CN108239019A - The synthetic method of one kind (2S, 5S or 5R)-N- tertbutyloxycarbonyls -5- hydroxyls -2-piperidinecarboxylic acid ethyl ester - Google Patents
The synthetic method of one kind (2S, 5S or 5R)-N- tertbutyloxycarbonyls -5- hydroxyls -2-piperidinecarboxylic acid ethyl ester Download PDFInfo
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- CN108239019A CN108239019A CN201611228091.XA CN201611228091A CN108239019A CN 108239019 A CN108239019 A CN 108239019A CN 201611228091 A CN201611228091 A CN 201611228091A CN 108239019 A CN108239019 A CN 108239019A
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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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Abstract
The invention discloses the synthetic methods of 5 hydroxyl of one kind (2S, 5S or 5R) N tertbutyloxycarbonyls, 2 piperidine ethyl formate.The method of 5 hydroxyl of synthesis (2S, 5S) N tertbutyloxycarbonyls, 2 piperidine ethyl formate exists apparent insufficient at present, and difficult point is the structure of cis- nipecotic acid hexatomic ring.The present invention is using 5 hydroxyl, 2 pyridine carboxylic acid as starting material; 9 steps are restored into salt, reduction, upper Boc, oxidation, upper protection, lipase chiral resolution, upper Boc, deprotection and reductase by esterification and obtain (2S; 5S) 2 piperidine ethyl formate of 5 hydroxyl of N tertbutyloxycarbonyls, 2 piperidine ethyl formate or/and 5 hydroxyl of (2S, 5R) N tertbutyloxycarbonyls.The reaction condition of the present invention is mild easily-controllable, easy to operate, and reaction reagent used is cheap, greatly reduces production cost, and byproduct of reaction toxicity is smaller, more friendly to environment, is conducive to mass produce.
Description
Technical field
The invention belongs to pharmaceutical intermediates to synthesize field, specifically one kind (2S, 5S)-N- tertbutyloxycarbonyl -5- hydroxyls
The synthetic method of base -2-piperidinecarboxylic acid ethyl ester or/and (2S, 5R)-N- tertbutyloxycarbonyls -5- hydroxyls -2-piperidinecarboxylic acid ethyl ester.
Background technology
Nipecotic acid and its derivative are very important synthetic intermediate, have on such compound hexatomic ring piperidine structure
Two hand-type centers, synthesis is difficult, and generally to pass through very cumbersome synthesis step can synthesize, and be widely used in drug
Such as the preparation of AVM hereinafter Batan sodium and the substance of many bioactivity.But it since presently commercially available price is very expensive, not only limits
It is applied in pharmaceutical industry and complicated natural products organic synthesis, also drawn high significantly with its drug as raw material into
This.
As the method for existing preparation (2S, 5S)-N- tertbutyloxycarbonyls -5- hydroxyls -2-piperidinecarboxylic acid ethyl ester, United States Patent (USP)
In US20130296555, describe using N- tertbutyloxycarbonyls-ethyl L-pyroglutamate as the tertiary fourth oxygen of Material synthesis (2S, 5S)-N-
The two methods of carbonyl -5- hydroxyls -2-piperidinecarboxylic acid ethyl ester, synthetic route are as follows：
Method A：
Method B：
With the open loop of (trimethylsilyl) diazomethane, rhodium acetate cyclization, sodium borohydride reduction synthesizes method A
(2S, 5S)-N- tertbutyloxycarbonyls -5- hydroxyls -2-piperidinecarboxylic acid ethyl ester；Method B is pungent with Trimethylsulfoxonium Iodide open loop, 1,5- rings
Diene iridium chloride dimer cyclization, sodium borohydride reduction synthesize (2S, 5S)-N- tertbutyloxycarbonyl -5- hydroxyl -2- piperidines
Ethyl formate.Two lines are right there are severe reaction conditions, reaction reagent used are expensive, and by-product toxicity is larger
Environmental pollution is serious, thus is unfavorable for large-scale production.
It is described in document (RSC.Adv., 2015,5,52154-52160) with (t-butoxycarbonyl amino) malonic acid diethyl
Ester is the method for Material synthesis (2S, 5S)-N- tertbutyloxycarbonyls -5- hydroxyls -2-piperidinecarboxylic acid ethyl ester, and synthetic route is as follows：
There are synthetic route is longer, reaction agents useful for same is expensive, and two chiral centres need to pass through twice for the synthetic method
It splits, causes yield relatively low, it is difficult to accomplish scale production.
