[go: up one dir, main page]

CN117510398A - Preparation method of (3R, 4R)/(3S, 4S) -N-BOC-4-amino-3-hydroxy piperidine with high optical purity - Google Patents

Preparation method of (3R, 4R)/(3S, 4S) -N-BOC-4-amino-3-hydroxy piperidine with high optical purity Download PDF

Info

Publication number
CN117510398A
CN117510398A CN202311450292.4A CN202311450292A CN117510398A CN 117510398 A CN117510398 A CN 117510398A CN 202311450292 A CN202311450292 A CN 202311450292A CN 117510398 A CN117510398 A CN 117510398A
Authority
CN
China
Prior art keywords
compound
formula
solvent
reaction
preparation
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN202311450292.4A
Other languages
Chinese (zh)
Inventor
贺峰
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shanghai Panso Pharmaceutical Technology Co ltd
Shanghai Nodingtai Biotechnology Co ltd
Original Assignee
Shanghai Panso Pharmaceutical Technology Co ltd
Shanghai Nodingtai Biotechnology Co ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shanghai Panso Pharmaceutical Technology Co ltd, Shanghai Nodingtai Biotechnology Co ltd filed Critical Shanghai Panso Pharmaceutical Technology Co ltd
Priority to CN202311450292.4A priority Critical patent/CN117510398A/en
Publication of CN117510398A publication Critical patent/CN117510398A/en
Pending legal-status Critical Current

Links

Classifications

    • 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
    • C07D211/36—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B57/00—Separation of optically-active compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/47—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The invention discloses a preparation method of (3R, 4R)/(3S, 4S) -N-BOC-4-amino-3-hydroxy piperidine with high optical purity. The invention provides a method for resolving a compound of formula III, which comprises the following steps: (1) In a solvent, carrying out salt forming reaction on a compound of a formula III and a resolving agent, wherein the resolving agent is N-acetyl-L-phenylalanine or N-acetyl-D-phenylalanine; (2) Reacting the salt obtained in step (1) with a base to obtain a compound of formula V or a compound of formula IX. The ring-opening reaction has high regioselectivity, can directly obtain the expected trans-racemate, and then can directly carry out resolution to obtain the target product with high optical purity. In the resolution method of the invention, the substrate is not required to be subjected toThe amino group is protected, the consumption of the resolving agent is small, the purification is easy, the process cost is low, the process flow is short, and the method is suitable for industrial production.

