CN109320515A - A kind of method of asymmetric synthesis of Capromorelin chiral intermediate - Google Patents
A kind of method of asymmetric synthesis of Capromorelin chiral intermediate Download PDFInfo
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Abstract
The invention discloses a kind of method of asymmetric synthesis of Capromorelin chiral intermediate.3- carbethoxyl group -4- piperidone hydrochloride reacts under alkalinity effect with cylite, gained compound 1- benzyl -4- oxo-piperidine -3- carboxylic acid, ethyl ester and cylite are under the action of cinchona alkaloid phase transfer bationase-catalsis, 1 is obtained by Unsymmetrical alkylation, 3- dibenzyl -4- oxo-piperidine -3- Ethyl formate, it is then passed through de- Bn protecting group and upper Boc protecting group two-step reaction, then 3 α R- benzyl -1- (tert-butyl) oxygen carbonyl -2- methyl -4 of compound has been obtained in a heated condition, 5, 6, 7- tetrahydro -2H- pyrazolo [4, 3-c] pyridine -3- (3H) -one, this compound is the important intermediate of Capromorelin.Raw material of the present invention is cheap and easy to get, cost is relatively low, it is easy to operate, reaction condition is mild, it avoids using chiral resolution or the method for enzymatic and constructs chiral quaternary carbon center, use cinchona alkaloid as phase transfer catalyst, yield is apparently higher than the chiral product that method for splitting obtains, and environmentally protective, no danger.
Description
Technical field
The present invention relates to technical field of medicine synthesis, more particularly to construct drug molecule by asymmetric alkylation
The chiral centre of Capromorelin.
Background technique
Leptin (Ghrelin) is a kind of newfound Growth Hormone Releasing Peptide containing 28 amino acid, is growth
The endogenic ligand of hormone secretagogue receptor, plays key effect in various physiological processes.According to current the study found that
Although Ghrelin to stimulate appetite with play the role of in food intake dose it is critically important, since there are half-life period for Leptin
It is short and need through the application that the disadvantages of drug administration by injection, which limits it in clinic outside stomach.And Capromorelin
(molecular structural formula is as shown in Figure 1), which has proven to one kind, can directly improve insulin growth factor-1 (IGF-1) and life
The pharmaceutical activity molecule of long hormonal readiness, and there is longer half-life period.It is all deposited in Capromorelin and its similar structures
It is the synthesis difficult point of this kind of complicated drug molecule in a chiral quaternary carbon center.
2003, Carpino et al., which is reported, was first protected 4- oxo-nipecotic acid methyl esters with Boc acid anhydrides (Boc2O)
Shield, is then alkylated with cylite as alkali using sodium hydride and is reacted, the piperidine intermediate and methylsulfuric acid hydrazine for obtaining racemization exist
The heterocycle product of cyclization has been obtained under heating condition, then sloughs protecting group Boc in acid condition, obtained product and Boc-
Aib- (D)-O-Bn-Ser-OH obtains two diastereoisomers under EDC and HOBT coupling condition, passes through thin-layer chromatographic analysis
It obtains, biggish polarity is S configuration, and lesser polarity is R configuration, uses L-TARTARIC ACID in the second of heating after then sloughing protecting group
Under the conditions of alcohol, obtain Caprmorelin (synthetic route is as shown in Figure 2).The defect of the method be by the method for fractionation come
Required chipal compounds are obtained, yield is lower, and the method operation split is relatively difficult.
2009, Janine et al. was reported first by carrotene by carbonyl enantioselective reduction, then -78
Under the conditions of DEG C, Unsymmetrical alkylation is carried out with LDA and cylite and has obtained alkylate, then passes through this compound
Dess-Martin reagent oxidation obtains chiral 3- benzyl piepridine intermediate (synthetic route is as shown in Figure 3), and the intermediate is referring to text
Offering can synthesize to obtain final product Capromorelin.Although the product that the method can be final, uses in the process
Carrotene, the enzymatic structure of carrotene is more easily damaged during stirring, therefore cannot obtain reduzate well,
And LDA and more expensive Dai Si-Martin's oxidant are also used in the process, this not only adds cost and there are also certain
Danger.
Summary of the invention
The purpose of the present invention is to provide a kind of asymmetry of synthetic drug molecule Capromorelin chiral intermediate to close
At new method.The present invention overcomes the operating difficulties of the prior art, yield is lower, higher cost and tool is dangerous lacks
Point constructs chiral centre by Unsymmetrical alkylation, this committed step yield is improved.Synthetic route of the invention is such as
Shown in Fig. 4.
