CN109369513B - Preparation method of FBDD common molecular fragment - Google Patents
Preparation method of FBDD common molecular fragment Download PDFInfo
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- CN109369513B CN109369513B CN201811389805.4A CN201811389805A CN109369513B CN 109369513 B CN109369513 B CN 109369513B CN 201811389805 A CN201811389805 A CN 201811389805A CN 109369513 B CN109369513 B CN 109369513B
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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
- C07D211/36—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
- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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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
- C07D211/36—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
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
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- C07B2200/07—Optical isomers
Abstract
The invention discloses a preparation method of FBDD common molecular fragments, and relates to the technical field of drug synthesis. The technical key points are as follows: according to the invention, through improving synthesis steps and parameters, the hydroxyl positions of the cis-4-hydroxy-1, 3-piperidinedicarboxylic acid 1-benzyl ester 3-carboxylic acid and the trans-4-hydroxy-1, 3-piperidinedicarboxylic acid 1-benzyl ester 3-carboxylic acid are the same, so that the total yield can be increased to 15-20%, which is higher than that of the prior art by 10-14%; the invention does not need tube sealing reaction, has lower temperature and mild reaction and improves the safety.
Description
Technical Field
The invention relates to the technical field of drug synthesis, in particular to a preparation method of an FBDD common molecular fragment.
Background
Fragment-Based Drug Design (FBDD) has its practical advantages: firstly, it is easier to collect, maintain and screen thousands of fragment libraries than millions of macromolecular databases, which enables enterprises and academic institutions to do the discovery work of leads; secondly, the higher screening hit rate can realize the treatment of complex targets, particularly protein-protein interaction targets; in addition, the fragments have small size and high solubility, generally have better pharmaceutical properties, are easy to structurally optimize at the later stage, and have more potential to become pharmaceutical molecules. Cis-trans 3-amino-4-hydroxy-N-Cbz piperidine is such an effective and commonly used fragment that has good ClogP values, can have good water solubility, and can be readily derivatized at the N-and 3-amino and 4-hydroxy positions of piperidine to design a variety of desired compounds.
The existing synthesis process is as follows:
in the above route, the reaction condition of step 2 is a tube-sealing reaction, the temperature is high, the reaction is dangerous, only trans-3-amino-4-hydroxy-N-Cbz piperidine racemate can be obtained, the 3-hydroxy-4-amino-N-Cbz piperidine generated by the reaction is a byproduct, the total yield of the compound 7 is about 10-14%, and the total yield is low.
Disclosure of Invention
Aiming at the defects in the prior art, the invention aims to provide a preparation method of FBDD common molecular fragments, which has the advantages of mild reaction and high total yield.
In order to achieve the purpose, the invention provides the following technical scheme:
a preparation method of FBDD common molecular fragment comprises the following steps:
adding 4-oxo-1, 3-piperidinedicarboxylic acid 1-benzyl ester 3-methyl ester into a reaction container, adding tetrahydrofuran to dissolve the 4-oxo-1, 3-piperidinedicarboxylic acid 1-benzyl ester 3-methyl ester, cooling to below 0 ℃ under the protection of a nitrogen system, slowly adding sodium borohydride in batches, and after the reaction is finished, sequentially performing extraction, liquid separation and evaporation to obtain 4-hydroxy-1, 3-piperidinedicarboxylic acid 1-benzyl ester 3-methyl ester;
