CN103951588B - A kind of method synthesizing onglyza intermediate N-tertbutyloxycarbonyl-3-hydroxyl-1-adamantyl-D-glycine - Google Patents
A kind of method synthesizing onglyza intermediate N-tertbutyloxycarbonyl-3-hydroxyl-1-adamantyl-D-glycine Download PDFInfo
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- 239000004471 Glycine Substances 0.000 title claims abstract description 22
- QGJUIPDUBHWZPV-SGTAVMJGSA-N saxagliptin Chemical compound C1C(C2)CC(C3)CC2(O)CC13[C@H](N)C(=O)N1[C@H](C#N)C[C@@H]2C[C@@H]21 QGJUIPDUBHWZPV-SGTAVMJGSA-N 0.000 title claims abstract description 15
- 108010033693 saxagliptin Proteins 0.000 title claims abstract description 15
- 229940001450 onglyza Drugs 0.000 title claims description 7
- 238000000034 method Methods 0.000 title abstract description 12
- 230000002194 synthesizing effect Effects 0.000 title 1
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 claims abstract description 19
- 238000006243 chemical reaction Methods 0.000 claims abstract description 18
- 239000003054 catalyst Substances 0.000 claims abstract description 10
- 238000010189 synthetic method Methods 0.000 claims abstract description 7
- 150000002148 esters Chemical class 0.000 claims abstract description 4
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 claims abstract description 3
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims abstract 13
- 150000001875 compounds Chemical class 0.000 claims description 20
- 125000006575 electron-withdrawing group Chemical group 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 3
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims description 3
- 125000001424 substituent group Chemical group 0.000 claims description 3
- -1 C1~C4Alkyl Chemical group 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical group 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 239000000463 material Substances 0.000 claims 1
- 229960004937 saxagliptin Drugs 0.000 abstract description 8
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 230000007062 hydrolysis Effects 0.000 abstract description 2
- 238000006460 hydrolysis reaction Methods 0.000 abstract description 2
- 239000007858 starting material Substances 0.000 abstract description 2
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 abstract 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract 6
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 abstract 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 10
- 238000002360 preparation method Methods 0.000 description 8
- 239000010410 layer Substances 0.000 description 7
- 239000012044 organic layer Substances 0.000 description 7
- 239000002994 raw material Substances 0.000 description 7
- 238000003756 stirring Methods 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 108090000790 Enzymes Proteins 0.000 description 4
- 102000004190 Enzymes Human genes 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000002808 molecular sieve Substances 0.000 description 4
- 238000006722 reduction reaction Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 0 CC(*)(CC(C1)C2)CC1CC2(C)[N+](*)[O-] Chemical compound CC(*)(CC(C1)C2)CC1CC2(C)[N+](*)[O-] 0.000 description 3
- 108010067722 Dipeptidyl Peptidase 4 Proteins 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000004176 ammonification Methods 0.000 description 3
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- 238000003786 synthesis reaction Methods 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 102100025012 Dipeptidyl peptidase 4 Human genes 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 238000006859 Swern oxidation reaction Methods 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000006356 dehydrogenation reaction Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 230000000640 hydroxylating effect Effects 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- 238000011031 large-scale manufacturing process Methods 0.000 description 2
- 238000012423 maintenance Methods 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- GEJJWYZZKKKSEV-KGLIPLIRSA-N (1s,2r)-2-amino-1,2-diphenylethanol Chemical compound C1([C@H](O)[C@H](N)C=2C=CC=CC=2)=CC=CC=C1 GEJJWYZZKKKSEV-KGLIPLIRSA-N 0.000 description 1
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 1
- GZDFHIJNHHMENY-UHFFFAOYSA-N Dimethyl dicarbonate Chemical class COC(=O)OC(=O)OC GZDFHIJNHHMENY-UHFFFAOYSA-N 0.000 description 1
- 102000051325 Glucagon Human genes 0.000 description 1
- 108060003199 Glucagon Proteins 0.000 description 1
- QMXOFBXZEKTJIK-UHFFFAOYSA-N Glycinol Natural products C1=C(O)C=C2OCC3(O)C4=CC=C(O)C=C4OC3C2=C1 QMXOFBXZEKTJIK-UHFFFAOYSA-N 0.000 description 1
- 102100023915 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 1
- JFBZPFYRPYOZCQ-UHFFFAOYSA-N [Li].[Al] Chemical class [Li].[Al] JFBZPFYRPYOZCQ-UHFFFAOYSA-N 0.000 description 1