To achieve the above object, The technical solution adopted by the invention is as follows:
A kind of method of asymmetric synthesis of Capromorelin chiral intermediate, comprising the following steps:
(1) under inorganic base effect, 3- carbethoxyl group -4- piperidone hydrochloride and cylite at room temperature, in N,
It is reacted in dinethylformamide, generates 1- benzyl -4- oxo-piperidine -3- carboxylic acid, ethyl ester;
(2) by 1- benzyl -4- oxo-piperidine -3- carboxylic acid, ethyl ester and cylite under the conditions of certain reaction temperature, in golden pheasant
It receives under biological phase transfer bationase-catalsis and inorganic base effect, reacts in a solvent, obtain (R) -1,3- dibenzyl -4- oxo piperazine
Pyridine -3- Ethyl formate;
(3) under the catalysis of the catalyst, (R) -1,3- dibenzyl -4- oxo-piperidine -3- Ethyl formate is in room temperature reaction
Under the conditions of, it reacts in a solvent, generates (R) -3- benzyl -4- oxo-piperidine -3- carboxylic acid, ethyl ester;
(4) under organic base effect, (R) -3- benzyl -4- oxo-piperidine -3- carboxylic acid, ethyl ester and Boc acid anhydrides are in room temperature condition
Under, it reacts in a solvent, (R) -3- benzyl -1- (tert-butyl) oxygen carbonyl -4- oxo-piperidine -3- Ethyl formate is made;
(5) under alkaline condition, (R) -3- benzyl -1- (tert-butyl) oxygen carbonyl -4- oxo-piperidine -3- Ethyl formate and first
Base hydrazine sulfate reacts in a solvent under the conditions of certain reaction temperature, generates 3 α R- benzyl -1- (tert-butyl) oxygen carbonyl -2-
Methyl -4,5,6,7- tetrahydro -2H- pyrazolo [4,3-c] pyridine -3- (3H) -one.
Further, the molar ratio of 3- carbethoxyl group -4- piperidone hydrochloride and cylite described in step (1) is 1:
1~3, preferably 1:1.5;The inorganic base is sodium bicarbonate, sodium hydroxide, potassium carbonate or cesium carbonate, preferably potassium carbonate.
Further, cinchona alkaloid phase transfer bationase-catalsis described in step (2) is (1S, 2R, 4S, 8R) -1-
(anthracene -9- ylmethyl) -2- ((S)-hydroxyl (quinolyl-4) methyl) -8- vinyl -1- nitrogen two ring [2.2.2] octane chlorination
Object, (1S, 2R, 4S, 8R) -1- benzyl -2- ((S)-hydroxyl (quinolyl-4) methyl) -8- vinyl -1- azabicyclo
[2.2.2] octane bromide, (1S, 2R, 4S, 8R) -2- ((S)-allyloxy (quinolyl-4) methyl) -1- (3,5- bis- (three
Methyl fluoride) benzyl) -8- vinyl -1- nitrogen two ring [2.2.2] octane bromide, (1S, 2R, 4S, 8R) -2- ((S)-allyl oxygen
Base (quinolyl-4) methyl) -1- (3- (trifluoromethyl) benzyl) -8- vinyl -1- nitrogen two ring [2.2.2] octane bromide
Or (1S, 2R, 4S, 8R) -2- ((S)-allyloxy (quinolyl-4) methyl) -1- (anthracene -9- ylmethyl) -8- vinyl -1- nitrogen
Two rings [2.2.2] octane bromide, preferably (1S, 2R, 4S, 8R) -2- ((S)-allyloxy (quinolyl-4) methyl) -
Two ring [2.2.2] octane bromide of 1- (anthracene -9- ylmethyl) -8- vinyl -1- nitrogen;The inorganic base is potassium carbonate, hydrogen
Potassium oxide, sodium hydroxide, cesium carbonate, potassium phosphate or 50%KOH aqueous solution, preferably 50%KOH aqueous solution;The solvent is
Toluene, tetrahydrofuran, methylene chloride, dimethylbenzene, chlorobenzene or paraxylene, preferably paraxylene;The cinchona alkaloid
Phase transfer bationase-catalsis dosage is the 5~20mol%, preferably 10mol% of 1- benzyl -4- oxo-piperidine -3- carboxylic acid, ethyl ester;Institute
The molar ratio of the 1- benzyl -4- oxo-piperidine -3- carboxylic acid, ethyl ester and cylite stated is 1:2~5, preferably 1:3;The 1- benzyl
The molar ratio of base -4- oxo-piperidine -3- carboxylic acid, ethyl ester and inorganic base is 1:1~5, preferably 1:5;The reaction temperature be-
30~25 DEG C, preferably 25 DEG C.