Description

Preparation method of (3R, 4R)/(3S, 4S) -N-BOC-4-amino-3-hydroxy piperidine with high optical purity
Technical Field
The invention relates to the field of pharmaceutical chemical synthesis, in particular to a preparation method of (3R, 4R)/(3S, 4S) -N-BOC-4-amino-3-hydroxy piperidine with high optical purity.
Background
(3R, 4R) -N-BOC-4-amino-3-hydroxypiperidine and (3S, 4S) -N-BOC-4-amino-3-hydroxypiperidine are an important class of molecular building blocks, which occupy an important position in drug development. The ADME properties of many drugs can be significantly altered.
Patent WO2015095097 reports a process for preparing compound iii.
The method reports that N-BOC-1,2,3, 6-tetrahydropyridine is taken as a raw material, racemic N-BOC-3, 4-epoxy piperidine is obtained through m-CPBA oxidation, then in ethanol/water as a solvent, the ring opening is carried out through sodium azide, and then the hydrogenation reduction is carried out, so that trans-racemic N-BOC-3 hydroxyl 4-amino piperidine is obtained.
Patent US20090163472 reports a process for preparing compound v.
The method reports that the racemized N-BOC-3, 4-epoxy piperidine is taken as a raw material, a large amount of N-BOC-3-azide 4-hydroxyl products are generated through the ring opening of sodium azide, and the yield of the reaction in the step is only 42%; then, carrying out hydrogenation reduction to obtain trans-racemized N-BOC-3 hydroxyl 4-aminopiperidine; then subjecting benzaldehyde to reductive amination to obtain a compound VI, then in a 5% water/acetonitrile solution, carrying out salting-out crystallization resolution by using D-tartaric acid, recrystallizing to obtain a compound IV with qualified optical purity, then carrying out alkalization and ionization, extracting to remove tartaric acid, then carrying out palladium-carbon hydrogenation, and removing benzyl to obtain (3S, 4S) -N-BOC-4-amino-3-hydroxy piperidine.
The process flow of the route is complex, the benzyl protecting group is added through additional reductive amination, then the benzyl protecting group is split, then palladium carbon is used for hydrogenation, the benzyl is removed, the yield is low, a large amount of waste liquid is generated, and the method is not suitable for industrial production.
Disclosure of Invention
The invention aims to overcome the defects of the technical route and provide a preparation method of (3R, 4R) -N-BOC-4-amino-3-hydroxy piperidine and (3S, 4S) -N-BOC-4-amino-3-hydroxy piperidine with high optical purity. The invention takes racemized N-BOC-3, 4-epoxy piperidine as a raw material, takes an inorganic halogenated lithium reagent as a catalyst to control the regioselectivity of a ring-opening reaction to obtain trans-racemized N-BOC-3 hydroxy 4-azidopiperidine, then obtains trans-racemized N-BOC-3 hydroxy 4-aminopiperidine through hydrogenation reduction reaction, and obtains N-BOC-4-amino-3-hydroxypiperidine with single absolute configuration and high chiral purity through resolution with a resolving agent Cheng Yanxi crystal. The ring-opening reaction has high regioselectivity, can directly obtain the expected trans-racemate, and then can directly carry out resolution to obtain the target product with high optical purity. In the resolution method, the amino of the substrate is not required to be protected, the consumption of the resolving agent is small, the purification is easy, the process cost is low, the process flow is short, and the method is suitable for industrial production.
The invention provides a method for resolving a compound of formula III, which comprises the following steps:
(1) In a solvent, carrying out salt forming reaction on a compound of a formula III and a resolving agent, wherein the resolving agent is N-acetyl-L-phenylalanine or N-acetyl-D-phenylalanine;
(2) Reacting the salt obtained in step (1) with a base to obtain a compound of formula V or a compound of formula IX;
in one embodiment, the compound of formula III is a mixture of the compound of formula V and the compound of formula IX; preferably the mass ratio of the compound of formula V to the compound of formula IX is 1:1;
in a certain embodiment, in step (1), the solvent may be an alcoholic solvent, preferably methanol, ethanol or isopropanol, more preferably ethanol, such as absolute ethanol, or a ketone solvent, preferably acetone; the solvent is preferably an alcoholic solvent such as absolute ethanol.
In one embodiment, in step (1), the molar ratio of the compound of formula III to the resolving agent may be from 1:1 to 1:0.5, preferably from 1:0.8 to 1:0.5, for example 1:0.6 or 1:0.78.
In one embodiment, in step (1), the temperature of the salification reaction may be from 50 ℃ to 60 ℃, for example 50 ℃; meanwhile, the temperature should not exceed the reflux temperature of the solvent according to common knowledge in the art.
In one embodiment, in step (1), the salification reaction may further comprise a post-treatment step comprising one or more of cooling, filtering, recrystallizing, and drying.