- XVIYCJDWYLJQBG-UHFFFAOYSA-N acetic acid;adamantane Chemical compound CC(O)=O.C1C(C2)CC3CC1CC2C3 XVIYCJDWYLJQBG-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000003466 anti-cipated effect Effects 0.000 description 1
- 229940127003 anti-diabetic drug Drugs 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 1
- 150000003939 benzylamines Chemical class 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 125000004744 butyloxycarbonyl group Chemical group 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000004316 dimethyl dicarbonate Substances 0.000 description 1
- 235000010300 dimethyl dicarbonate Nutrition 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- MASNOZXLGMXCHN-ZLPAWPGGSA-N glucagon Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 MASNOZXLGMXCHN-ZLPAWPGGSA-N 0.000 description 1
- 229960004666 glucagon Drugs 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- MGXWVYUBJRZYPE-YUGYIWNOSA-N incretin Chemical class C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(N)=O)C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1C=CC(O)=CC=1)[C@@H](C)O)[C@@H](C)CC)C1=CC=C(O)C=C1 MGXWVYUBJRZYPE-YUGYIWNOSA-N 0.000 description 1
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- CLYOOVNORYNXMD-UHFFFAOYSA-N methyl adamantane-1-carboxylate Chemical compound C1C(C2)CC3CC2CC1(C(=O)OC)C3 CLYOOVNORYNXMD-UHFFFAOYSA-N 0.000 description 1
- FJCCWUVWFDOSAU-UHFFFAOYSA-N n-benzylnitramide Chemical group [O-][N+](=O)NCC1=CC=CC=C1 FJCCWUVWFDOSAU-UHFFFAOYSA-N 0.000 description 1
- ANORDWOIBSUYBN-UHFFFAOYSA-N n-chloro-1-phenylmethanamine Chemical compound ClNCC1=CC=CC=C1 ANORDWOIBSUYBN-UHFFFAOYSA-N 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a kind of new method preparing BMS-477118 important intermediate N tertbutyloxycarbonyl 3 hydroxyl 1 adamantyl D glycine, comprise the following steps: step 1, by 2 (3 hydroxyl 1 adamantyl) 2 Oxoacetic Acid tert-butyl esters under homemade chiral dioxocyclen catalyst action with benzylamine generation asymmetric reduction ammoxidation, hydrolysis ester after obtain 3 hydroxyl 1 adamantyl D glycine；3 hydroxyl 1 adamantyl D glycine are reacted with Bis(tert-butoxycarbonyl)oxide and i.e. prepare N tertbutyloxycarbonyl 3 hydroxyl 1 adamantyl D glycine by step 2.The synthetic method cheaper starting materials of the BMS-477118 important intermediate IV tertbutyloxycarbonyl 3 hydroxyl 1 adamantyl D glycine that the present invention provides is easy to get, step is short, reaction condition is gentle, easy and simple to handle, combined coefficient is high, environmentally friendly, be suitable to industrialized production, provide a new approach for preparing BMS-477118 and intermediate.
Description
Technical field
The invention belongs to organic preparing technical field, be specifically related to a kind of onglyza intermediate N-tertbutyloxycarbonyl-3-
The novel preparation method of hydroxyl-1-adamantyl-D-glycine.
Background technology
BMS-477118, chemistry entitled (1S, 3S, 5S)-2-[(2S)-2-amino-2-(3-hydroxyl three ring [3.3.1.13,7]
Decyl-1-yl) acetyl group]-2-azabicyclo [3.1.0]-hexane-3-nitrile, be Bristol-Myers Squibb company with
The joint research and development exploitation of AstraZeneca company, ratifies Initial Public Offering, trade name through FDA (Food and Drug Adminstration) in July, 2009
For Onglyza.BMS-477118 is a kind of high selectivity, reversible competitive DPP IV (DPP-IV) inhibitor, resistance to
Good by property and do not cause obesity, it is clinically used for treating type 2 diabetes mellitus.This medicine mechanism of action is unique, by suppressing DPP-IV enzyme, from
And increase and extend the effect of incretin, promote pancreas to accelerate the secretion of insulin, reduce the level of glucagon, mesh
Front BMS-477118 has become that hypoglycemic effect is significant, one of the less antidiabetic drug of side effect.Within 2010, this kind sales volume is just more than 2
Hundred million dollars.Anticipated this medicine soon will be more than 1,000,000,000 dollars in the sale of the U.S..
Formula (I) compound N-tertbutyloxycarbonyl-3-hydroxyl-1-adamantyl-D-glycine is the pass of synthesis BMS-477118
Key intermediate, the chemosynthesis for BMS-477118 is significant, the most existing about formula (I) compound N-tertiary butyloxycarbonyl
The report of base-3-hydroxyl-1-adamantyl-D-glycine, mainly has three kinds of preparation methoies.
First method is as raw material with 2-(3-hydroxyl-1-adamantyl)-2-glyoxalic acid, by after raw material ammonification in dehydrogenation
Enzyme effect issues raw reduction reaction, selectively obtains 3-hydroxyl-1-adamantyl-D-glycine, then with two dimethyl dicarbonates
Butyl ester reaction protection amino i.e. prepares formula (I) compound N-tertbutyloxycarbonyl-3-hydroxyl-1-adamantyl-D-glycine.