Further, catalyst described in step (3) is palladium carbon, Raney's nickel or platinum oxide, preferably palladium carbon;Described
(R) it is preferably 5:1 that the mass ratio of -1,3- dibenzyl -4- oxo-piperidine -3- Ethyl formate and catalyst, which is 10~5:1,;Described
Solvent is methanol, ethyl alcohol or tetrahydrofuran, preferably ethyl alcohol.
Further, solvent described in step (4) be methylene chloride, hexane, Isosorbide-5-Nitrae-dioxane or toluene, preferably
Methylene chloride;The molar ratio of (R) -3- benzyl -4- oxo-piperidine -3- carboxylic acid, ethyl ester and Boc acid anhydrides is 1:1~2, preferably
For 1:1.
Further, reaction temperature described in step (5) is 60~120 DEG C, preferably 80 DEG C;The alkali is acetic acid
Sodium, sodium carbonate, sodium bicarbonate or potassium carbonate, preferably sodium acetate;The solvent is methanol, ethyl alcohol, isopropanol or tetrahydro furan
It mutters, preferably ethyl alcohol;(R) -3- benzyl -1- (tert-butyl) oxygen carbonyl -4- oxo-piperidine -3- Ethyl formate and methyl sulphur
The molar ratio of sour hydrazine is 1:1~3, preferably 1:2.
Beneficial effects of the present invention:
Raw material of the present invention is cheap and easy to get, and cost is relatively low, easy to operate, and reaction condition is mild, avoids using chiral resolution
Or the method for enzymatic constructs chiral quaternary carbon center, uses cinchona alkaloid as phase transfer catalyst, yield is obvious
Higher than the chiral product that method for splitting obtains, and it is environmentally protective, and whole preparation process is suitble to large-scale production without risk.
Detailed description of the invention
Fig. 1 is the molecular structural formula of Capromorelin;
Fig. 2 is the Capromorelin synthetic route chart of Carpino et al. report;
Fig. 3 is the chiral 3- benzyl piepridine intermediate synthetic route figure of Janine et al. report;
Fig. 4 is synthetic route chart of the invention;Wherein, 1 is 3- carbethoxyl group -4- piperidone hydrochloride, and 2 be 1- benzyl -
4- oxo-piperidine -3- carboxylic acid, ethyl ester, 3 be (R) -1,3- dibenzyl -4- oxo-piperidine -3- Ethyl formate, and 4 be (R) -3- benzyl -
4- oxo-piperidine -3- carboxylic acid, ethyl ester, 5 be (R) -3- benzyl -1- (tert-butyl) oxygen carbonyl -4- oxo-piperidine -3- Ethyl formate, 6
For 3 α R- benzyl -1- (tert-butyl) oxygen carbonyl -2- methyl -4,5,6,7- tetrahydro -2H- pyrazolo [4,3-c] pyridine -3- (3H) -
Ketone.
Specific embodiment
Presently in connection with embodiment, the present invention is described in further detail.
Step 1: the preparation of 1- benzyl -4- oxo-piperidine -3- carboxylic acid, ethyl ester
Embodiment 1: being added 3- carbethoxyl group -4- piperidone hydrochloride (968mg, 5.0mmol) into 50mL round-bottomed flask,
10mLN is added in potassium carbonate (1.38g, 10.0mmol) afterwards, then 0.9mL cylite is slowly dropped to by dinethylformamide
In reaction solution, ambient temperature overnight reaction.After TLC monitoring raw material has reacted, by N, N- dimethyl after the solid in reaction solution is filtered
Formamide is spin-dried for, and is extracted with water and methylene chloride (3 × 20mL), and the organic phase merged is simultaneously added saturation NaCl aqueous solution and washes
It washs, anhydrous Na2SO4It is dry, rear pillar Chromatographic purification is concentrated under reduced pressure, obtains colorless and transparent grease, yield 76%.1H NMR
(300MHz,CDCl3):δ11.96(s,1H),7.34-7.32(m,5H),4.14-4.00(m,2H),3.62(s,2H),3.17
(t, J=1.8Hz, 2H), 2.61 (t, J=6.0Hz, 2H), 2.43-2.29 (m, 2H), 1.11 (t, J=7.2Hz, 3H)
Embodiment 2: other conditions are changed to sodium bicarbonate with embodiment 1, by inorganic base, and products therefrom yield is 65%.