In one embodiment, in step (1), the cooling may be to room temperature, more preferably to 20 ℃.
In one embodiment, in step (1), the recrystallization includes the steps of: mixing the salt obtained by the salification reaction with a recrystallization solvent, dissolving the solution, and filtering.
In a certain embodiment, in step (1), the recrystallization solvent may be an alcohol solvent, preferably methanol, ethanol or isopropanol, more preferably ethanol, such as absolute ethanol, or a ketone solvent, preferably acetone.
In one embodiment, in step (1), the solvent may be one that dissolves at 50 ℃.
In one embodiment, in step (2), the base may be an inorganic base, such as sodium carbonate; the inorganic base generally participates in the reaction in the form of an aqueous alkali solution; the concentration of the aqueous alkali solution is preferably 5% to 10%, for example, 10% by mass.
In one embodiment, in step (2), the reaction temperature of the salt produced by the salt formation reaction with the base is conventional in the art for such reactions, e.g., 15 ℃ to 25 ℃.
In a certain scheme, in the step (2), the salt prepared by the salification reaction is reacted with the alkali, and then the post-treatment step is further included, wherein the post-treatment step includes one or both of extraction and concentration.
The method for resolving the compound of formula III may further comprise a preparation method of the compound of formula III, which comprises the steps of: in a solvent, in the presence of a catalyst, carrying out catalytic hydrogenation reaction on the compound of the formula II and hydrogen to obtain the compound of the formula III,
in one embodiment, the catalyst may be palladium on carbon or Raney nickel, preferably palladium on carbon, such as 5% wet palladium on carbon. The percentage is mass percent.
In one embodiment, the mass ratio of the catalyst to the compound of formula II is conventional in the art for such reactions, preferably from 1% to 10%, for example 5%.
In one embodiment, the temperature of the catalytic hydrogenation reaction is a reaction temperature conventional in the art for such reactions, preferably 15 ℃ to 25 ℃, for example 20 ℃ to 25 ℃.
In one embodiment, the solvent may be an alcoholic solvent, such as methanol.
In one embodiment, the mass to volume ratio of the compound of formula II to the solvent may be from 100g/L to 200g/L, such as 140g/L or 158g/L.
In one embodiment, the starting material for the catalytic hydrogenation reaction consists of the solvent, the catalyst, the compound of formula II and the hydrogen.
In one embodiment, the method of preparing the compound of formula III may further comprise a post-treatment step comprising one or more of filtration, concentration and column chromatography.
In one embodiment, the method for preparing the compound of formula III may include the step of eluting with an ester solvent, preferably ethyl acetate, and an alkane solvent, preferably n-heptane.
In one embodiment, the volume ratio of the ester solvent to the alkane solvent in the process for preparing the compound of formula III may be 1:9 to 1:11, for example 1:10.
The method for resolving the compound of formula III may further comprise a preparation method of the compound of formula II, which comprises the steps of: in a solvent, in the presence of a catalyst, carrying out ring-opening reaction on the compound of the formula I and sodium azide to obtain the compound of the formula II,
in one embodiment, the solvent may be a nitrogen-containing compound solvent, preferably N, N-Dimethylformamide (DMF), a nitrile solvent, preferably acetonitrile, an alcohol solvent, preferably ethanol, or an nitrile solvent, preferably acetonitrile.
In one embodiment, the starting material for the ring-opening reaction consists of the solvent, the catalyst, the compound of formula I and the sodium azide.
In one embodiment, the catalyst may be an inorganic lithium halide reagent, preferably lithium chloride or lithium perchlorate, such as lithium chloride.
In one embodiment, the mass to volume ratio of the compound of formula I to the solvent may be from 100g/L to 200g/L, for example 100g/L or 200g/L.
In one embodiment, the molar ratio of the compound of formula I to the catalyst may be from 1:2 to 1:0.1, preferably from 1:1 to 1:0.1, for example 1:0.2 or 1:0.4.
In one embodiment, the molar ratio of the compound of formula I to the sodium azide may be from 1:1 to 1:2, such as 1:1.5.
In one embodiment, the temperature of the ring opening reaction may be from 0 to 150 ℃, preferably from 60 to 80 ℃, for example from 70 to 75 ℃.
In one embodiment, the method of preparing the compound of formula II may further comprise a post-treatment step comprising one or more of concentration, washing and column chromatography.
In one embodiment, the method for preparing the compound of formula II, the eluting solvent of the column chromatography may be an ester solvent, preferably ethyl acetate, and an alkane solvent, preferably n-heptane.
In one embodiment, the volume ratio of the ester solvent to the alkane solvent may be from 1:90 to 1:110, for example 1:100.