This synthetic method need to be carried out under the effect of biological dehydrogenation enzyme, and general enzyme is not readily available, if can develop
Preferable industrial applications prospect can will be had with the enzyme of industrialized production.
Second method is with adamantanecarboxylic acid methyl ester as raw material, hydrogenated lithium aluminium reducing, Swern oxidation and R-2-benzene
Base glycinol is condensed, hydrolyzes, protects amino and hydroxylating to prepare, total recovery about 23%.
This synthetic method need to be with the chiral auxiliary of chemical dose, and the process steps of stereoselective syntheses is longer, and yield is low,
And Swern oxidation need to be carried out at-78 DEG C, severe reaction conditions, it is unsuitable for large-scale production.
The third method is with adamantane acetic acid as raw material, through bromination, hydroxylating, ammonification, protection, racemate resolution system
Obtain formula (I) compound.
This process route is long, and disadvantage also resides in the method that final step have employed chemical resolution, chiral separation meeting
Causing the waste of another configuration of compound, the conversion ratio of raw material is no more than 50%, and therefore, total recovery is low, and cost becomes
Increase again, and also produce a large amount of industrial residue, be unfavorable for environmental protection.
Summary of the invention
The technical problem to be solved be overcome existing preparation formula (I) compound N-tertbutyloxycarbonyl-3-hydroxyl-
1-adamantyl-D-glycine report technology in processing step length, raw material is not easy to obtain, yield is low, pollute environment, operation uneasiness
Entirely, the defect of industrialization large-scale production it is unfavorable for, it is provided that a kind of effective preparation N-tertbutyloxycarbonyl-3-hydroxyl-1-Buddha's warrior attendant
The method of alkyl-D-glycine, the method cheaper starting materials is easy to get, step is short, reaction condition is gentle, easy and simple to handle, combined coefficient
High, environmentally friendly, it is suitable for industrialized production.
Technical scheme is summarized as follows:
Step (1), by formula (II) compound 2-(3-hydroxyl-1-the adamantyl)-2-Oxoacetic Acid tert-butyl ester homemade
With benzylamine generation asymmetric reduction ammoxidation under chiral dioxocyclen catalyst action, after hydrolysis ester, obtain formula (III)
Compound 3-hydroxyl-1-adamantyl-D-glycine；Step (2), formula (III) compound reacts guarantor with Bis(tert-butoxycarbonyl)oxide
Protect amino and i.e. prepare formula (I) compound N-tertbutyloxycarbonyl-3-hydroxyl-1-adamantyl-D-glycine.
Synthetic route is:
The described catalyst in step (1) is homemade chiral dioxocyclen, and structure is:
This catalyst preparation process is simple, by side's acid di-n-butyl and (1S, 2R)-2-amino-1,2-diphenyl ethanol
React can prepare with benzylamine or alpha substituted benzylamine again after reaction.In catalyst structure, R is hydrogen atom, C1～C4Alkyl, electrophilic
Base such as nitro, halogen etc., wherein preferably R is electron-withdrawing group.
This catalyst efficiency is the highest, and its consumption is only the 5～10% of formula (II) compound molal weight.
The benzylamine that benzylamine is the various structures being connected with electron-withdrawing group and electron-donating group on aromatic ring in described step (1),
Wherein it is connected with the benzylamine of electron-withdrawing group on preferred aromatic ring；Substituent group can be in the ortho position of methylamino, meta or para position, the most preferably
Substituent group is at the ortho position of methylamino.
This asymmetric reduction ammoxidation is simple to operate, and reaction condition is gentle, and concrete reaction temperature is: ammonification temperature is
60～80 DEG C, reduction temperature is 40～60 DEG C.
Formula (I) compound N-tertbutyloxycarbonyl-3-hydroxyl-1-adamantyl-D-glycine prepared by this technique only needs
Two steps, total recovery reaches more than 80%, and optical purity is up to 98%.
Detailed description of the invention
Below in conjunction with implementing specific embodiment, further illustrate the present invention.Should be understood that these embodiments are merely to illustrate this
Invention rather than restriction the scope of the present invention.
Raw material used in embodiment or reagent are in addition to special instruction, the most commercially.