Embodiment 3: other conditions are changed to sodium hydroxide with embodiment 1, by inorganic base, and products therefrom yield is 48%.
Embodiment 4: other conditions are changed to cesium carbonate with embodiment 1, by inorganic base, and products therefrom yield is 59%.
Embodiment 5: other conditions are with embodiment 1, by the molar ratio of 3- carbethoxyl group -4- piperidone hydrochloride and cylite
It is changed to 1:1, products therefrom yield is 67%.
Embodiment 6: other conditions are with embodiment 1, by the molar ratio of 3- carbethoxyl group -4- piperidone hydrochloride and cylite
It is changed to 1:3, products therefrom yield is 64%.
Step 2: the preparation of (R) -1,3- dibenzyl -4- oxo-piperidine -3- Ethyl formate
Embodiment 7: 1- benzyl -4- oxo-piperidine -3- carboxylic acid, ethyl ester is sequentially added into dry 100mL round-bottomed flask
(1.2g, 4.0mmol), 50%KOH aqueous solution (1.6g, 20.0mmol), (1S, 2R, 4S, 8R) -2- ((S)-allyloxy (quinoline
Quinoline -4- base) methyl) two ring [2.2.2] octane bromide (1- benzyl -4- of -1- (anthracene -9- ylmethyl) -8- vinyl -1- nitrogen
The 10mol% of oxo-piperidine -3- carboxylic acid, ethyl ester) and paraxylene (20mL).Bromine is added after mixture 30min is stirred at room temperature
Change benzyl (1.4mL, 12.0mmol), and continues that 12h is stirred at room temperature.It after TLC monitors fully reacting, is concentrated under reduced pressure, crude product is logical
Flash column chromatography is crossed, colourless liquid yield 70% is obtained.[α] 24D-43.6 (c=0.5, CH2Cl2);76%ee;1H NMR
(400MHz,CDCl3): δ 7.34-7.26 (m, 5H), 7.22-7.16 (m, 5H), 4.14-4.00 (m, 2H), 3.60 (d, J=
13.2Hz, 1H), 3.54 (d, J=13.2Hz, 1H), 3.42 (dd, J=11.6,2.4Hz, 1H), 3.22 (d, J=13.6Hz,
1H), 2.98-2.91 (m, 2H), 2.86-2.78 (m, 1H), 2.47-2.35 (m, 2H), 2.30 (d, J=11.6Hz, 1H), 1.11
(t, J=7.2Hz, 3H);13C NMR(100MHz,CDCl3):δ205.9,170.9,138.0,136.4,130.7,129.0,
128.4,128.1,127.4,126.8,62.8,61.9,61.3,61.2,53.2,40.7,37.6,14.0;HRMS(ESI,
positive):Calcd for C23H25NO5[M+H]+352.1907,found:352.1906.
Embodiment 8: other conditions change (1S, 2R, 4S, 8R) -1- (anthracene -9- base into embodiment 7, by phase transfer catalyst
Methyl) -2- ((S)-hydroxyl (quinolyl-4) methyl) -8- vinyl -1- nitrogen two ring [2.2.2] octane chloride, yield is
50%, ee value are 40%.
Embodiment 9: other conditions change (1S, 2R, 4S, 8R) -1- benzyl -2- into embodiment 7, by phase transfer catalyst
((S)-hydroxyl (quinolyl-4) methyl) -8- vinyl -1- azabicyclo [2.2.2] octane bromide, yield 65%, ee
Value is 30%.
Embodiment 10: other conditions change (1S, 2R, 4S, 8R) -2- ((S) allyl into embodiment 7, by phase transfer catalyst
Oxygroup (quinolyl-4) methyl) -1- (bis- (trifluoromethyl) benzyls of 3,5-) -8- vinyl -1- nitrogen two ring [2.2.2] octane
Bromide, yield 60%, ee value are 39%.
Embodiment 11: other conditions change (1S, 2R, 4S, 8R) -2- ((S)-alkene into embodiment 7, by phase transfer catalyst
Propoxyl group (quinolyl-4) methyl) -1- (3- (trifluoromethyl) benzyl) -8- vinyl -1- nitrogen two ring [2.2.2] octane bromine
Compound, yield 45%, ee value are 41%.