In conclusion document above report synthesis (2S, 5S)-N- tertbutyloxycarbonyls -5- hydroxyls -2-piperidinecarboxylic acid ethyl ester
There is apparent deficiency in method, difficult point is the structure of cis- nipecotic acid hexatomic ring；Therefore, be badly in need of exploitation it is a kind of it is environmental-friendly,
Selectivity is good, yield is good, the inexpensive method for preparing (2S, 5S)-N- tertbutyloxycarbonyls -5- hydroxyls -2-piperidinecarboxylic acid ethyl ester.
Invention content
The technical problems to be solved by the invention are to overcome the problems of the above-mentioned prior art, provide it is a kind of (2S, 5S or
5R) the synthetic method of-N- tertbutyloxycarbonyls -5- hydroxyls -2-piperidinecarboxylic acid ethyl ester, using 5- hydroxyl -2- pyridine carboxylic acids as raw material,
It, can be with the controllable synthesis of very high chiral purity (2S, 5S)-N- tertbutyloxycarbonyl -5- hydroxyls -2- by two step enzyme reactions
Piperidine ethyl formate or/and (2S, 5R)-N- tertbutyloxycarbonyls -5- hydroxyls -2-piperidinecarboxylic acid ethyl ester.
For this purpose, the present invention adopts the following technical scheme that：One kind (2S, 5S or 5R)-N- tertbutyloxycarbonyl -5- hydroxyls -2-
The synthetic method of piperidine ethyl formate, using -2 pyridine carboxylic acid of 5- hydroxyls as starting material, by esterification into salt, reduction, on
Boc, oxidation, upper protection, lipase chiral resolution, upper Boc, deprotection and reductase restore 9 steps and obtain the tertiary fourth oxygen of (2S, 5S)-N-
Carbonyl -5- hydroxyls -2-piperidinecarboxylic acid ethyl ester or/and (2S, 5R)-N- tertbutyloxycarbonyls -5- hydroxyls -2-piperidinecarboxylic acid ethyl ester.
The specific reaction route of above-mentioned synthetic method is as follows：
Further, the lipase chiral resolution, with 5,5- diethoxies -2-piperidinecarboxylic acid ethyl ester for raw material,
Selective hydrolysis under fatty enzyme effect obtains (S) -5,5- diethoxies -2-piperidinecarboxylic acid ethyl ester of single configuration.
Further, described reductase reduction, using (S)-N- tertbutyloxycarbonyls -5- carbonyls -2-piperidinecarboxylic acid ethyl ester as
Raw material is added in the reaction system containing ketoreductase and carries out selective reduction, obtains (2S, 5S)-N- tertbutyloxycarbonyls -5-
Hydroxyl -2-piperidinecarboxylic acid ethyl ester or/and (2S, 5R)-N- tertbutyloxycarbonyls -5- hydroxyls -2-piperidinecarboxylic acid ethyl ester.
Further, above-mentioned synthetic method includes step in detail below：
1) -2 pyridine carboxylic acid of 5- hydroxyls under the action of the concentrated sulfuric acid, thionyl chloride or hydrogen chloride (preferably thionyl chloride) with second
Alcohol reacts, and generates 5- hydroxyl -2- pyridine carboxylic acid carbethoxy hydrochlorides, and the reaction time is 2~24 hours, and reaction temperature is 20~80 DEG C
(most preferably 70 DEG C)；
2) 5- hydroxyls -2- pyridine carboxylic acid carbethoxy hydrochlorides are dissolved in ethyl alcohol, methanol, isopropanol, acetone (preferred alcohol)
One or more restore hydrogenation, generation 5- hydroxyls -2-piperidinecarboxylic acid carbethoxy hydrochloride, reaction time under rhodium catalyst
It it is 2~48 hours, reaction temperature is 20~50 DEG C (most preferably 35 DEG C)；
3) 5- hydroxyls -2-piperidinecarboxylic acid carbethoxy hydrochloride is dissolved in tetrahydrofuran, dichloromethane, acetonitrile, DMF (preferably tetrahydrochysenes
One or more of furans), with BOC anhydride reactions under the action of organic base, generate N- tertbutyloxycarbonyl -5- hydroxyls -2-
Piperidine ethyl formate, reaction time are 2~24 hours, and reaction temperature is 25~50 DEG C (most preferably 35 DEG C), and the organic base is
Triethylamine, pyridine, diisopropylethylamine or 2,6- lutidines (most preferably diisopropylethylamine),；
4) N- tertbutyloxycarbonyls -5- hydroxyls -2-piperidinecarboxylic acid ethyl ester is dissolved in dichloromethane, chloroform, carbon tetrachloride, 1,2- bis-