The preparation of embodiment 1 formula (III) compound 3-hydroxyl-1-adamantyl-D-glycine
By 10mmol 2-(3-hydroxyl-1-the adamantyl)-2-Oxoacetic Acid tert-butyl ester, 1.5gMolecular sieve, 10mmol
Adjacent nitro-benzylamine and 20mL toluene add in reaction bulb, are uniformly mixed.System temperature is risen to 65～75 DEG C, and temperature at this
Lower stirring reaction 5h, stops heating, treats that system temperature is down to 40～50 DEG C, by homemade for 0.8mmol chiral dioxocyclen (R
=NO2) catalyst and 20mL toluene adds, maintenance system temperature is at 45～55 DEG C, and stirring reaction overnight, stops under this temperature
Reaction, filters off after coolingMolecular sieve, adds 20mL 5N HCl in filtrate, stands, separate organic after stirring 1h under room temperature
Layer, washs with 5mL 5N HCl, combining water layer, with sodium carbonate solid, water layer pH value is transferred to 8.0, adds 90mL dichloromethane,
Separate organic layer, add 20mL 5N NaOH solution, after 30min is stirred at room temperature, with 5N HCl, solution ph is transferred to 10, point
Go out organic layer, and wash water layer at twice with 30mL dichloromethane, merge organic layer, reduce pressure after drying with anhydrous sodium sulfate and boil off
Solvent, obtains formula (III) compound, yield 89%, ee value 98.5%.
The preparation of embodiment 2 formula (III) compound 3-hydroxyl-1-adamantyl-D-glycine
By 10mmol 2-(3-hydroxyl-1-the adamantyl)-2-Oxoacetic Acid tert-butyl ester, 1.5gMolecular sieve, 10mmol
Between chlorobenzylamine and 20mL toluene add in reaction bulb, be uniformly mixed.System temperature is risen to 65～75 DEG C, and under this temperature
Stirring reaction 5h, stops heating, treats that system temperature is down to 45 DEG C, by homemade for 0.7mmol chiral dioxocyclen (R=H) and
20mL toluene adds, and maintenance system temperature is at 45～55 DEG C, and stirring is reacted overnight under this temperature, and stopped reaction is filtered after cooling
GoMolecular sieve, adds 20mL 5N HCl in filtrate, stands, separate organic layer, use 5mL 5N after stirring 1h under room temperature
HCl washs, combining water layer, with sodium carbonate solid, water layer pH value is transferred to 8.0, adds 90mL dichloromethane, separates organic layer, then
Add 20mL5NNaOH solution, after 2h is stirred at room temperature, with 5N HCl, solution ph is transferred to 10, separate organic layer, and with 30mL bis-
Chloromethanes washs water layer at twice, merges organic layer, reduces pressure after drying with anhydrous sodium sulfate and boil off solvent, obtain formula (III) chemical combination
Thing, yield 85%, ee value 97%.
The preparation of embodiment 3 formula (I) compound N-tertbutyloxycarbonyl-3-hydroxyl-1-adamantyl-D-glycine
By 10mmol 3-hydroxyl-1-adamantyl-D-glycine, 0.6mmol potassium carbonate, 12mmol bis-dimethyl dicarbonate fourth
Ester and 30mL oxolane add in reaction bulb, are uniformly mixed rear room temperature reaction 12 hours.Decompression boils off solvent, to residual
Thing adds 50mL petroleum ether, then adjusts pH value to 1 with 5M HCl, has white solid to separate out, and sucking filtration, drying under reduced pressure obtains formula (I) chemical combination
Thing, yield 98%.
Claims (3)
1. the onglyza intermediate N-tertbutyloxycarbonyl-3-hydroxyl-1-adamantyl-D-glycine as shown in formula (I)
Synthetic method, the reaction equation of this synthetic method is:
It is characterized in that comprising the following steps: step (1), by formula (II) compound 2-(3-hydroxyl-1-adamantyl)-2-oxo
Tert-butyl acetate chiral dioxocyclen catalyst 1 act under with benzylamine generation asymmetric reduction ammoxidation, hydrolyze ester
After obtain formula (III) compound 3-hydroxyl-1-adamantyl-D-glycine；Step (2), in the presence of potassium carbonate, formula
(III) compound and Bis(tert-butoxycarbonyl)oxide react protection amino i.e. prepare formula (I) compound N-tertbutyloxycarbonyl-3-hydroxyl-
1-adamantyl-D-glycine；The structure of the described chiral dioxocyclen catalyst 1 in step (1) is:
Wherein R is hydrogen atom, C1～C4Alkyl, nitro, halogen.
A kind of onglyza intermediate N-tertbutyloxycarbonyl-3-hydroxyl-1-adamantyl-D-the most according to claim 1
The synthetic method of glycine, it is characterised in that: described chiral dioxocyclen catalyst 1 consumption in step (1) is formula
(II) the 5～10% of the amount of combinations of materials.
A kind of onglyza intermediate N-tertbutyloxycarbonyl-3-hydroxyl-1-adamantyl-D-the most according to claim 1
The synthetic method of glycine, it is characterised in that: the described benzylamine in step (1) is to be connected with electron-withdrawing group and supplied for electronic on aromatic ring
The benzylamine of base；Substituent group is in the ortho position of methylamino, meta or para position.
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