with a lid. Reaction at 20-25 deg.C under 0.5MPa for 4-6 h until the central control material disappears. Filtering with celite, and concentrating the filtrate; slowly pouring the concentrated solution into petroleum ether (1.4kg), crystallizing at 10 deg.C to obtain white solid wet product, and oven drying to obtain white solid compound 5 with yield of 73%, GC ═ 96%, and ee% ═ 99.4%.
Example 3
Preparation of Compound 2
Introducing nitrogen into a 50L double-layer glass reaction kettle at room temperature, adding N, N-dimethylformamide (32.0 kg) and a compound 1(3.0kg, 18.22mol), and adding potassium carbonate (6.23kg, 45.08mol) in batches after the compound 1 is dissolved; after the system was cooled to 10 ℃ benzyl bromide (3.12kg,18.24 mol) was initially added dropwise and, after the addition was complete, the reaction was carried out at 10-20 ℃ for 18 h.
Pouring the reaction solution into ice water (75.0kg), stirring for 1h, and filtering by a centrifugal machine to obtain a crude product of a white solid; extracting the crude product with methyl tert-butyl ether (12.0kg), and drying the organic phase with anhydrous sodium sulfate (2.0kg) for 1 h; desolventizing under reduced pressure until no solvent is distilled out, slowly pouring the concentrated solution into petroleum ether (5.0kg), and stirring for 1 h; filtration gave a wet white solid which was oven dried at 50 ℃ under reduced pressure to give compound 2 as an off-white solid in 50.2% yield and 95.5% HPLC.
Preparation of Compound 3
Introducing nitrogen into a 50L double-layer glass reaction kettle, adding tetrahydrofuran (11.398kg), adding lithium aluminum hydride (0.556kg, 14.656mol) in batches, and heating to 40 ℃ after the addition is finished; compound 2(2.0kg, 9.16mol) dissolved in tetrahydrofuran (3.6kg) was slowly dropped into the reaction system while controlling the temperature at 40-55 ℃. The HPLC detection control raw material is less than 0.2 percent, and the reaction is finished; tetrahydrofuran (2.7kg) was added to water (0.52kg) and slowly dropped into the reaction kettle, the mixture was filtered through celite, the filtrate was washed twice with tetrahydrofuran, and the filtrate was concentrated under reduced pressure to obtain compound 3 as a yellow oil in a yield of 83% and an HPLC of 95.3%.
Preparation of Compound 4
Water (16.4kg) was poured into a 50L double-glazed reaction vessel at room temperature, potassium carbonate (1.369 kg, 9.909mol) and compound 3(1.575kg, 7.707mol) were added in portions, the temperature was lowered to 15 ℃ and di-tert-butyldicarbonate (1.683kg, 7.707mol) was dissolved in ethanol (2.5kg) and slowly dropped into the reaction vessel, and the temperature was controlled at 10-20 ℃ to react the system. The HPLC detection control raw material is less than 0.2%; after the completion of the reaction, the reaction mixture was directly filtered to obtain a wet product, which was purified with petroleum ether (7.0kg) to obtain compound 4 as a white solid in a yield of 85% and an HPLC of 99.0%.
Preparation of Compound 5
A20L autoclave was purged with nitrogen, charged with methanol (13.0kg), starting material (1.92kg) and 5% platinum/carbon (0.2kg), and closed with the lid. Reaction at 20-25 deg.C under 0.5MPa for 4-6 h until the central control material disappears. Filtering with celite, and concentrating the filtrate; slowly pouring the concentrated solution into petroleum ether (1.4kg), crystallizing at 10 deg.C to obtain white solid wet product, and oven drying to obtain white solid compound 5 with yield of 71%, GC 95%, and ee% 99.0%.