One or more of chloroethanes (preferably dichloromethane) under the action of dimethyl sulfoxide (DMSO), oxalyl chloride and triethylamine, generates N-
Tertbutyloxycarbonyl -5- carbonyls -2-piperidinecarboxylic acid ethyl ester, reaction time are 2~8 hours, and reaction temperature is (best for -78~0 DEG C
It it is -70 DEG C)；
5) N- tertbutyloxycarbonyls -5- carbonyls -2-piperidinecarboxylic acid ethyl ester is dissolved in ethyl alcohol, in the concentrated sulfuric acid, thionyl chloride or chlorine
With ethanol synthesis under the action of change hydrogen (preferably thionyl chloride), 5,5- diethoxies -2-piperidinecarboxylic acid ethyl ester, reaction time are generated
It it is 1~6 hour, reaction temperature is 20~80 DEG C (most preferably 70 DEG C)；
6) 5,5- diethoxies -2-piperidinecarboxylic acid ethyl ester is in n-hexane, ether or isopropyl ether (preferably n-hexane) and phosphoric acid
In the two-phase system of salt buffer solution, the selective hydrolysis under fatty enzyme effect, obtain (S) -5,5- diethoxies of single configuration -
2-piperidinecarboxylic acid ethyl ester, reaction time are 1~6 hour, and reaction temperature is 20~40 DEG C (most preferably 35 DEG C)；
7) (S) -5,5- diethoxies -2-piperidinecarboxylic acid ethyl ester is dissolved in tetrahydrofuran, dichloromethane, acetonitrile, DMF (preferably
One or more of tetrahydrofuran), with BOC anhydride reactions under the action of organic base, (S)-N- tertbutyloxycarbonyl -5 are generated,
5- diethoxies -2-piperidinecarboxylic acid ethyl ester, reaction time are 2~24 hours, and reaction temperature is 25~50 DEG C (most preferably 25 DEG C),
The organic base be triethylamine, pyridine, diisopropylethylamine or 2,6- lutidines (most preferably diisopropylethylamine),；
8) (S)-N- tertbutyloxycarbonyls -5,5- diethoxy -2-piperidinecarboxylic acid ethyl ester hydrolyzes in acid condition, generation
(S)-N- tertbutyloxycarbonyls -5- carbonyls -2-piperidinecarboxylic acid ethyl ester, reaction time are 2~24 hours, and reaction temperature is 20~50 DEG C
(most preferably 25 DEG C)；
9) (S)-N- tertbutyloxycarbonyls -5- carbonyls -2-piperidinecarboxylic acid ethyl ester is dissolved in methanol, ethyl alcohol, isopropanol, acetonitrile or two
One or more of methyl sulfoxide (preferably methanol) is added in the reaction system containing ketoreductase and carries out selectivity also
Original, using different ketoreductases, controllable reduction obtains (2S, 5S)-N- tertbutyloxycarbonyls -5- hydroxyls -2-piperidinecarboxylic acid second
Ester or/and (2S, 5R)-N- tertbutyloxycarbonyls -5- hydroxyls -2-piperidinecarboxylic acid ethyl ester, reaction time are 2~24 hours, reaction temperature
It spends for 20~50 DEG C (most preferably 35 DEG C).
The present invention has screened more than 40 kinds reductases altogether in step reaction, and specific enzyme screening table and selectivity are as follows
Table：
In the selection result as can be seen that number ES-KRED-191,192,195,217,224,225,235,246,250
Ketoreductase can be worth to (2S, 5S)-N-Boc-5- hydroxyls -2-piperidinecarboxylic acid ethyl ester with 100% DE.S-KRED-214 energy
It is enough that (2S, 5R)-N-Boc-5- hydroxyls -2-piperidinecarboxylic acid ethyl ester is worth to 89.5% DE.
Further, in step 1), the concentrated sulfuric acid, thionyl chloride or hydrogen chloride and reactant molar ratio for 0.5~
10：1 (most preferably 5:1)；
In step 2), the rhodium catalyst is rhodium charcoal, and the dosage of rhodium catalyst is 5- hydroxyl -2- pyridine carboxylic acid ethyl esters
1~50% (most preferably 10%) of salt weight, reaction pressure are 0.01~10MPa (most preferably 3MPa).
Further, in step 3), the BOC acid anhydrides is with 5- hydroxyls -2-piperidinecarboxylic acid carbethoxy hydrochloride molar ratio
1.05~3.0:1 (most preferably 2:1)；The organic base and 5- hydroxyls -2-piperidinecarboxylic acid carbethoxy hydrochloride molar ratio for 2.02~
3.5:1 (most preferably 2.2:1).