Embodiment 12: other conditions are changed to toluene with embodiment 7, by solvent, and products therefrom yield is that 60%, ee value is
60。
Embodiment 13: other conditions are changed to tetrahydrofuran with embodiment 7, by solvent, and products therefrom yield is 54%, ee value
It is 53%.
Embodiment 14: other conditions are changed to methylene chloride with embodiment 7, by solvent, and the yield of products therefrom is 39%, ee
Value is 54%.
Embodiment 15: other conditions are changed to dimethylbenzene with embodiment 7, by solvent, and the yield of products therefrom is 60%, ee value
It is 64%.
Embodiment 16: other conditions are changed to chlorobenzene with embodiment 7, by solvent, and products therefrom yield is that 54%, ee value is
58%.
Embodiment 17: other conditions are changed to 1- benzyl -4- oxo-piperidine -3- with embodiment 7, by the amount of phase transfer catalyst
The 5mol% of carboxylic acid, ethyl ester, the yield of products therefrom are that 66%, ee value is 65%.
Embodiment 18: other conditions are changed to 1- benzyl -4- oxo-piperidine -3- with embodiment 7, by the amount of phase transfer catalyst
The 20mol% of carboxylic acid, ethyl ester, the yield of products therefrom are that 69%, ee value is 67%.
Embodiment 19: other conditions are changed to potassium carbonate with embodiment 7, by alkali, and the yield of products therefrom is that 65%, ee value is
62%.
Embodiment 20: other conditions are changed to potassium hydroxide with embodiment 7, by inorganic base, and the yield of products therefrom is 56%,
Ee value is 61%.
Embodiment 21: other conditions are changed to sodium hydroxide with embodiment 7, by inorganic base, and the yield of products therefrom is 54%,
Ee value is 60%.
Embodiment 22: other conditions are changed to cesium carbonate with embodiment 7, by inorganic base, and the yield of products therefrom is 40%, ee
Value is 62%.
Embodiment 23: other conditions are changed to potassium phosphate with embodiment 7, by inorganic base, and the yield of products therefrom is 46%, ee
Value is 64%.
Embodiment 24: other conditions are with embodiment 7, by rubbing for 1- benzyl -4- oxo-piperidine -3- carboxylic acid, ethyl ester and cylite
You are changed to 1:2 by ratio, and the yield of products therefrom is that 48%, ee value is 56%.
Embodiment 25: other conditions are with embodiment 7, by rubbing for 1- benzyl -4- oxo-piperidine -3- carboxylic acid, ethyl ester and cylite
You are changed to 1:5 by ratio, and the yield of products therefrom is that 68%, ee value is 65%.
Embodiment 26: other conditions are with embodiment 7, by 1- benzyl -4- oxo-piperidine -3- carboxylic acid, ethyl ester and 50%KOH water
The molar ratio of solution is changed to 1:1, and the yield of products therefrom is that 65%, ee value is 67%.
Embodiment 27: other conditions are with embodiment 7, by 1- benzyl -4- oxo-piperidine -3- carboxylic acid, ethyl ester and 50%KOH water
The molar ratio of solution is changed to 1:3, and the yield of products therefrom is that 68%, ee value is 71%.
Embodiment 28: other conditions are changed to -30 DEG C with embodiment 7, by reaction temperature, and the yield of products therefrom is 58%,
Ee value is 70%.
Embodiment 29: other conditions are changed to -10 DEG C with embodiment 7, by reaction temperature, and the obstetrics of products therefrom are 61%,
Ee value is 71%.
Embodiment 30: other conditions are changed to 0 DEG C with embodiment 7, by reaction temperature, and the yield of products therefrom is 64%, ee
Value is 70%.