Example 4
Preparation of Compound 2
Introducing nitrogen into a 50L double-layer glass reaction kettle at room temperature, adding N, N-dimethylformamide (31.2 kg) and a compound 1(3.0kg, 18.22mol), and adding potassium carbonate (7.55kg, 54.66mol) in batches after the compound 1 is dissolved; after the system was cooled to 10 ℃ the dropwise addition of benzyl bromide (3.428 kg,20.042mol) was started and, after the dropwise addition was complete, the reaction was carried out at 10-20 ℃ for 18 h.
Pouring the reaction solution into ice water (75.0kg), stirring for 1h, and filtering by a centrifugal machine to obtain a crude product of a white solid; the crude product was extracted with dichloromethane (12.0kg) and the organic phase was dried over anhydrous sodium sulphate (2.0kg) for 1 h; desolventizing under reduced pressure until no solvent is distilled out, slowly pouring the concentrated solution into petroleum ether (5.0kg), and stirring for 1 h; filtration gave a wet white solid which was oven dried at 50 ℃ under reduced pressure to give compound 2 as an off-white solid in 54.2% yield and 96.2% HPLC.
Preparation of Compound 3
Introducing nitrogen into a 50L double-layer glass reaction kettle, adding tetrahydrofuran (10.7kg), adding lithium aluminum hydride (0.52kg, 13.6mol) in batches, and heating to 40 ℃ after the addition is finished; compound 2(2.0kg, 9.16mol) dissolved in tetrahydrofuran (3.6kg) was slowly dropped into the reaction system while controlling the temperature at 40-55 ℃. The HPLC detection control raw material is less than 0.2 percent, and the reaction is finished; tetrahydrofuran (2.7kg) was added to water (0.52kg) and slowly dropped into the reaction kettle, the mixture was filtered through celite, the filtrate was washed twice with tetrahydrofuran, and the filtrate was concentrated under reduced pressure to obtain compound 3 as a yellow oil in a yield of 80% and an HPLC of 94.0%.
Preparation of Compound 4
Water (15.0kg) was poured into a 50L double-glazed reaction vessel at room temperature, potassium carbonate (1.31 kg, 9.48mol) and compound 3(1.5kg, 7.34mol) were added in portions, the temperature was lowered to 15 ℃ and di-tert-butyldicarbonate (1.59kg, 7.28mol) was dissolved in ethanol (2.5kg) and slowly dropped into the reaction vessel, and the temperature was controlled at 10-20 ℃ for reaction. The HPLC detection control raw material is less than 0.2%; after the completion of the reaction, the reaction mixture was directly filtered to obtain a wet product, which was purified with petroleum ether (7.0kg) to obtain a white solid compound 4 with a yield of 86% and an HPLC of 98.9%.
Preparation of Compound 5
A20L autoclave was purged with nitrogen, charged with methanol (13.6kg), starting material (1.96kg) and 5% palladium on carbon (0.2kg), and closed with a lid. Reaction at 20-25 deg.C under 0.5MPa for 4-6 h until the central control material disappears. Filtering with celite, and concentrating the filtrate; slowly pouring the concentrated solution into petroleum ether (1.4kg), crystallizing at 10 deg.C to obtain white solid wet product, and oven drying to obtain white solid compound 5 with yield of 73%, GC 96.1%, and ee% 98.9%.
Example 5
Preparation of Compound 6
Introducing nitrogen into a 100mL three-necked flask at room temperature, adding tetrahydrofuran (30mL), N-benzyloxycarbonyl-L-proline (3.5g) and N-methylmorpholine (2.1g), cooling to 0 ℃ by using an ice salt, starting dropwise adding ethyl chloroformate (1.6g), stirring for 30min after dropwise adding is finished, and controlling in TLC until the reaction is complete; then, compound 5(3g) was added dropwise, and after completion of the addition, the reaction was allowed to warm naturally for 12 hours, the reaction was controlled to completion by TLC, the reaction solution was quenched by adding 50mL of ice water, extracted twice with ethyl acetate (50mL), washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to obtain an off-white solid with a yield of 85%, ee% 99.6%, and HPLC 99.4%.