Further, in step 4), the dimethyl sulfoxide (DMSO) and N- tertbutyloxycarbonyls -5- hydroxyls -2-piperidinecarboxylic acid second
Ester molar ratio is 1.05~3.0:1 (most preferably 2:1), oxalyl chloride rubs with N- tertbutyloxycarbonyls -5- hydroxyls -2-piperidinecarboxylic acid ethyl ester
You are than being 1.05~2.5:1 (most preferably 1.5:1), triethylamine and N- tertbutyloxycarbonyls -5- hydroxyls -2-piperidinecarboxylic acid ethyl ester mole
Than being 2.0~4.0:1 (most preferably 3:1).
Further, in step 5), the concentrated sulfuric acid, thionyl chloride or hydrogen chloride and reactant molar ratio are 2~10:
1 (most preferably 5:1)；In step 6), phosphate in the phosphate buffer solution is sodium phosphate or potassium phosphate, phosphate-buffered
The pH value of solution is 6~8 (most preferably 7.5).
Further, in step 6), the lipase believes CALB for Novi's letter 435 or Novi, and the dosage of lipase is
50~150% (most preferably 100%) of 5,5- diethoxies -2-piperidinecarboxylic acid ethyl ester weight.
Further, in step 7), the BOC acid anhydrides and (S) -5,5- diethoxies -2-piperidinecarboxylic acid ethyl ester mole
Than being 1.05~3.0:1 (most preferably 2:1)；The organic base and (S) -5,5- diethoxies -2-piperidinecarboxylic acid ethyl ester molar ratio
It is 1.1~3.5:1 (most preferably 2.2:1).
Further, in step 8), the acid condition for methanol, ethyl alcohol, isopropanol, acetone or acetonitrile (preferably
Ethyl alcohol) one or more of organic solvent and 1mol/L hydrochloric acid composition mixed solution, organic solvent is with hydrochloric acid volume ratio
0.5~2.5:1 (most preferably 1:1).
Further, in step 9), solution in reaction system is deionized water, reaction system pH=6~8；Reaction
In system, contain 0.9-1.1mg (preferably 1mg) ketoreductase, 0.9-1.2mg (preferably 1.07mg) phosphoric acid in every 0.1ml solution
Hydrogen dipotassium, 0.4-0.6mg (preferably 0.52mg) potassium dihydrogen phosphate, 0.01-0.03mg (preferably 0.02mg) NADP+、0.3-0.5mg
(preferably 0.4mg) glucose and 0.1-0.3mg (preferably 0.2mg) glucose dehydrogenase.
The present invention relative to other synthetic routes, using cheap and easily-available -2 pyridine carboxylic acid of 5- hydroxyls as Material synthesis (2S,
5S)-N- tertbutyloxycarbonyls -5- hydroxyls -2-piperidinecarboxylic acid ethyl ester or/and (2S, 5R)-N- tertbutyloxycarbonyl -5- hydroxyl -2- piperidines
Ethyl formate, reaction condition is mild easily-controllable, easy to operate, and reaction reagent used is cheap, greatly reduces and is produced into
This, byproduct of reaction toxicity is smaller, more friendly to environment, is conducive to mass produce.
Specific embodiment
The present invention will be described further in conjunction with specific embodiments, but present disclosure is not limited by this embodiment
System.
1.5- hydroxyl -2- pyridine carboxylic acids carbethoxy hydrochlorides (abbreviation compound 1)
5- hydroxyl -2- pyridine carboxylic acids (20g, 143.8mmol) and 200ml ethyl alcohol are added in 500ml single port bottles, stirring adds
Heat extremely flows back.Thionyl chloride (52.2ml, 719mmol) is slowly added dropwise in reaction solution, is maintained the reflux for the reaction was complete, is depressurized
Revolving removes solvent and obtains compound 1 (27.5g, 93.9%).1H NMR (500MHZ, DMSO-d6)：8.30 (d, 1H), 8.02 (d,
1H), 7.47 (dd, 1H), 4.32 (q, 2H), 1.32 (t, 3H)；MS(m/z)：168.1[M+1]+。
The synthesis (abbreviation compound 2) of 2.5- hydroxyls -2-piperidinecarboxylic acid carbethoxy hydrochloride
Compound 1 (27.5g, 135mmol), rhodium carbon (2.75g, 10%Rh/C) and 150ml ethyl alcohol are added in hydriding reactor
Stirring and dissolving, pressurized with hydrogen to 200psi react 12h.Vacuum rotary steam removes solvent and obtains 2 crude product of compound (27.6g), and product is not
It is purified directly to carry out next step reaction.