Step 3: the preparation of (R) -3- benzyl -4- oxo-piperidine -3- carboxylic acid, ethyl ester
Embodiment 31: (R) -1,3- dibenzyl -4- oxo-piperidine -3- Ethyl formate is successively added into 50mL round-bottomed flask
(351mg, 1.0mmol), palladium carbon (70mg) and ethyl alcohol (10mL), and mixture is stirred into 12h under room temperature and atmosphere of hydrogen.Instead
After answering completely, reaction mixture is filtered by diatomite, filtrate decompression is concentrated, and is slightly produced by flash column chromatography
Object obtains faint yellow oil product, yield 86%.[α] 24D-150.8 (c=0.5, CH2Cl2)。1H NMR(400MHz,
CDCl3):δ7.27-7.20(m,3H),7.11-7.09(m,2H),4.18-4.08(m,2H),3.71-3.67(m,1H),3.41-
3.36 (m, 2H), 2.93-2.86 (m, 1H), 2.82 (d, J=14.0Hz, 1H), 2.63 (d, J=13.6Hz, 1H), 2.48-
2.42 (m, 2H), 1.87 (s, 1H), 1.20 (t, J=7.2Hz, 3H);13C NMR(75MHz,CDCl3):δ204.6,170.6,
136.0,130.1,128.2,126.8,64.4,61.6,55.3,48.0,43.5,37.5,14.0;HRMS(ESI,
positive):Calcd for C15H19NO3[M+H]+262.1438,found:262.1438.
Embodiment 32: other conditions are changed to Raney's nickel with embodiment 31, by catalyst, and the yield of products therefrom is 80%.
Embodiment 33: other conditions are changed to platinum oxide with embodiment 31, by catalyst, and the yield of products therefrom is 79%.
Embodiment 34: other conditions are with embodiment 31, by (R) -1,3- dibenzyl -4- oxo-piperidine -3- Ethyl formate with
The mass ratio of palladium carbon is changed to 10:1, and products therefrom yield is 83%.
Embodiment 35: other conditions are changed to methanol with embodiment 31, by solvent, and products therefrom yield is 80%.
Embodiment 36: other conditions are changed to tetrahydrofuran with embodiment 31, by solvent, substantially reactionless.
Step 4: the preparation of (R) -3- benzyl -1- (tert-butyl) oxygen carbonyl -4- oxo-piperidine -3- Ethyl formate
Embodiment 37: (R) -3- benzyl -4- oxo-piperidine -3- carboxylic acid, ethyl ester (120mg, 0.46mmol) is dissolved in dichloromethane
It in alkane (5mL), is added triethylamine (0.13mL, 0.92mmol), 4-dimethylaminopyridine (5.6mg, 0.046mmol) and Boc acid
Acid anhydride (0.11mL, 0.46mmol), and reaction mixture is stirred into 15min at room temperature.Reaction is monitored by TLC to complete
Afterwards, NaHCO is saturated by being added3Aqueous solution (3mL) quenching reaction, and gained mixture is extracted with DCM (25mL × 3).It closes
And organic phase is washed with saturated brine (30mL), anhydrous Na2SO4It is dry, flash column chromatography is concentrated under reduced pressure, obtains white
Solid, yield 87%.mp 89-91℃;[α] 24D-53.5 (c=3, CH2Cl2);66%ee;1H NMR(300MHz,CDCl3):
δ 7.28-7.15 (m, 5H), 4.62 (s, 1H), 4.17 (br, 1H), 4.11-4.06 (m, 2H), 3.26 (d, J=13.8Hz, 1H),
3.19-3.11 (m, 1H), 3.01 (d, J=13.5Hz, 2H), 2.75-2.65 (m, 1H), 2.44 (d, J=14.4Hz, 1H),
1.45 (s, 9H), 1.15 (t, J=7.2Hz, 3H);13C NMR(75MHz,CDCl3):δ204.6,169.8,154.3,135.7,
130.5,128.3,127.0,80.5,62.3,61.8,50.4,43.2,40.1,37.4,28.3,14.0;HRMS(ESI,
positive):Calcd for C20H27NNaO5[M+Na]+384.1781,found:384.1781.
Embodiment 38: other conditions are changed to hexane with embodiment 37, by solvent, and the yield of products therefrom is 76%.
Embodiment 39: other conditions are changed to Isosorbide-5-Nitrae-dioxane with embodiment 37, by solvent, and the yield of products therefrom is
70%.
Embodiment 40: other conditions are changed to toluene with embodiment 37, by solvent, and the yield of products therefrom is 56%.