The compound 6 is prepared by taking the compound 5 and N-benzyloxycarbonyl-L-proline as raw materials and carrying out a derivatization reaction, and the single crystal diffraction test of the compound 6 shows that:
the structure of N-benzyloxycarbonyl-L-proline is confirmed and the single crystal diffraction pattern of the compound 6 is analyzed to obtain the compound 5 with the configuration of (S) -3-Boc-aminomethyl piperidine, and further proves that the novel method for synthesizing the compound 5 is feasible.
A methanol solution having a concentration of 1g/100mL was prepared, and the optical rotation value was measured, whereby the optical rotation value at 589nm was-8.98.
The invention is not limited to the foregoing embodiments. The invention extends to any novel feature or any novel combination of features disclosed in this specification and any novel method or process steps or any novel combination of features disclosed.
Claims (17)
- A process for preparing (S) -3-Boc-aminomethylpiperidine characterized in that the synthetic route is as follows:
wherein, the benzyl halide is one of benzyl bromide, benzyl chloride and benzyl iodide; the reducing agent is lithium aluminum hydride; the weak base is potassium carbonate; the catalyst is one of palladium/carbon, platinum/carbon, rhodium/carbon and ruthenium/carbon. - 2. The process for the preparation of (S) -3-Boc-aminomethylpiperidine according to claim 1, wherein said compound 2 is prepared by the following steps: dissolving the compound 1 in N, N-dimethylformamide at room temperature, adding potassium carbonate in batches, cooling to 8-12 ℃, dropwise adding benzyl halide, controlling the temperature to be 10-20 ℃, and reacting the system for 18-22 h; pouring the reaction solution into ice water, stirring and centrifuging to obtain a crude product; extracting, concentrating, purifying and drying the crude product to obtain the compound 2.
- 3. The method of claim 2, wherein the molar ratio of compound 1 to benzyl halide in said specific step of preparing compound 2 is 1: 1.0 to 1: 1.1; the molar ratio of the compound 1 to the potassium carbonate is 1: 2.5-1: 3.0; the mass ratio of the compound 1 to the N, N-dimethylformamide is 1: 10.6-1: 10.8.
- 4. The process for preparing (S) -3-Boc-aminomethylpiperidine according to claim 1, wherein said compound 3 is prepared by the steps of: adding a reducing agent into tetrahydrofuran in batches at room temperature, and heating the system to 40 ℃ after the addition is finished; adding 50-55 mass percent of compound 2 dissolved in tetrahydrofuran into a reaction system, and controlling the temperature to be 40-55 ℃ for reaction; after the reaction is finished, adding 500-520% by mass of tetrahydrofuran aqueous solution into the reaction system, filtering with diatomite, washing, concentrating and drying to obtain yellow oily compound 3.
- 5. The method of claim 4, wherein the molar ratio of Compound 2 to the reducing agent in the step of preparing Compound 3 is 1: 1.4 to 1: 1.6; the mass ratio of the tetrahydrofuran to the reducing agent is 20: 1-21: 1.
- 6. The process for preparing (S) -3-Boc-aminomethylpiperidine according to claim 1, wherein said compound 4 is prepared by the steps of: adding weak base into water in batches at room temperature, adding a compound 3 after dissolving, and cooling to 15 ℃; boc with the mass percent of 62-67 percent2Slowly dripping an O-ethanol solution, and controlling the temperature to be 10-20 ℃ for reaction; after the reaction is finished, filtering and purifying to obtain the compound 4.
- 7. The process for preparing (S) -3-Boc-aminomethyl piperidine according to claim 6, wherein said weak base, compound 3 and Boc in the specific preparation step of compound 4 are2The molar ratio of O is 1.30-1.35: 1.01-1.06: 1.00-1.05; the mass ratio of the water to the weak base is 11: 1-13: 1.