The invention also provides compounds of formula IV, formula VII as shown below,
the invention also provides a preparation method of the compound of the formula IV and the compound of the formula VII, which comprises the following steps: in a solvent, carrying out salt formation reaction on a compound of the formula V and N-acetyl-L-phenylalanine to obtain a compound of the formula IV; in a solvent, carrying out salt formation reaction on a compound of a formula IX and N-acetyl-D-phenylalanine to obtain a compound of a formula VII;
in one embodiment, in the method for preparing the compound of formula IV, the compound of formula VII, the reaction conditions may be as described in step (1).
The invention also provides application of the compound of the formula IV and the compound of the formula VII in preparing the compound of the formula V and the compound of the formula IX. The preparation method and the reaction conditions for the application may be as described in the step (2).
The invention also provides a preparation method of the compound of the formula II, which comprises the following steps: in a solvent, in the presence of lithium chloride, carrying out ring-opening reaction on the compound of the formula I and sodium azide to obtain the compound of the formula II;
in one embodiment, the reaction conditions for the preparation of the compound of formula II are as described above.
The above preferred conditions can be arbitrarily combined on the basis of not deviating from the common knowledge in the art, and thus, each preferred embodiment of the present invention can be obtained.
The reagents and materials used in the present invention are commercially available.
In the present invention, the room temperature is 15-25 ℃.
The invention has the positive progress effects that: the ring-opening reaction has high regioselectivity, can directly obtain the expected trans-racemate, and then can directly carry out resolution to obtain the target product with high optical purity. In the resolution method, the amino of the substrate is not required to be protected, the consumption of the resolving agent is small, the purification is easy, the process cost is low, the process flow is short, and the method is suitable for industrial production.
Detailed Description
For a clearer understanding of the technical content of the present invention, the following examples are set forth to illustrate, but are not to be construed as limiting, the present invention. The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications.
Example 1
Preparation of Compound II
Acetonitrile (1L), N-BOC-3, 4-epoxypiperidine (199g, 1 mol), lithium chloride (8.4 g,0.2 mol) were added to the flask and stirred for 30 minutes. Sodium azide (97 g,1.5 mol) was added, stirred for 10 minutes, and reacted at 70-75℃for 4 hours. TLC monitoring showed that the main raw material had reacted, concentrating under reduced pressure, removing the solvent, adding methyl tert-butyl ether (1L), water (0.5L), stirring and washing, separating out the organic phase, concentrating again under reduced pressure to obtain crude product (i.e.)242g of compound II) is oily, 5g of crude product is taken, ethyl acetate/n-heptane=1/100 (volume ratio) is used as eluent, 300-mesh silica gel is used as filler, 3.8g of pure product of compound II is obtained through column chromatography purification, and nuclear magnetism qualitative test is carried out. The crude product is detected by GC-MS, and the ratio of the target product to the isomer thereof is 85%/15%. Benzyl benzoate is used as a nuclear magnetic internal standard, nuclear magnetic internal calibration test is carried out on the crude product, and the content of the crude product is 80%. The reaction yield of the step: 80%. 1 HNMR(400MHz，CDCl 3 )δ1.48(s，9H)，1.84(s，lH),1.97-2.01(m，lH)，2.74-2.89(m，2H),3.37-3.40(m，lH)，3.50(s，lH),3.91(s，lH)，4.09(dd，lH).
Preparation of Compound III
The crude product (237 g, content 80%,0.78 mol) of the compound II is added into a reaction kettle, 1200mL of methanol is added, 24g of 5% wet palladium carbon is added, stirring is completed for 10 minutes, nitrogen replacement and hydrogen replacement are carried out, stirring reaction is started for 4 hours at a temperature of 20-25 ℃, sampling detection is carried out, and TLC shows that the raw material reaction is completed. Removing palladium carbon by suction filtration, evaporating the solvent under reduced pressure to obtain 211g of crude oily substance, namely the compound III, taking 5g of crude oily substance, eluting with ethyl acetate/n-heptane=1/10 (volume ratio), filling with 300-mesh silica gel, purifying by column chromatography, separating and purifying to obtain 3.8g of pure product of the compound III, and performing nuclear magnetism qualitative test. Benzyl benzoate is used as a nuclear magnetic internal standard, nuclear magnetic internal calibration test is carried out on the crude product, and the content of the crude product is 80%. The reaction yield of the step: 99%. 1 H NMR(400MHz，CDCl 3 )δ1.29-1.32(m,1H),1.43(s，9H)，1.79-1.82(dd，lH),2.51-2.70(m，6H)，3.17-3.18(m，lH),4.01-4.30(s，lH)，4.16-4.19(dd，lH).