step two, adding 4-hydroxy-1, 3-piperidinedicarboxylic acid 1-benzyl ester 3-methyl ester, methanol, water and sodium hydroxide into a reaction vessel, standing overnight at room temperature, performing rotary evaporation to remove the methanol after complete reaction, adding ethyl acetate for extraction, removing organic phase impurities, adjusting the pH of a water phase to 1, then extracting with ethyl acetate, performing rotary evaporation to separate out a first white solid, performing suction filtration to obtain a first filtrate for later use, rinsing the first white solid with ethyl acetate, performing rotary evaporation to the first filtrate to obtain a suspension, performing suction filtration to obtain a second white solid and a second filtrate, and combining the first white solid and the second white solid to obtain cis-4-hydroxy-1, 3-piperidinedicarboxylic acid 1-benzyl ester 3-carboxylic acid;
adding anhydrous calcium chloride into the second filtrate, drying, and spin-drying to obtain trans-4-hydroxy-1, 3-piperidinedicarboxylic acid 1-benzyl ester 3-carboxylic acid;
step three, 3 a: under the protection of nitrogen, sequentially adding cis-4-hydroxy-1, 3-piperidinedicarboxylic acid 1-benzyl ester 3-carboxylic acid, azido diphenyl phosphate, triethylamine and toluene into a reaction vessel, heating and reacting completely, and sequentially performing extraction, concentration and silica gel column treatment to obtain cis-oxazolone [4,5-c ] piperidine 5(6H) -N-Cbz;
3 b: under the protection of nitrogen, adding trans-4-hydroxy-1, 3-piperidinedicarboxylic acid 1-benzyl ester 3-carboxylic acid, azido diphenyl phosphate, triethylamine and toluene into a reaction vessel in sequence, heating and reacting completely, and obtaining trans-oxazolone [4,5-c ] piperidine 5(6H) -N-Cbz after extraction, concentration and silica gel column treatment in sequence;
step four, 4 a: sequentially adding cis-oxazolone [4,5-c ] piperidine 5(6H) -N-Cbz, BOC acid anhydride, triethylamine and dichloromethane into a reaction container, dropwise adding 4-dimethylaminopyridine under the protection of nitrogen, reacting completely at room temperature, and reacting to obtain cis-3-amino-4-hydroxy-N-Cbz piperidine;
4 b: adding trans-oxazolone [4,5-c ] piperidine 5(6H) -N-Cbz, BOC acid anhydride, triethylamine and dichloromethane into a reaction container in sequence, dropwise adding 4-dimethylaminopyridine under the protection of nitrogen, reacting completely at room temperature, and reacting to obtain trans-3-amino-4-hydroxy-N-Cbz piperidine;
the reaction formula of the above reaction is as follows:
more preferably, the amount of sodium borohydride used in the first step is 0.4 to 0.6 equivalent times of the 4-oxo-1, 3-piperidinedicarboxylic acid 1-benzyl ester 3-methyl ester.
More preferably, the amount of sodium hydroxide used in the second step is 1.1 to 1.2 times equivalent of 4-hydroxy-1, 3-piperidinedicarboxylic acid 1-benzyl ester 3-methyl ester.
More preferably, the amount of diphenyl phosphorazidate used in step three, 3a, is 1.1 to 1.3 times equivalent of cis-4-hydroxy-1, 3-piperidinedicarboxylic acid 1-benzyl ester 3-carboxylic acid; the amount of triethylamine is 1.1-1.5 times equivalent to cis-4-hydroxy-1, 3-piperidinedicarboxylic acid 1-benzyl ester 3-carboxylic acid.
More preferably, the amount of diphenyl phosphorazidate used in step three, 3b, is 1.1 to 1.3 times equivalent of trans-4-hydroxy-1, 3-piperidinedicarboxylic acid 1-benzyl ester 3-carboxylic acid; the amount of triethylamine is 1.1 to 1.5 times equivalent to trans-4-hydroxy-1, 3-piperidinedicarboxylic acid 1-benzyl ester 3-carboxylic acid.
More preferably, in steps 3a and 3b of the third step, the temperature is raised to 85 ℃ and the reaction is carried out for 4 hours.
More preferably, the amount of BOC anhydride in the step four, 4a, is 1.1-1.3 times equivalent of cis-oxazolone [4,5-c ] piperidine 5(6H) -N-Cbz; the dosage of triethylamine is 1.3-1.5 times equivalent of cis-oxazolone [4,5-c ] piperidine 5(6H) -N-Cbz.
More preferably, the amount of BOC anhydride used in the step four 4b is 1.1-1.2 times equivalent of trans-oxazolone [4,5-c ] piperidine 5(6H) -N-Cbz; the dosage of triethylamine is 1.3-1.5 times equivalent of trans-oxazolone [4,5-c ] piperidine 5(6H) -N-Cbz.
More preferably, the amount of 4-dimethylaminopyridine used in step four, 4a, is 0.1 equivalent of cis-oxazolone [4,5-c ] piperidine 5(6H) -N-Cbz; the dosage of the 4-dimethylamino pyridine in the 4b in the step four is 0.1 time equivalent of the trans-oxazolone [4,5-c ] piperidine 5(6H) -N-Cbz.