- 8. The method of claim 1, wherein said compound 5 is prepared by the steps of: dissolving a compound 4, 5-8% of a catalyst in methanol, reacting for 3-5 h at 20-25 ℃, and filtering, concentrating, purifying and drying by using kieselguhr to obtain a compound 5; the mass ratio of the methanol to the compound 4 to the catalyst is 65-68: 9.60-10.00: 1.00-1.05.
- 9. The method of preparing (S) -3-Boc-aminomethyl piperidine according to any one of claims 1 to 8, wherein the extractant used in the specific preparation step is one of dichloromethane, methyl tert-butyl ether and ethyl tert-butyl ether; the solvent used for purification is one of petroleum ether, n-heptane and diethyl ether; the drying agent is at least one of anhydrous sodium sulfate, anhydrous magnesium sulfate, activated carbon, anhydrous calcium chloride and the like.
- 10. The process for preparing (S) -3-Boc-aminomethylpiperidine as in claim 9, wherein the drying agent is anhydrous sodium sulfate.
- 11. The method of claim 9, wherein said extracting step comprises extracting dichloromethane with an extractant.
- 12. The process for preparing (S) -3-Boc-aminomethylpiperidine according to claim 9, wherein the solvent used for the purification is petroleum ether.
- 13. The process for preparing (S) -3-Boc-aminomethylpiperidine as in claim 9, wherein the drying agent is anhydrous sodium sulfate.
- A method for confirming the structure of (S) -3-Boc-aminomethylpiperidine, which comprises the following specific derivatization reaction scheme:
the specific operation method of the reaction is as follows: dissolving N-benzyloxycarbonyl-L-proline and N-methylmorpholine in tetrahydrofuran, cooling an ice salt to-5-0 ℃, dropwise adding ethyl chloroformate, and stirring for reaction after dropwise adding; after the reaction is finished, dropwise adding the compound 5, and naturally returning the temperature to react for 12-15 h after the dropwise adding is finished; quenching the reaction by ice water, extracting, washing, drying, filtering, concentrating, and passing through a silica gel column to obtain a white solid, namely the compound 6. - 15. The method of confirming the structure of (S) -3-Boc-aminomethyl piperidine according to claim 14, wherein the mass ratio of N-benzyloxycarbonyl-L-proline, N-methylmorpholine to ethyl chloroformate is 2.2 to 2.5: 1.3 to 1.5: 0.8 to 1.0; the mass ratio of the compound 5 to the N-benzyloxycarbonyl-L-proline is 1: 1.15-1: 1.18; the extracting agent used for extraction is at least one of ethyl acetate, butyl acetate and butanone; the drying agent is at least one of anhydrous sodium sulfate, anhydrous magnesium sulfate, activated carbon, anhydrous calcium chloride and the like.
- 16. The method of claim 15, wherein the extractant used for the extraction is ethyl acetate.
- 17. The method of claim 15, wherein said drying agent is anhydrous sodium sulfate.
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| WO2012104866A1 (en) * | 2011-01-31 | 2012-08-09 | Council Of Scientific & Industrial Research | Chiral 1-(4-methylphenylmethyl)-5-oxo-{n-[(3-t-butoxycarbonyl- aminomethyl)]-piperidin-1-yl}-pyrrolidine-2-carboxamides as inhibitors of collagen induced platelet activation and adhesion |
| CN103435538A (en) * | 2013-08-08 | 2013-12-11 | 爱斯特（成都）医药技术有限公司 | (R)-3-amino piperidine hydrochloride preparation method |
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| WO2012104866A1 (en) * | 2011-01-31 | 2012-08-09 | Council Of Scientific & Industrial Research | Chiral 1-(4-methylphenylmethyl)-5-oxo-{n-[(3-t-butoxycarbonyl- aminomethyl)]-piperidin-1-yl}-pyrrolidine-2-carboxamides as inhibitors of collagen induced platelet activation and adhesion |
| CN103435538A (en) * | 2013-08-08 | 2013-12-11 | 爱斯特（成都）医药技术有限公司 | (R)-3-amino piperidine hydrochloride preparation method |
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