Preparation of Compound IV
Crude III (206 g, 80% content, 0.76mol, compound V: compound IX=1:1) was added to a reaction flask, 2060mL of acetone was added, the temperature was raised to 50 ℃, N-acetyl-L-phenylalanine (95 g,0.46mol,0.6 eq) was added, the system quickly precipitated out a solid, the reaction was stirred for 2h, the internal temperature was reduced to 20 ℃, and the product (i.e., compound IV) was obtained by suction filtration. Adding the product into acetone (1860 mL) again, heating to 50 ℃ for dissolving, cooling, filtering, and drying to obtain 118g of product, wherein the yield is: 37%. Chiral liquid phase detection, optical purity 98.6%.
Preparation of Compound IV
Adding the crude product III (206 g,0.76 mol) obtained in the previous step into a reaction bottle, adding 2060mL of absolute ethyl alcohol, heating to 50 ℃, adding N-acetyl-L-phenylalanine (95 g,0.46mol,0.6 eq), quickly separating out solid from a reaction system, stirring for reacting for 2h, cooling to room temperature, and carrying out suction filtration to obtain 169g of a product (namely the compound IV). Adding the product into absolute ethyl alcohol (1690 mL) again, heating to 50 ℃ to dissolve, cooling, filtering, and drying to obtain 128g of the product (namely the compound IV), wherein the yield is: 40%. Chiral liquid phase detection, optical purity 99.6%.
Chiral liquid phase detection conditions: aglinet 1100 normal phase. Chiral column: AY-H (4.6X250 mm,5 μm), mobile phase A: n-hexane. Mobile phase B: ethanol (0.1% diethylamine), a/b=95/5 (V/V), flow rate: 1mL/min, detection wavelength: 210nm, column temperature: 37 ℃, sample injection amount: 5. Mu.L.
Peak time of compound IV: 17.57min.
1 Preparation of Compound V by H NMR (400 MHz, DMSO). Delta.1.30-1.44 (m, 10H), 1.77 (s, 3H), 1.89-1.92 (dd, lH), 2.51-2.72 (m, 3H), 2.80-2.85 (m, 2H), 3.05-3.08 (m, lH), 3.34 (s, 1H), 3.90-4.01 (dd, 2H), 4.20-4.21 (m, 1H), 6.62-7.10 (m, 3H), 7.16-7.22 (m, 5H), 7.54-7.56 (m, 1H)
Sodium carbonate (212 g,2 mol)/water (2120 g) is added into a reaction bottle, the compound IV (423 g,1 mol) prepared in the previous step is added into the reaction bottle, stirred for 30 minutes at room temperature, dichloromethane (1L) is added into the mixture, the mixture is stirred and extracted, an organic phase is separated, and the mixture is concentrated and dried under reduced pressure to obtain 200g of a product (namely a compound V), and the yield is: 93%. Gas phase detection, chemical purity 98.6%. Chiral liquid phase detection, optical purity 99.6%.
The obtained product is consistent with outsourcing standard substance by using nuclear magnetic hydrogen spectrum, gas phase and chiral liquid phase detection method (Nanjing medicinal stone, batch number PB 0023945-002-01).
1 H NMR(400MHz，CDCl 3 )δ1.30-1.35(m,1H),1.44(s，9H)，1.80-1.83(dd，lH),2.53-2.57(m，6H)，3.18-3.21(m，lH),4.03-4.05(s，lH)，4.18-4.21(dd，lH).
Gas phase detection conditions: shimaduz 2014, column: SHB-624 (30 m. Times.0.25 mm,1.4 μm), split ratio: 20:1, detector: and (3) FID. Hydrogen flow rate: 3mL/min.
Peak time of Compound V: 18.01min
Chiral liquid phase detection conditions are the same as above.
Example 2
Preparation of Compound II
Acetonitrile (1L), N-BOC-3, 4-epoxypiperidine (100 g,0.5 mol), lithium chloride (8.4 g,0.2 mol) and stirred for 30 minutes were added to the reaction flask. Sodium azide (48.5 g,0.75 mol) was added, stirred for 30 minutes, and reacted at 70-75℃for 6 hours. TLC monitoring shows that the main raw material is reacted completely, concentrating under reduced pressure, removing solvent, adding methyl tert-butyl ether (0.6L), water (0.3L), stirring and washing, separating out organic phase, concentrating under reduced pressure again to obtain 130g of crude product (namely compound II), taking 10g of crude product, eluting with ethyl acetate/n-heptane=1/100 (volume ratio), packing into 300 mesh silica gel, purifying by column chromatography to obtain 7g of pure product of compound II, performingAnd (5) nuclear magnetism qualitative testing. The crude product was detected by GC-MS and showed a target product ratio of 81%/19%. And (3) taking benzyl benzoate as a nuclear magnetic internal standard substance, and carrying out nuclear magnetic internal standard quantitative test on the crude product, wherein the content of the crude product is 70%. The reaction yield of the step: 75%. 1 H NMR(400MHz，CDCl 3 )δ1.48(s，9H)，1.84(s，lH),1.97-2.01(m，lH)，2.74-2.89(m，2H),3.37-3.40(m，lH)，3.50(s，lH),3.91(s，lH)，4.09(dd，lH).
Preparation of Compound III