Step 5: 3 α R- benzyl -1- (tert-butyl) oxygen carbonyl -2- methyl -4,5,6,7- tetrahydro -2H- pyrazolos [4,3-c]
The preparation of pyridine -3- (3H) -one
Embodiment 41: by (R) -3- benzyl -1- (tert-butyl) oxygen carbonyl -4- oxo-piperidine -3- Ethyl formate (940mg,
2.6mmol), ethyl alcohol (35mL) solution is added in methylsulfuric acid hydrazine (750mg, 5.2mmol) and sodium acetate (854mg, 10.4mmol)
In, in 80 DEG C and N212h is reacted under atmosphere.Reaction solution is restored to room temperature, vacuum concentration after fully reacting.Crude product DCM
(100mL) dilution, and be saturated NaHCO3Aqueous solution (30mL) and NaCl aqueous solution (30mL) washing, anhydrous Na2SO4It is dry.It is logical
Flash column chromatography crude product is crossed, obtaining white solid is required product, yield 70%.mp 123-125℃;[α]
24D 44.8 (c=1, CH2Cl2);69%ee;1H NMR(300MHz,CDCl3):δ7.18-7.09(m,3H),7.02-6.97
(m, 2H), 4.60 (br, 1H), 4.39 (d, J=12.6Hz, 1H), 3.17 (d, J=13.2Hz, 1H), 3.00 (s, 3H), 2.95
(d, J=13.5Hz, 1H), 2.64 (br, 3H), 2.49 (d, J=9.6Hz, 1H), 1.47 (s, 9H);13C NMR(75MHz,
CDCl3):δ174.5,162.0,154.6,134.7,128.6,128.3,127.2,81.0,60.3,56.7,50.8,45.5,
37.9,30.7,28.3;HRMS(ESI,positive):Calcd for C19H25N3NaO3[M+Na]+366.1788,found:
366.1791.
Embodiment 42: other conditions are changed to 60 DEG C with embodiment 41, by temperature, and the yield of products therefrom is 43%.
Embodiment 42: other conditions are changed to 120 DEG C with embodiment 41, by temperature, and the yield of products therefrom is 60%.
Embodiment 44: other conditions change sodium carbonate into embodiment 41, by alkali, and the yield of products therefrom is 29%.
Embodiment 45: other conditions change sodium bicarbonate into embodiment 41, by alkali, and the yield of products therefrom is 34%.
Embodiment 46: other conditions change potassium carbonate into embodiment 41, by alkali, and the yield of products therefrom is 39%.
Embodiment 47: other conditions change methanol into embodiment 41, by solvent, and the yield of products therefrom is 64%.
Embodiment 48: other conditions change isopropanol into embodiment 41, by solvent, and the yield of products therefrom is 55%.
Embodiment 49: other conditions change tetrahydrofuran into embodiment 41, by solvent, and the yield of products therefrom is 39%.
Claims (6)
1. a kind of method of asymmetric synthesis of Capromorelin chiral intermediate, which comprises the following steps:
(1) under inorganic base effect, 3- carbethoxyl group -4- piperidone hydrochloride and cylite at room temperature, in N, N- bis-
It is reacted in methylformamide, generates 1- benzyl -4- oxo-piperidine -3- carboxylic acid, ethyl ester;
(2) raw in quinine by 1- benzyl -4- oxo-piperidine -3- carboxylic acid, ethyl ester and cylite under the conditions of certain reaction temperature
Under alkaloids phase transfer catalyst and inorganic base effect, reacts in a solvent, obtain (R) -1,3- dibenzyl -4- oxo-piperidine -3-
Ethyl formate;
(3) under the catalysis of the catalyst, (R) -1,3- dibenzyl -4- oxo-piperidine -3- Ethyl formate is in room temperature reaction condition
Under, it reacts in a solvent, generates (R) -3- benzyl -4- oxo-piperidine -3- carboxylic acid, ethyl ester;
(4) under organic base effect, (R) -3- benzyl -4- oxo-piperidine -3- carboxylic acid, ethyl ester and Boc acid anhydrides under room temperature,
It reacts in a solvent, (R) -3- benzyl -1- (tert-butyl) oxygen carbonyl -4- oxo-piperidine -3- Ethyl formate is made;
(5) under alkaline condition, (R) -3- benzyl -1- (tert-butyl) oxygen carbonyl -4- oxo-piperidine -3- Ethyl formate and methyl sulphur
Sour hydrazine reacts in a solvent under the conditions of certain reaction temperature, generates 3 α R- benzyl -1- (tert-butyl) oxygen carbonyl -2- methyl -
4,5,6,7- tetrahydro -2H- pyrazolo [4,3-c] pyridine -3- (3H) -one.