The synthesis (abbreviation compound 3) of 3.N-Boc-5- hydroxyls -2-piperidinecarboxylic acid ethyl ester
2 crude product of compound (27.6g, 131.6mmol) is added in 500ml single port bottles and 200ml tetrahydrofurans, room temperature are stirred
It mixes and lower Boc acid anhydrides (57.4g, 263.2mmol) and diisopropylethylamine (47.8ml, 289.5mmol) is slowly added dropwise into reaction
Liquid is stirred at room temperature to the reaction was complete.Vacuum rotary steam removes solvent, adds in ethyl acetate and water, liquid separation obtain organic phase, washing and drying
It is spin-dried for, obtains 3 crude product of compound (23.65g).
The synthesis (abbreviation compound 4) of 4.N-Boc-5- carbonyls -2-piperidinecarboxylic acid ethyl ester
Dimethyl sulfoxide (DMSO) (12.3ml, 173mmol) and 200ml dichloromethane are added in 500ml there-necked flasks, at -78 DEG C
It is lower that oxalyl chloride (11.1ml, 129.8mmol) is slowly added dropwise in reaction solution, this temperature is kept to stir 15min；By compound 3
After crude product (23.65g, 86.5mmol) is dissolved with 50ml dichloromethane, it is slowly added dropwise in reaction solution at -78 DEG C；After continuation of insurance
Hold this temperature stirring 1h；Triethylamine (36.2ml, 259.5mmol) is slowly added dropwise in reaction solution at -78 DEG C, keeps this temperature extremely
The reaction was complete.Ice water is slowly added dropwise to be quenched, is slowly increased to that 15min is stirred at room temperature, adds in dichloromethane and water, liquid separation obtains organic
Phase, washing and drying are spin-dried for, column chromatography for separation (PE:EA=10:1) compound 4 (21.5g, 91.5%) is obtained.1H NMR (500MHZ,
CDCl3)：4.69 (dt, 1H), 4.30-4.21 (m, 3H), 3.91 (dd, 1H), 2.47-2.32 (m, 3H), 2.23-2.07 (m,
1H), 1.47,1.45 (both S, 9H), 1.29 (q, 3H)；MS(m/z)：172.0[M+1-100]+。
The synthesis (abbreviation compound 5) of 5.5,5- diethoxies -2-piperidinecarboxylic acid ethyl ester
Compound 4 (21.5g, 79.2mmol) and 200ml ethyl alcohol are added in 500ml single port bottles, by protochloride at 0 DEG C
Sulfone (28.7ml, 396mmol) is slowly added dropwise in reaction solution, and 1h is heated to reflux after being added dropwise.It is cooled to room temperature, uses saturated carbon
Sour hydrogen sodium water solution adjusts pH=8, adds in ethyl acetate and water, liquid separation obtain organic phase, washing and drying is spin-dried for, column chromatography for separation
(PE:EA=8:1) compound 5 (16.3g, 84.1%) is obtained.1H NMR (500MHZ, CDCl3)：(4.21-4.16 m, 2H), 3.55-
3.40 (m, 4H), 3.37-3.34 (m, 1H), 3.16-3.12 (m, 1H), 2.60 (d, 1H), 2.10-2.05 (m, 1H), 1.96-
1.91 (m, 1H), 1.70-1.55 (m, 2H), 1.274 (t, 3H), 1.21-1.15 (m, 6H)；MS(m/z)：201.1[M+1-45
]+。
The synthesis (abbreviation compound 6) of (6. S) -5,5- diethoxies -2-piperidinecarboxylic acid ethyl ester
In 500ml single port bottles, add in compound 5 (16.3g, 66.4mmol) and 150ml n-hexanes, after stirring and dissolving according to
Secondary addition 150ml buffer solution of potassium phosphate (pH=8) and Novi's letter CALB liquid aliphatics enzyme (5g, 5000LU/g), are stirred at room temperature
React 1.5h.After LC tracing detections (R) -5,5- diethoxies -2-piperidinecarboxylic acid ethyl ester hydrolysis completely, liquid separation obtains organic phase, water
It washes and dries to obtain compound 6 (7.5g).MS(m/z)：172.0[M+1-100]+。
The synthesis (abbreviation compound 7) of (7. S)-N-Boc-5,5- diethoxies -2-piperidinecarboxylic acid ethyl ester
Compound 6 (7.5g, 30.6mmol) and 150ml tetrahydrofurans are added in 250ml single port bottles, lower incite somebody to action is stirred at room temperature