Crude product II (24 g, content 70%,0.0694 mol) is added into a reaction kettle, 120mL of methanol is added, 2.4g of 5% wet palladium carbon is added, stirring is completed for 10 minutes, nitrogen replacement and hydrogen replacement are carried out, stirring reaction is started at a temperature of 20-25 ℃ for 4 hours, sampling detection is carried out, and TLC shows that the raw material reaction is completed. Removing palladium carbon by suction filtration, evaporating the solvent under reduced pressure to obtain 21g of crude product, namely a compound III, taking 5g of crude product, eluting with ethyl acetate/n-heptane=1/10 (volume ratio), filling with 300-mesh silica gel, purifying by column chromatography, separating and purifying to obtain 3.7g of pure product of the compound III, and performing nuclear magnetism qualitative test. The benzyl benzoate is used as a nuclear magnetic internal standard substance, the nuclear magnetic internal standard quantitative test is carried out on the crude product, the crude product content is 70%, and the reaction yield is: 98%. 1 H NMR(400MHz，CDCl 3 )δ1.29-1.32(m,1H),1.43(s，9H)，1.79-1.82(dd，lH),2.51-2.70(m，6H)，3.17-3.18(m，lH),4.01-4.30(s，lH)，4.16-4.19(dd，lH).
Preparation of Compound VII
Crude III (21 g, content 80%,0.076mol, compound V: compound IX=1:1) was added to a reaction flask, 210mL of absolute ethanol was added, the temperature was raised to 50 ℃, N-acetyl-D-phenylalanine (15.7 g,0.076mol,0.78 eq) was added, the reaction system quickly precipitated out a solid, the reaction was stirred for 2 hours, the temperature was lowered to 20℃in the internal temperature, and the product (i.e., compound VII) was obtained by suction filtration. Adding the product into absolute ethyl alcohol (200 mL) again, heating to 50 ℃ to dissolve, cooling, filtering, drying to obtain 13g of the product (namely the compound VII), and obtaining the yield: 41%. Chiral liquid phase detection, optical purity 98.6%. The chiral liquid phase detection conditions were the same as those in the preparation of compound IV in example 1. The peak time of compound VII was 19.28min.
1 H NMR(400MHz，DMSO)δ1.30-1.44(m，10H)，1.77(s,3H),1.89-1.92(dd，lH),2.51-2.72(m，3H)，2.80-2.85(m,2H),3.05-3.08(m，lH),3.34(s,1H),3.90-4.01(dd，2H)，4.20-4.21(m,1H),6.62-7.10(m,3H),7.16-7.22(m,5H),7.54-7.56(m,1H)
Preparation of Compound IX
Sodium carbonate (212 g,2 mol)/water (2120 g) was added to a reaction flask, and compound VII (423 g,1 mol) obtained in the above step was added to the reaction flask, stirred at room temperature for 30 minutes, dichloromethane (1L) was added thereto, stirred and extracted, and an organic phase was separated, and concentrated to dryness under reduced pressure to obtain 200g of a product (i.e., compound IX). Yield: 93%. Gas phase detection, chemical purity 98.6%, chiral liquid phase detection and optical purity 98.6%. 1 HNMR(400MHz，CDCl 3 )δ1.30-1.35(m,1H),1.44(s，9H)，1.80-1.83(dd，lH),2.53-2.57(m，6H)，3.18-3.21(m，lH),4.03-4.05(s，lH)，4.18-4.21(dd，lH).
The obtained product is consistent with the outsourcing standard substance by the detection method of nuclear magnetic hydrogen spectrum, gas phase and chiral liquid phase (Nanjing medical stone, batch number PB 0021001-005-01).
Chiral liquid phase detection conditions: aglinet 1100 normal phase. Chiral column: AY-H (4.6X250 mm,5 μm), mobile phase A: n-hexane. Mobile phase B: ethanol (0.1% diethylamine), a/b=95/5 (V/V), flow rate: 1mL/min, detection wavelength: 210nm, column temperature: 37 ℃, sample injection amount: 5. Mu.L.
Peak time of compound IX: 19.28min.
Comparative example 1:
acetonitrile (500 mL), 3, 4-epoxypyran (50 g), lithium chloride (4.2 g) were added to the reaction flask, and stirred for 30 minutes. Sodium azide (49 g) was added thereto, and the reaction was carried out at 70-75℃for 16 hours. GC monitoring shows that the main raw materials are reacted completely, concentrating under reduced pressure, removing the solvent to obtain 72g of crude product, detecting the crude product by GC-MS to show that the target product accounts for 72%/28%, and quantitatively testing the nuclear magnetic internal standard by taking benzyl benzoate as the nuclear magnetic internal standard of the crude product, wherein the content of the crude product is 70%. The reaction yield of the step: 72%.
Comparative example 2: resolution experiment of unprotected amino group
Trans 3-hydroxy 4-aminopiperidine (11.6 g,0.1 mol) was added to a reaction flask, 116mL of absolute ethanol was added, the temperature was raised to 50 ℃, N-acetyl-D-phenylalanine (12.4 g,0.06mol,0.6 eq) was added, the reaction was stirred for 2 hours, no solid was precipitated in the system, the temperature was lowered to 0℃and stirred for 12 hours, no solid was precipitated in the system, and resolution failed.
Comparative example 3: resolution experiments with different resolving Agents
The compound III prepared in example 1 was resolved according to the preparation methods of the compound IV and the compound V in example 1 using R-mandelic acid, L-tartaric acid and L-dibenzoyltartaric acid as resolving agents, respectively. Experimental results: (1) R-mandelic acid and L-tartaric acid are taken as resolving agents, and after resolution, the ratio of two absolute configurations in the obtained product is about 50 percent to 50 percent, and no resolution effect is achieved; (2) After the compound III and the L-dibenzoyltartaric acid are subjected to salt formation reaction, no solid is separated out from the system, and resolution fails.