2. a kind of method of asymmetric synthesis of Capromorelin chiral intermediate according to claim 1, feature exist
In, the molar ratio of 3- carbethoxyl group -4- piperidone hydrochloride and cylite described in step (1) be 1:1~3, preferably 1:
1.5;The inorganic base is sodium bicarbonate, sodium hydroxide, potassium carbonate or cesium carbonate, preferably potassium carbonate.
3. a kind of method of asymmetric synthesis of Capromorelin chiral intermediate according to claim 1, feature exist
In cinchona alkaloid phase transfer bationase-catalsis described in step (2) is (1S, 2R, 4S, 8R) -1- (anthracene -9- ylmethyl) -2-
Two ring [2.2.2] octane chloride of ((S)-hydroxyl (quinolyl-4) methyl) -8- vinyl -1- nitrogen, (1S, 2R, 4S, 8R) -
1- benzyl -2- ((S)-hydroxyl (quinolyl-4) methyl) -8- vinyl -1- azabicyclo [2.2.2] octane bromide, (1S,
2R, 4S, 8R) -2- ((S)-allyloxy (quinolyl-4) methyl) -1- (3,5- bis- (trifluoromethyl) benzyls) -8- vinyl -
Two ring of 1- nitrogen [2.2.2] octane bromide, (1S, 2R, 4S, 8R) -2- ((S)-allyloxy (quinolyl-4) methyl) -1-
Two ring [2.2.2] octane bromide of (3- (trifluoromethyl) benzyl) -8- vinyl -1- nitrogen or (1S, 2R, 4S, 8R) -2-
Two ring [2.2.2] octane of ((S)-allyloxy (quinolyl-4) methyl) -1- (anthracene -9- ylmethyl) -8- vinyl -1- nitrogen
Bromide, preferably (1S, 2R, 4S, 8R) -2- ((S)-allyloxy (quinolyl-4) methyl) -1- (anthracene -9- ylmethyl) -8-
Vinyl -1- nitrogen two ring [2.2.2] octane bromide;The inorganic base is potassium carbonate, potassium hydroxide, sodium hydroxide, carbon
Sour caesium, potassium phosphate or 50%KOH aqueous solution, preferably 50%KOH aqueous solution;The solvent is toluene, tetrahydrofuran, dichloro
Methane, dimethylbenzene, chlorobenzene or paraxylene, preferably paraxylene;The cinchona alkaloid phase transfer bationase-catalsis dosage
For the 5~20mol%, preferably 10mol% of 1- benzyl -4- oxo-piperidine -3- carboxylic acid, ethyl ester;1- benzyl -4- the oxo
The molar ratio of piperidines -3- carboxylic acid, ethyl ester and cylite is 1:2~5, preferably 1:3;1- benzyl -4- oxo-piperidine-the 3-
The molar ratio of carboxylic acid, ethyl ester and inorganic base is 1:1~5, preferably 1:5;The reaction temperature be -30~25 DEG C, preferably 25
℃。
4. a kind of method of asymmetric synthesis of Capromorelin chiral intermediate according to claim 1, feature exist
In catalyst described in step (3) is palladium carbon, Raney's nickel or platinum oxide, preferably palladium carbon;Described (the R) -1,3- dibenzyl
The mass ratio of base -4- oxo-piperidine -3- Ethyl formate and catalyst is that 10~5:1 is preferably 5:1;The solvent be methanol,
Ethyl alcohol or tetrahydrofuran, preferably ethyl alcohol.
5. a kind of method of asymmetric synthesis of Capromorelin chiral intermediate according to claim 1, feature exist
In solvent described in step (4) is methylene chloride, hexane, Isosorbide-5-Nitrae-dioxane or toluene, preferably methylene chloride;It is described
(R) -3- benzyl -4- oxo-piperidine -3- carboxylic acid, ethyl ester and Boc acid anhydrides molar ratio be 1:1~2, preferably 1:1.
6. a kind of method of asymmetric synthesis of Capromorelin chiral intermediate according to claim 1, feature exist
In reaction temperature described in step (5) is 60~120 DEG C, preferably 80 DEG C;The alkali is sodium acetate, sodium carbonate, carbonic acid
Hydrogen sodium or potassium carbonate, preferably sodium acetate;The solvent is methanol, ethyl alcohol, isopropanol or tetrahydrofuran, preferably ethyl alcohol;
(R) -3- benzyl -1- (tert-butyl) oxygen carbonyl -4- oxo-piperidine -3- Ethyl formate and the molar ratio of methylsulfuric acid hydrazine be
1:1~3, preferably 1:2.
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