Boc acid anhydrides (13.4g, 61.2mmol) and diisopropylethylamine (11.1ml, 67.3mmol) are slowly added dropwise into reaction solution, and room temperature is stirred
It mixes to the reaction was complete.It adds in ethyl acetate and water, liquid separation obtains organic phase, washing and drying is spin-dried for, column chromatography for separation (PE:EA=8：
1) compound 7 (10.2g, 96.6%) is obtained,.1H NMR (500MHZ, CDCl3)：4.92-4.70 (m, 1H), 4.28-4.13 (m,
3H), 3.55-3.41 (m, 4H), 2.87-2.73 (m, 1H), 2.17-2.10 (m, 1H), 2.02-1.92 (m, 2H), 1.47,1.44
(both S, 9H), 1.29-1.25 (m, 3H), 1.18-1.15 (m, 6H)；MS(m/z)：200.1[M+1-145]+。
The synthesis (abbreviation compound 8) of (8. S)-N-Boc-5- carbonyls -2-piperidinecarboxylic acid ethyl ester
Add in compound 7 (10.2g 29.5mmol) and 50ml ethyl acetate in 250ml single port bottles, after stirring and dissolving according to
Secondary addition 50ml methanol and 50ml 1M hydrochloric acid, are stirred at room temperature to the reaction was complete.Revolving removes methanol, adds in ethyl acetate and water,
Liquid separation obtains organic phase, and washing and drying is spin-dried for, column chromatography for separation (PE:EA=10:1) compound 8 (7g, 84.5%) is obtained1H NMR
(500MHZ, CDCl3)：4.69 (dt, 1H), 4.30-4.21 (m, 3H), 3.91 (dd, 1H), 2.47-2.32 (m, 3H), 2.23-
2.07 (m, 1H), 1.47,1.45 (both S, 9H), 1.29 (q, 3H)；MS(m/z)：172.0[M+1-100]+。
The synthesis (abbreviation compound 9) of (9. 2S, 5S)-N-Boc-5- hydroxyls -2-piperidinecarboxylic acid ethyl ester
Compound 8 (100mg, 0.37mmol) 10ml methanol is dissolved, is added to the 90ml reactions containing ketoreductase
In system, it is put into constant-temperature table (120rpm) reaction for 24 hours.With LC tracing detections after the reaction was complete, the inactivation of 100ml acetonitriles is added in,
Ultrasonic oscillation 10min, centrifugation 10min (4000rpm, 3220xg) obtain supernatant liquor, are spin-dried for removing solvent, column chromatography for separation
(PE:EA=4:1) compound 9 (95.5mg, 95.4%) is obtained.1H NMR (500MHZ, CDCl3)：(4.87-4.58 m, 1H),
4.28-4.04 (m, 3H), 3.71-3.58 (m, 1H), 2.82-2.64 (m, 1H), 2.35-2.19 (m, 1H), 2.04-1.94 (m,
1H), 1.78-1.67 (m, 1H), 1.62-1.53 (m, 1H), 1.47,1.44 (both S, 9H), 1.29 (q, 3H)；MS(m/z)：
274.1[M+1]+。
The synthesis (abbreviation compound 10) of (10. 2S, 5R)-N-Boc-5- hydroxyls -2-piperidinecarboxylic acid ethyl ester
Compound 8 (100mg, 0.37mmol) 10ml methanol is dissolved, is added to the 90ml reactions containing ketoreductase
In system, it is put into constant-temperature table (120rpm) reaction for 24 hours.With LC tracing detections after the reaction was complete, the inactivation of 100ml acetonitriles is added in,
Ultrasonic oscillation 10min, centrifugation 10min (4000rpm, 3220xg) obtain supernatant liquor, are spin-dried for removing solvent, column chromatography for separation
(PE:EA=6:1) compound 10 (91.5mg, 90.8%) is obtained.1H NMR (500MHZ, CDCl3)：(4.91-4.74 m, 1H),
4.28-4.04 (m, 2H), 4.08-3.95 (m, 1H), 3.24-3.10 (m, 1H), 2.35-2.19 (m, 1H), 2.16-2.00 (m,
2H), 1.89-1.76 (m, 2H), 1.47,1.45 (both S, 9H), 1.29 (q, 3H)；MS(m/z)：274.1[M+1]+。
Claims (10)
1. the synthetic method of one kind (2S, 5S or 5R)-N- tertbutyloxycarbonyls -5- hydroxyls -2-piperidinecarboxylic acid ethyl ester, feature exist
In：
Using -2 pyridine carboxylic acid of 5- hydroxyls as starting material, by being esterified into salt, reduction, upper Boc, oxidation, upper protection, lipase hand
Property fractionation, upper Boc, deprotection and reductase restore 9 steps and obtain (2S, 5S)-N- tertbutyloxycarbonyls -5- hydroxyls -2-piperidinecarboxylic acid second
Ester or/and (2S, 5R)-N- tertbutyloxycarbonyls -5- hydroxyls -2-piperidinecarboxylic acid ethyl ester.
2. synthetic method according to claim 1, which is characterized in that the lipase chiral resolution, with 5,5- diethyls
Oxygroup -2-piperidinecarboxylic acid ethyl ester is raw material, and the selective hydrolysis under fatty enzyme effect obtains (S) -5,5- diethoxies of single configuration
Base -2-piperidinecarboxylic acid ethyl ester.
3. synthetic method according to claim 1, which is characterized in that the reductase reduction, with the tertiary fourth oxygen of (S)-N-
Carbonyl -5- carbonyls -2-piperidinecarboxylic acid ethyl ester is raw material, is added in the reaction system containing ketoreductase and carries out selectivity also
Original obtains (2S, 5S)-N- tertbutyloxycarbonyls -5- hydroxyls -2-piperidinecarboxylic acid ethyl ester or/and (2S, 5R)-N- tertbutyloxycarbonyls -5-
Hydroxyl -2-piperidinecarboxylic acid ethyl ester.
4. according to the synthetic method described in claim 1,2 or 3, which is characterized in that it includes step in detail below：
1) -2 pyridine carboxylic acid of 5- hydroxyls generates 5- hydroxyls -2- with ethanol synthesis under the effect of the concentrated sulfuric acid, thionyl chloride or hydrogen chloride
Pyridine carboxylic acid carbethoxy hydrochloride, reaction time are 2~24 hours, and reaction temperature is 20~80 DEG C；
2) 5- hydroxyls -2- pyridine carboxylic acid carbethoxy hydrochlorides are dissolved in one or more of ethyl alcohol, methanol, isopropanol, acetone, in rhodium
Hydrogenation, generation 5- hydroxyls -2-piperidinecarboxylic acid carbethoxy hydrochloride are restored under catalyst action, the reaction time is 2~48 hours, reaction
Temperature is 20~50 DEG C；
3) 5- hydroxyls -2-piperidinecarboxylic acid carbethoxy hydrochloride is dissolved in one kind or several in tetrahydrofuran, dichloromethane, acetonitrile, DMF
Kind, it is reacted under the action of organic base with BOC anhydride reactions, generation N- tertbutyloxycarbonyls -5- hydroxyls -2-piperidinecarboxylic acid ethyl ester
Time is 2~24 hours, and reaction temperature is 25~50 DEG C, and the organic base is triethylamine, pyridine, diisopropylethylamine or 2,
6- lutidines；
4) N- tertbutyloxycarbonyls -5- hydroxyls -2-piperidinecarboxylic acid ethyl ester is dissolved in dichloromethane, chloroform, carbon tetrachloride, bis- chloroethenes of 1,2-
One or more of alkane, under the action of dimethyl sulfoxide (DMSO), oxalyl chloride and triethylamine, generation N- tertbutyloxycarbonyl -5- carbonyls -
2-piperidinecarboxylic acid ethyl ester, reaction time are 2~8 hours, and reaction temperature is -78~0 DEG C；
5) N- tertbutyloxycarbonyls -5- carbonyls -2-piperidinecarboxylic acid ethyl ester is dissolved in ethyl alcohol, in the concentrated sulfuric acid, thionyl chloride or hydrogen chloride
Effect is lower and ethanol synthesis, 5,5- of generation diethoxies -2-piperidinecarboxylic acid ethyl ester, reaction time are 1~6 hour, reaction temperature
It is 20~80 DEG C；
6) 5,5- diethoxies -2-piperidinecarboxylic acid ethyl ester is in n-hexane, ether or isopropyl ether and the two-phase of phosphate buffer solution
In system, the selective hydrolysis under fatty enzyme effect obtains (S) -5,5- diethoxies -2-piperidinecarboxylic acid ethyl ester of single configuration,
Reaction time is 1~6 hour, and reaction temperature is 20~40 DEG C；
7) (S) -5,5- diethoxies -2-piperidinecarboxylic acid ethyl ester be dissolved in one kind in tetrahydrofuran, dichloromethane, acetonitrile, DMF or
It is several, with BOC anhydride reactions under the action of organic base, generate (S)-N- tertbutyloxycarbonyl -5,5- diethoxy -2- piperidines first
Acetoacetic ester, reaction time are 2~24 hours, and reaction temperature is 25~50 DEG C, and the organic base is triethylamine, pyridine, two different
Propylethylamine or 2,6- lutidines；
8) (S)-N- tertbutyloxycarbonyls -5,5- diethoxy -2-piperidinecarboxylic acid ethyl ester hydrolyzes in acid condition, generates (S)-N-
Tertbutyloxycarbonyl -5- carbonyls -2-piperidinecarboxylic acid ethyl ester, reaction time are 2~24 hours, and reaction temperature is 20~50 DEG C；
9) (S)-N- tertbutyloxycarbonyls -5- carbonyls -2-piperidinecarboxylic acid ethyl ester is dissolved in methanol, ethyl alcohol, isopropanol, acetonitrile or dimethyl
One or more of sulfoxide is added in the reaction system containing ketoreductase and carries out selective reduction, utilizes different ketone
Reductase, controllable reduction obtain (2S, 5S)-N- tertbutyloxycarbonyls -5- hydroxyls -2-piperidinecarboxylic acid ethyl ester or/and (2S, 5R) -
N- tertbutyloxycarbonyls -5- hydroxyls -2-piperidinecarboxylic acid ethyl ester, reaction time are 2~24 hours, and reaction temperature is 20~50 DEG C.
5. synthetic method according to claim 4, which is characterized in that in step 1), the concentrated sulfuric acid, thionyl chloride or chlorine
Change hydrogen and reactant molar ratio for 0.5~:10：1；
In step 2), the rhodium catalyst is rhodium charcoal, and the dosage of rhodium catalyst is 5- hydroxyl -2- pyridine carboxylic acid carbethoxy hydrochloride weights
The 1~50% of amount, reaction pressure are 0.01~10MPa；
In step 3), the BOC acid anhydrides is 1.05~3.0 with 5- hydroxyls -2-piperidinecarboxylic acid carbethoxy hydrochloride molar ratio:1；It is described
Organic base is 2.02~3.5 with 5- hydroxyls -2-piperidinecarboxylic acid carbethoxy hydrochloride molar ratio:1.
6. synthetic method according to claim 4, which is characterized in that in step 4), the dimethyl sulfoxide (DMSO) and the tertiary fourths of N-
Oxygen carbonyl -5- hydroxyls -2-piperidinecarboxylic acid ethyl ester molar ratio is 1.05~3.0:1, oxalyl chloride and N- tertbutyloxycarbonyl -5- hydroxyls -
2-piperidinecarboxylic acid ethyl ester molar ratio is 1.05~2.5:1, triethylamine and N- tertbutyloxycarbonyls -5- hydroxyls -2-piperidinecarboxylic acid ethyl ester
Molar ratio is 2.0~4.0:1；
In step 5), the concentrated sulfuric acid, thionyl chloride, hydrogen chloride and reactant molar ratio are 2~10:1；It is described in step 6)
Phosphate in phosphate buffer solution is sodium phosphate or potassium phosphate, and the pH value of phosphate buffer solution is 6~8.
7. synthetic method according to claim 4, which is characterized in that in step 6), the lipase for Novi letter 435 or
Novi believes CALB, and the dosage of lipase is the 50~150% of (S) -5,5- diethoxies -2-piperidinecarboxylic acid ethyl ester weight.
8. synthetic method according to claim 4, which is characterized in that in step 7), the BOC acid anhydrides and (S) -5,5- bis-
Ethyoxyl -2-piperidinecarboxylic acid ethyl ester molar ratio is 1.05~3.0:1；The organic base and (S) -5,5- diethoxy -2- piperidines
Ethyl formate molar ratio is 1.1~3.5:1.
9. synthetic method according to claim 4, which is characterized in that in step 8), the acid condition is methanol, second
The mixed solution of one or more of alcohol, isopropanol, acetone, acetonitrile organic solvent and 1mo l/L hydrochloric acid composition, organic solvent
It is 0.5~2.5 with hydrochloric acid volume ratio:1.
10. synthetic method according to claim 4, which is characterized in that in step 9), solution in reaction system for go from
Sub- water, reaction system pH=6~8；In reaction system, contain 0.9-1.1mg ketoreductases, 0.9-1.2mg in every 0.1ml solution
Dipotassium hydrogen phosphate, 0.4-0.6mg potassium dihydrogen phosphates, 0.01-0.03mgNADP+, 0.3-0.5mg glucose and 0.1-0.3mg Portugals
Grape glucocorticoid dehydrogenase.
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