Claims (10)

1. A method for resolving a compound of formula III, comprising the steps of:
(1) In a solvent, carrying out salt forming reaction on a compound of a formula III and a resolving agent, wherein the resolving agent is N-acetyl-L-phenylalanine or N-acetyl-D-phenylalanine;
(2) Reacting the salt obtained in step (1) with a base to obtain a compound of formula V or a compound of formula IX;
2. the method of resolving a compound of formula III according to claim 1, wherein the method of resolving a compound of formula III satisfies one or more of the following conditions:
(1) The compound of formula III is a mixture of the compound of formula V and the compound of formula IX; preferably the mass ratio of the compound of formula V to the compound of formula IX is 1:1;
(2) In the step (1), the solvent is an alcoholic solvent or a ketone solvent, wherein the alcoholic solvent is preferably methanol, ethanol or isopropanol, more preferably ethanol, such as absolute ethanol, and the ketone solvent is preferably acetone; the solvent is preferably an alcoholic solvent such as absolute ethanol;
(3) In step (1), the molar ratio of the compound of formula III to the resolving agent is from 1:1 to 1:0.5, preferably from 1:0.8 to 1:0.5, for example 1:0.6 or 1:0.78;
(4) In step (1), the temperature of the salification reaction is 50 ℃ to 60 ℃, such as 50 ℃;
(5) In step (1), the salification reaction further comprises a post-treatment step comprising one or more of cooling, filtering, recrystallizing and drying;
preferably, the post-processing step satisfies one or more of the following conditions:
(a) The cooling is to cool to room temperature, more preferably to 20 ℃;
(b) The recrystallization includes the steps of: mixing the salt prepared by the salification reaction with a recrystallization solvent, dissolving the solution, and filtering; preferably, the solution is a solution at 50 ℃;
(c) The recrystallization solvent is an alcoholic solvent, preferably methanol, ethanol or isopropanol, more preferably ethanol, such as absolute ethanol, or a ketone solvent, preferably acetone;
(6) In step (2), the base is an inorganic base, such as sodium carbonate; preferably, the inorganic base participates in the reaction in the form of an aqueous alkali solution; the mass percentage concentration of the alkaline water solution is preferably 5-10%, such as 10%;
(7) In the step (2), the reaction temperature of the salt prepared by the salification reaction and the alkali is 15-25 ℃;
and (8) in the step (2), the salt prepared by the salification reaction is reacted with the alkali and then further comprises a post-treatment step, wherein the post-treatment step comprises one or two of extraction and concentration.
3. The method of resolving a compound of formula III according to claim 1 or 2, wherein the method of resolving a compound of formula III further comprises a process for the preparation of the compound of formula III comprising the steps of: in a solvent, in the presence of a catalyst, carrying out catalytic hydrogenation reaction on the compound of the formula II and hydrogen to obtain the compound of the formula III,
4. a process for the resolution of a compound of formula III according to claim 3, wherein the process for the preparation of the compound of formula III satisfies one or more of the following conditions:
(1) The catalyst is palladium carbon or Raney nickel, preferably palladium carbon, such as 5% wet palladium carbon;
(2) The mass ratio of the catalyst to the compound of formula II is 1% to 10%, for example 5%;
(3) The temperature of the catalytic hydrogenation reaction is 15 ℃ to 25 ℃, for example 20 ℃ to 25 ℃;
(4) The solvent is an alcoholic solvent such as methanol;
(5) The mass to volume ratio of the compound of formula II to the solvent is 100g/L to 200g/L, for example 140g/L or 158g/L;
(6) The raw materials of the catalytic hydrogenation reaction consist of the solvent, the catalyst, the compound of the formula II and the hydrogen;
(7) The process for the preparation of the compound of formula III further comprises a post-treatment step comprising one or more of filtration, concentration and column chromatography; preferably, the eluting solvent of the column chromatography is an ester solvent and an alkane solvent, wherein the ester solvent is preferably ethyl acetate, and the alkane solvent is preferably n-heptane;
and (8) the volume ratio of the ester solvent to the alkane solvent is 1:9 to 1:11, for example 1:10.
5. A process for resolving a compound of formula III according to claim 3, wherein the process for resolving a compound of formula III further comprises a process for the preparation of the compound of formula II comprising the steps of: in a solvent, in the presence of a catalyst, carrying out ring-opening reaction on the compound of the formula I and sodium azide to obtain the compound of the formula II,
6. the method of resolving a compound of formula III according to claim 5, wherein the method of preparation of the compound of formula II satisfies one or more of the following conditions:
(1) The solvent is a nitrogen-containing compound solvent, preferably N, N-dimethylformamide, a nitrile solvent, preferably acetonitrile, an alcohol solvent, preferably ethanol, or an alcohol solvent, preferably a nitrile solvent, for example acetonitrile;
(2) The raw materials of the ring-opening reaction consist of the solvent, the catalyst, the compound of the formula I and the sodium azide;
(3) The catalyst is an inorganic lithium halide reagent, preferably lithium chloride or lithium perchlorate, such as lithium chloride;
(4) The mass to volume ratio of the compound of formula I to the solvent is from 100g/L to 200g/L, for example 100g/L or 200g/L;
(5) The molar ratio of the compound of formula I to the catalyst is from 1:2 to 1:0.1, preferably from 1:1 to 1:0.1, for example 1:0.2 or 1:0.4;
(6) The molar ratio of the compound of formula I to the sodium azide is from 1:1 to 1:2, for example 1:1.5;
(7) The temperature of the ring opening reaction is 0 to 150 ℃, preferably 60 to 80 ℃, for example 70 to 75 ℃;
and (8) the process for the preparation of the compound of formula II further comprises a post-treatment step comprising one or more of concentration, washing and column chromatography;
preferably, the eluting solvent of the column chromatography is an ester solvent and an alkane solvent, wherein the ester solvent is preferably ethyl acetate, and the alkane solvent is preferably n-heptane;
and/or the volume ratio of the ester solvent to the alkane solvent is from 1:90 to 1:110, for example 1:100.
7. A compound of formula IV, a compound of formula VII as shown below,
8. a process for the preparation of a compound of formula IV, a compound of formula VII, characterized in that it comprises the steps of: in a solvent, carrying out salt formation reaction on a compound of the formula V and N-acetyl-L-phenylalanine to obtain a compound of the formula IV; in a solvent, carrying out salt formation reaction on a compound of a formula IX and N-acetyl-D-phenylalanine to obtain a compound of a formula VII;
preferably, the reaction conditions of the preparation method of the compound of the formula IV and the compound of the formula VII are as described in claim 1 or 2.
9. The use of a compound of formula IV, a compound of formula VII, for the preparation of a compound of formula V, a compound of formula IX; preferably, the preparation method and the reaction conditions for the use are as described in claim 1 or 2.
10. A process for the preparation of a compound of formula II, comprising the steps of: in a solvent, in the presence of lithium chloride, carrying out ring-opening reaction on the compound of the formula I and sodium azide to obtain the compound of the formula II;
preferably, the reaction conditions of the process for the preparation of the compound of formula II are as described in claim 5 or 6.
CN202311450292.4A 2023-11-02 2023-11-02 Preparation method of (3R, 4R)/(3S, 4S) -N-BOC-4-amino-3-hydroxy piperidine with high optical purity Pending CN117510398A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202311450292.4A CN117510398A (en) 2023-11-02 2023-11-02 Preparation method of (3R, 4R)/(3S, 4S) -N-BOC-4-amino-3-hydroxy piperidine with high optical purity