In summary, compared with the prior art, the invention has the following beneficial effects:
(1) according to the invention, through improving synthesis steps and parameters, the hydroxyl positions of the cis-4-hydroxy-1, 3-piperidinedicarboxylic acid 1-benzyl ester 3-carboxylic acid and the trans-4-hydroxy-1, 3-piperidinedicarboxylic acid 1-benzyl ester 3-carboxylic acid are the same, and the total yield can be increased to 15-20%;
(2) the invention does not need tube sealing reaction, has lower temperature and mild reaction and improves the safety.
Detailed Description
The present invention will be described in detail with reference to examples.
Example 1: a preparation method of FBDD common molecular fragment comprises the following steps:
step one, adding a reaction raw material, namely 4-oxo-1, 3-piperidinedicarboxylic acid 1-benzyl ester 3-methyl ester (500g, 1.72mol, 1.0eq), into a 5L reaction bottle, adding 2.5L tetrahydrofuran to dissolve the reaction raw material, cooling to below 0 ℃ under the protection of a nitrogen system, slowly adding sodium borohydride (26.12g, 0.69mol,0.40eq) in batches, and reacting for 4 hours, wherein TLC shows that: the reaction raw materials disappear to obtain a reaction solution. Adding 2L of methyl tert-butyl ether into the reaction solution, stirring, adding 1L of 50% salt solution, separating, and adding water phase2L of methyl tert-butyl ether was added and extracted once, the organic phases were combined, the organic phase was washed with 1.5L of saturated brine and the solvent of the organic phase was evaporated to dryness to give 490g (2.05mol) of 4-hydroxy-1, 3-piperidinedicarboxylic acid 1-benzyl 3-methyl ester as a brown liquid (yield)>95％)，LCMS[M+1]+294.0。
Step two, add 4-hydroxy-1, 3-piperidinedicarboxylic acid 1-benzyl ester 3-methyl ester (265g, 0.90mol,1.0eq), methanol (1.5L), water (1.5L), sodium hydroxide (41.0g,1.03mol,1.14eq) to a 5L reaction flask, overnight at room temperature, TLC showed completion of the reaction after 16 hours of reaction, post-reaction treatment: removing methanol by rotary evaporation, adding ethyl acetate for extraction for 600mL for 5 times, skimming an organic phase, adjusting the pH value of a water phase to 1 by using 95mL concentrated hydrochloric acid, extracting twice by using 1L ethyl acetate, combining the organic phases, removing most of an organic solvent by rotary evaporation, separating out a first white solid, reserving a first filtrate after suction filtration by a water pump, leaching the first white solid by using ethyl acetate to obtain 88g of a first white solid, removing most of the ethyl acetate by rotary evaporation of the first filtrate to obtain a suspension, performing suction filtration to obtain 10g of a second white solid and a second filtrate, and combining the first white solid and the second white solid to obtain the yield of the cis-4-hydroxy-1, 3-piperidinedicarboxylic acid 1-benzyl ester 3-carboxylic acid (98g,0.35mol) of 38.5%. [ M +1 ]]+280.01H NMR(400MHz,DMSO-d6)12.27(s,1H),7.51–7.14(m,5H),5.06-5.01(m,2H),4.92(s,1H),4.23(s,1H),3.87(d,J＝13.6Hz,1H),3.72(d,J＝13.6Hz,1H),3.20-3.03(m,2H),2.47-2.40(m,1H),1.68-1.49(m,2H)；
10g of anhydrous calcium chloride was added to the second filtrate and dried to give a pale yellow trans-1-hydroxy-1, 3-piperidinedicarboxylic acid 1-benzyl ester 3-carboxylic acid (106g, 0.38mol) in a crude yield of 42%. [ M +1 ]]+280.01H NMR(400MHz,DMSO-d6)7.49-7.16(m,5H),5.11–4.94(m,2H),4.00–3.92(m,1H),3.90-3.79(m,1H),3.77–3.68(m,1H),3.36(s,1H),3.15–2.83(m,2H),2.22-2.12(m,1H),1.84–1.72(m,1H),1.30-1.13(m,1H)。
Step three, 3 a: cis-4-hydroxy-1, 3-piperidinedicarboxylic acid 1-benzyl ester 3-carboxylic acid (330g,1.18mol,1.0eq), azido diphenyl phosphate (390g,1.42mol,1.2eq), triethylamine (179g,1.77mol,1.5eq), and toluene (500mL) were added to a reaction flask in this order under nitrogen protection, and the temperature was raisedReaction to 85 ℃ for 4 hours, post-reaction treatment: pouring the reaction solution into water, adding ethyl acetate for extraction, concentrating to obtain 220g of oily matter, carrying out silica gel chromatography purification on the oily matter, wherein the specification of a chromatographic column is 80cm in diameter and 800cm in length, the size of silica gel filled in the chromatographic column is 200-300 meshes, the using amount is 1600g, the height of a filler is 10-20 cm, a mobile phase is petroleum ether and ethyl acetate (v/v4:1), the flow rate is 25mL/min, collecting with a 100mL small bottle after 400mL, carrying out TLC monitoring, combining and concentrating to obtain (180g, 0.65mol) white solid cis-form oxazolone [4,5-c ] of the cis-oxazolone]And piperidine 5(6H) -N-Cbz, yield 55%; [ M +1 ]]+277.1；
3 b: under the protection of nitrogen, trans-4-hydroxy-1, 3-piperidinedicarboxylic acid 1-benzyl ester 3-carboxylic acid (320g,1.15mol,1.0eq), azido diphenyl phosphate (378g,1.38mol,1.2eq), triethylamine (174g,1.73mol,1.5eq) and toluene (500mL) were added in this order to a reaction flask, and the reaction was heated to 85 ℃ for 4 hours and post-reaction treatment: pouring the reaction solution into water, adding ethyl acetate for extraction, concentrating to obtain an oily substance, carrying out silica gel chromatography purification on the oily substance, wherein the specification of a chromatographic column is 80cm in diameter and 800cm in length, the size of the silica gel filled in the chromatographic column is 200-300 meshes, the using amount is 1600g, the height of a filler is 10-20 cm, mobile phases are petroleum ether and ethyl acetate (v/v4:1), the flow rate is 25mL/min, collecting by using a 100mL small bottle after 900mL, monitoring by TLC, combining and concentrating to obtain the white solid trans-oxazolone [4,5-c ] in a white solid state]And piperidine 5(6H) -N-Cbz (152g, 0.55mol), yield 48%. [ M +1 ]]+277.11HNMR(400MHz,Chloroform-d)7.42-7.29(m,5H),5.81-5.66(m,1H),5.13(s,2H),4.70-4.33(m,2H),4.00(td,J＝10.9,3.7Hz,1H),3.31(td,J＝10.9,3.7Hz,1H),3.01-2.70(m,2H),2.26-2.07(m,1H),1.96-1.77(m,1H)。
Step four, 4 a: sequentially adding cis-oxazolone [4,5-c ] into a reaction bottle]Piperidine 5(6H) -N-Cbz (110g,0.40mol,1.0eq), BOC anhydride (113g,0.52mol,1.3eq), triethylamine (60.5g,0.60mol,1.5eq), and dichloromethane (800mL), 50mL of 4-dimethylaminopyridine (4.86g,0.04mol,0.1eq) in dichloromethane was added dropwise under nitrogen protection at 20 deg.C, after the addition was complete, the reaction was carried out at room temperature for 30 minutes, TLC showed complete reaction, water and dichloromethane were added each 500mL and extracted twice, the organic phase was separated, dried and concentrated to obtain 170g of crude product, which was dissolved in 1.5L of methanol, potassium carbonate 55g (0.40mol, 1.0eq) was added, and the mixture was stirred at room temperatureOvernight, the methanol was removed by rotary evaporation, taken up in ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate and concentrated to give cis-3-amino-4-hydroxy-N-Cbz piperidine (140g, 0.40mol) in yield>95％；[M-99]+251.0。
4 b: adding trans-oxazolone [4,5-c ] in sequence into a reaction vessel]And piperidine 5(6H) -N-Cbz, BOC anhydride (110g,0.40mol,1.0eq), BOC anhydride (105g,0.48mol,1.2eq), triethylamine (60g,0.59mol,1.5eq), and dichloromethane (800mL), 50mL of a 4-dimethylaminopyridine (4.86g,0.04mol,0.1eq) solution in dichloromethane was added dropwise under nitrogen protection at 20 ℃, after completion of the addition, the reaction was carried out at room temperature for 30 minutes, TLC showed completion of the reaction, water and dichloromethane were each 500mL were added and extracted twice, the organic phase was separated, dried and concentrated to obtain a crude product, which was dissolved in 1.5L of methanol, potassium carbonate 55g (0.40mol, 1.0eq) was added, the mixture was stirred overnight at room temperature, methanol was removed by rotary evaporation, dissolved in ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated to obtain trans-3-amino-4-hydroxy-N-Cbz piperidine (140g, 0.40mol), yield>95％。[M-99]+251.0。
The reaction formula of the above reaction is as follows:
wherein the compound 1 is 4-oxo-1, 3-piperidinedicarboxylic acid 1-benzyl ester 3-methyl ester;
the compound 2 is 4-hydroxy-1, 3-piperidinedicarboxylic acid 1-benzyl ester 3-methyl ester;
the compound 3 is cis-4-hydroxy-1, 3-piperidinedicarboxylic acid 1-benzyl ester 3-carboxylic acid;
the compound 4 is trans-4-hydroxy-1, 3-piperidinedicarboxylic acid 1-benzyl ester 3-carboxylic acid;
compound 5 is cis-oxazolone [4,5-c ] piperidine 5(6H) -N-Cbz;
compound 6 is trans-oxazolone [4,5-c ] piperidine 5(6H) -N-Cbz;
compound 7 is cis-3-amino-4-hydroxy-N-Cbz piperidine;
compound 8 is trans-3-amino-4-hydroxy-N-Cbz piperidine.
Example 2: a preparation method of FBDD common molecular fragment is different from the preparation method of the FBDD in the embodiment 1, wherein the using amount of the sodium borohydride in the step one is 0.5 times of the equivalent of the 4-oxo-1, 3-piperidinedicarboxylic acid 1-benzyl ester 3-methyl ester.
Example 3: a preparation method of FBDD common molecular fragment is different from the preparation method of the FBDD in the embodiment 1, wherein the using amount of the sodium borohydride in the step one is 0.6 times of the equivalent of the 4-oxo-1, 3-piperidinedicarboxylic acid 1-benzyl ester 3-methyl ester.
Example 4: a preparation method of FBDD common molecular fragment is different from the preparation method of the FBDD common molecular fragment in the embodiment 1, wherein the using amount of the sodium hydroxide in the step two is 1.1 times of the equivalent of the 4-hydroxy-1, 3-piperidinedicarboxylic acid 1-benzyl ester 3-methyl ester.
Example 5: a preparation method of FBDD common molecular fragment is different from the preparation method of the FBDD common molecular fragment in the embodiment 1, wherein the using amount of sodium hydroxide in the step two is 1.2 times of the equivalent of the 4-hydroxy-1, 3-piperidinedicarboxylic acid 1-benzyl ester 3-methyl ester.
Example 6: a preparation method of FBDD common molecular fragment, which is different from the embodiment 1 in that the dosage of the diphenyl phosphorazidate in the step three 3a is 1.1 times of the equivalent of the cis-4-hydroxy-1, 3-piperidinedicarboxylic acid 1-benzyl ester 3-carboxylic acid; the dosage of triethylamine is 1.1 times equivalent of cis-4-hydroxy-1, 3-piperidinedicarboxylic acid 1-benzyl ester 3-carboxylic acid; in the third step 3b, the dosage of the diphenyl phosphorazidate is 1.1 times of the equivalent weight of the trans-4-hydroxy-1, 3-piperidinedicarboxylic acid 1-benzyl ester 3-carboxylic acid; the amount of triethylamine used was 1.1 times equivalent to that of trans-4-hydroxy-1, 3-piperidinedicarboxylic acid 1-benzyl ester 3-carboxylic acid.
Example 7: a preparation method of FBDD common molecular fragment, which is different from the embodiment 1 in that the dosage of the diphenyl phosphorazidate in the step three 3a is 1.3 times of the equivalent of the cis-4-hydroxy-1, 3-piperidinedicarboxylic acid 1-benzyl ester 3-carboxylic acid; the dosage of triethylamine is 1.3 times of equivalent of cis-4-hydroxy-1, 3-piperidinedicarboxylic acid 1-benzyl ester 3-carboxylic acid; in the third step 3b, the dosage of the diphenyl phosphorazidate is 1.3 times of the equivalent weight of the trans-4-hydroxy-1, 3-piperidinedicarboxylic acid 1-benzyl ester 3-carboxylic acid; the amount of triethylamine used was 1.3 times equivalent to that of trans-4-hydroxy-1, 3-piperidinedicarboxylic acid 1-benzyl ester 3-carboxylic acid.
Example 8: a preparation method of FBDD common molecular fragment, which is different from the embodiment 1 in that the amount of BOC acid anhydride in the step four, namely 4a, is 1.2 times of the equivalent weight of cis-oxazolone [4,5-c ] piperidine 5(6H) -N-Cbz; the dosage of triethylamine is 1.4 times equivalent of cis-oxazolone [4,5-c ] piperidine 5(6H) -N-Cbz; the dosage of BOC acid anhydride in the step four 4b is 1.15 times equivalent of trans-oxazolone [4,5-c ] piperidine 5(6H) -N-Cbz; the amount of triethylamine used was 1.4 times equivalent to trans-oxazolone [4,5-c ] piperidine 5(6H) -N-Cbz.
Example 9: a preparation method of FBDD common molecular fragment, which is different from the embodiment 1 in that the amount of BOC acid anhydride in the step four, namely 4a, is 1.1 times of the equivalent weight of cis-oxazolone [4,5-c ] piperidine 5(6H) -N-Cbz; the dosage of triethylamine is 1.3 times equivalent of cis-oxazolone [4,5-c ] piperidine 5(6H) -N-Cbz; the dosage of BOC acid anhydride in the step four 4b is 1.1 times of equivalent of trans-oxazolone [4,5-c ] piperidine 5(6H) -N-Cbz; the amount of triethylamine used was 1.3 times equivalent to trans-oxazolone [4,5-c ] piperidine 5(6H) -N-Cbz.
The above description is only a preferred embodiment of the present invention, and the protection scope of the present invention is not limited to the above embodiments, and all technical solutions belonging to the idea of the present invention belong to the protection scope of the present invention. It should be noted that modifications and embellishments within the scope of the invention may occur to those skilled in the art without departing from the principle of the invention, and are considered to be within the scope of the invention.
Claims (9)
1. A preparation method of FBDD common molecular fragments is characterized by comprising the following steps:
adding 4-oxo-1, 3-piperidinedicarboxylic acid 1-benzyl ester 3-methyl ester into a reaction container, adding tetrahydrofuran to dissolve the 4-oxo-1, 3-piperidinedicarboxylic acid 1-benzyl ester 3-methyl ester, cooling to below 0 ℃ under the protection of a nitrogen system, slowly adding sodium borohydride in batches, and after the reaction is finished, sequentially performing extraction, liquid separation and evaporation to obtain 4-hydroxy-1, 3-piperidinedicarboxylic acid 1-benzyl ester 3-methyl ester;
step two, adding 4-hydroxy-1, 3-piperidinedicarboxylic acid 1-benzyl ester 3-methyl ester, methanol, water and sodium hydroxide into a reaction vessel, standing overnight at room temperature, performing rotary evaporation to remove the methanol after complete reaction, adding ethyl acetate for extraction, removing organic phase impurities, adjusting the pH of a water phase to 1, then extracting with ethyl acetate, performing rotary evaporation to separate out a first white solid, performing suction filtration to obtain a first filtrate for later use, rinsing the first white solid with ethyl acetate, performing rotary evaporation to the first filtrate to obtain a suspension, performing suction filtration to obtain a second white solid and a second filtrate, and combining the first white solid and the second white solid to obtain cis-4-hydroxy-1, 3-piperidinedicarboxylic acid 1-benzyl ester 3-carboxylic acid;
adding anhydrous calcium chloride into the second filtrate, drying, and spin-drying to obtain trans-4-hydroxy-1, 3-piperidinedicarboxylic acid 1-benzyl ester 3-carboxylic acid;
step three, 3 a: under the protection of nitrogen, sequentially adding cis-4-hydroxy-1, 3-piperidinedicarboxylic acid 1-benzyl ester 3-carboxylic acid, azido diphenyl phosphate, triethylamine and toluene into a reaction vessel, heating and reacting completely, and sequentially performing extraction, concentration and silica gel column treatment to obtain cis-oxazolone [4,5-c ] piperidine 5(6H) -N-Cbz;
3 b: under the protection of nitrogen, adding trans-4-hydroxy-1, 3-piperidinedicarboxylic acid 1-benzyl ester 3-carboxylic acid, azido diphenyl phosphate, triethylamine and toluene into a reaction vessel in sequence, heating and reacting completely, and obtaining trans-oxazolone [4,5-c ] piperidine 5(6H) -N-Cbz after extraction, concentration and silica gel column treatment in sequence;
step four, 4 a: sequentially adding cis-oxazolone [4,5-c ] piperidine 5(6H) -N-Cbz, BOC anhydride, triethylamine and dichloromethane into a reaction container, dropwise adding N, N-dimethylformamide under the protection of nitrogen, reacting completely at room temperature, and reacting to obtain piperidine with BOC cis-3-amino-4-hydroxy-N-Cbz;
4 b: adding trans-oxazolone [4,5-c ] piperidine 5(6H) -N-Cbz, BOC anhydride, triethylamine and dichloromethane into a reaction container in sequence, dropwise adding N, N-dimethylformamide under the protection of nitrogen, reacting completely at room temperature, and reacting to obtain trans-3-amino-4-hydroxy-N-Cbz piperidine with BOC;
the reaction formula of the above reaction is as follows:
2. the method for preparing FBDD conventional molecular fragments as claimed in claim 1, wherein the amount of sodium borohydride used in the first step is 0.4-0.6 equivalent times of 4-oxo-1, 3-piperidinedicarboxylic acid 1-benzyl ester 3-methyl ester.
3. The method for preparing FBDD conventional molecular fragments as claimed in claim 1, wherein the amount of sodium hydroxide used in step two is 1.1-1.2 times equivalent of 1-benzyl 3-methyl 4-hydroxy-1, 3-piperidinedicarboxylate.
4. The method for preparing FBDD common molecular fragment as claimed in claim 1, wherein the amount of diphenyl phosphorazidate used in step three, 3a, is 1.1-1.3 times equivalent of cis-4-hydroxy-1, 3-piperidinedicarboxylic acid 1-benzyl ester 3-carboxylic acid; the amount of triethylamine is 1.1-1.5 times equivalent to cis-4-hydroxy-1, 3-piperidinedicarboxylic acid 1-benzyl ester 3-carboxylic acid.
5. The method for preparing FBDD common molecular fragment as claimed in claim 1, wherein diphenyl phosphorazidate is used in an amount of 1.1-1.3 times equivalent to trans 4-hydroxy-1, 3-piperidinedicarboxylic acid 1-benzyl ester 3-carboxylic acid in step three, 3 b; the amount of triethylamine is 1.1 to 1.5 times equivalent to trans-4-hydroxy-1, 3-piperidinedicarboxylic acid 1-benzyl ester 3-carboxylic acid.
6. The method for preparing FBDD general molecular fragments as claimed in claim 1, wherein the temperature in 3a and 3b of the third step is raised to 85 ℃ and reacted for 4 hours.
7. The method for preparing FBDD common molecular fragment as claimed in claim 1, wherein the amount of BOC anhydride used in 4a of step four is 1.1-1.3 times equivalent of cis-oxazolone [4,5-c ] piperidine 5(6H) -N-Cbz; the dosage of triethylamine is 1.3-1.5 times equivalent of cis-oxazolone [4,5-c ] piperidine 5(6H) -N-Cbz.
8. The method for preparing FBDD common molecular fragment as claimed in claim 1, wherein the amount of BOC anhydride used in 4b of step four is 1.1-1.2 times equivalent of trans-oxazolone [4,5-c ] piperidine 5(6H) -N-Cbz; the dosage of triethylamine is 1.3-1.5 times equivalent of trans-oxazolone [4,5-c ] piperidine 5(6H) -N-Cbz.
9. The method for preparing FBDD general molecular fragment as claimed in claim 1, wherein the N, N-dimethylformamide is used in 4a of step four in an amount of 0.1 times equivalent to cis-oxazolone [4,5-c ] piperidine 5(6H) -N-Cbz; the dosage of the N, N-dimethylformamide in the step four 4b is 0.1 time equivalent of the trans-oxazolone [4,5-c ] piperidine 5(6H) -N-Cbz.
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