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202311450292.4A CN117510398A (en) 2023-11-02 2023-11-02 Preparation method of (3R, 4R)/(3S, 4S) -N-BOC-4-amino-3-hydroxy piperidine with high optical purity

Publications (1)

Publication Number Publication Date
CN117510398A true CN117510398A (en) 2024-02-06

Family

ID=89754219

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202311450292.4A Pending CN117510398A (en) 2023-11-02 2023-11-02 Preparation method of (3R, 4R)/(3S, 4S) -N-BOC-4-amino-3-hydroxy piperidine with high optical purity

Country Status (1)

Country Link
CN (1) CN117510398A (en)

Similar Documents

Publication Publication Date Title
CA2412047C (en) Shortened synthesis of 3,3-diarylpropylamine derivatives
EP2387556B1 (en) Separation of an enantiomer mixture of (r)- and (s)-3-amino-1-butanol
JP5133705B2 (en) Process for producing 7-ethyl-10-hydroxycamptothecin
JP2021505682A (en) Intermediates of optically active piperidine derivatives and methods for producing them
EP3057966B1 (en) Process for the industrial synthesis of lurasidone
US9771317B2 (en) Process for preparing lacosamide and related compounds
JP5585822B2 (en) Method for producing optically active nipecotic acid derivative
CN112679498A (en) Sulfonic acid quaternary ammonium salt compound and preparation method and application thereof
CN117510398A (en) Preparation method of (3R, 4R)/(3S, 4S) -N-BOC-4-amino-3-hydroxy piperidine with high optical purity
EA019031B1 (en) Process for preparing 6-{4-[3-((r)-2-methylpyrrolidine-1-yl)propoxy]phenyl}-2h-piridazin-3-one and pharmaceutically acceptable salt thereof
CN115197178B (en) Synthesis method of brivaracetam key intermediate
CN108440349B (en) Preparation method of chiral optical pure p-toluenesulfinamide
CN111689869A (en) Preparation method of L-phenylephrine hydrochloride
CN101570506A (en) Novel method for preparing chiral amlodipine
KR100743617B1 (en) Process for the preparation of chiral 3-hydroxy pyrrolidine compound and derivatives thereof having high optical purity
CN115403509A (en) Preparation method of lefenacin intermediate
CN110885315A (en) Preparation method of important intermediate of levosimendan
CN111302996A (en) Preparation method of high-chiral-purity chloromalastine fumarate
CN106478506B (en) The preparation method of half light green Ka Selin hydrochloride
CN110922354B (en) Chemical resolution preparation method of 1-R-3-haloperidol-4-carboxylic acid and product thereof
CN114605241B (en) Preparation method of esketamine hydrochloride intermediate and intermediate thereof
JP2002371060A (en) Method for producing optically active aminopiperidine derivative
CN108484455B (en) Method for synthesizing chiral optical pure p-toluenesulfinamide
TW202504888A (en) Separation method and intermediates of phenylalanine derivatives
JP5397706B2 (en) Method for producing high purity 1-benzyl-3-aminopyrrolidine

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination