CN105130879A - Preparation method of (R)-3-Boc-aminopiperidine - Google Patents
Preparation method of (R)-3-Boc-aminopiperidine Download PDFInfo
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- CN105130879A CN105130879A CN201510438440.XA CN201510438440A CN105130879A CN 105130879 A CN105130879 A CN 105130879A CN 201510438440 A CN201510438440 A CN 201510438440A CN 105130879 A CN105130879 A CN 105130879A
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- WUOQXNWMYLFAHT-MRVPVSSYSA-N tert-butyl n-[(3r)-piperidin-3-yl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@@H]1CCCNC1 WUOQXNWMYLFAHT-MRVPVSSYSA-N 0.000 title claims abstract description 33
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- 150000001875 compounds Chemical class 0.000 claims abstract description 79
- -1 piperidine heterocyclic compounds Chemical class 0.000 claims abstract description 44
- 238000006243 chemical reaction Methods 0.000 claims abstract description 32
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims abstract description 24
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims abstract description 19
- FFLPIVZNYJKKDM-UHFFFAOYSA-N 1-phenylmethoxycarbonylpiperidine-3-carboxylic acid Chemical compound C1C(C(=O)O)CCCN1C(=O)OCC1=CC=CC=C1 FFLPIVZNYJKKDM-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000002994 raw material Substances 0.000 claims abstract description 6
- 238000006731 degradation reaction Methods 0.000 claims abstract description 5
- 238000006482 condensation reaction Methods 0.000 claims abstract description 3
- 238000005984 hydrogenation reaction Methods 0.000 claims abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 57
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 54
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 33
- 230000015572 biosynthetic process Effects 0.000 claims description 31
- 238000003786 synthesis reaction Methods 0.000 claims description 31
- 238000000605 extraction Methods 0.000 claims description 26
- 238000010792 warming Methods 0.000 claims description 23
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 20
- 238000009413 insulation Methods 0.000 claims description 19
- 238000000967 suction filtration Methods 0.000 claims description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 14
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 10
- 239000003960 organic solvent Substances 0.000 claims description 10
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 claims description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 10
- 239000012359 Methanesulfonyl chloride Substances 0.000 claims description 9
- 229910021529 ammonia Inorganic materials 0.000 claims description 9
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims description 9
- 238000003756 stirring Methods 0.000 claims description 9
- MFPWEWYKQYMWRO-UHFFFAOYSA-N tert-butyl carboxy carbonate Chemical compound CC(C)(C)OC(=O)OC(O)=O MFPWEWYKQYMWRO-UHFFFAOYSA-N 0.000 claims description 9
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 7
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- 239000012141 concentrate Substances 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- 150000001408 amides Chemical class 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims description 2
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 claims description 2
- 238000000926 separation method Methods 0.000 claims description 2
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 238000000034 method Methods 0.000 abstract description 6
- 238000005265 energy consumption Methods 0.000 abstract description 3
- OBTZDIRUQWFRFZ-UHFFFAOYSA-N 2-(5-methylfuran-2-yl)-n-(4-methylphenyl)quinoline-4-carboxamide Chemical compound O1C(C)=CC=C1C1=CC(C(=O)NC=2C=CC(C)=CC=2)=C(C=CC=C2)C2=N1 OBTZDIRUQWFRFZ-UHFFFAOYSA-N 0.000 abstract 2
- DRSHXJFUUPIBHX-UHFFFAOYSA-N COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 Chemical compound COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 DRSHXJFUUPIBHX-UHFFFAOYSA-N 0.000 abstract 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 abstract 2
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 54
- 239000012074 organic phase Substances 0.000 description 17
- 239000008346 aqueous phase Substances 0.000 description 9
- 238000004128 high performance liquid chromatography Methods 0.000 description 9
- 238000010583 slow cooling Methods 0.000 description 9
- 206010012601 diabetes mellitus Diseases 0.000 description 6
- 239000012043 crude product Substances 0.000 description 5
- 0 CC(N(CCC1)CC1C(*)=*)=C Chemical compound CC(N(CCC1)CC1C(*)=*)=C 0.000 description 4
- 239000005708 Sodium hypochlorite Substances 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- 230000007935 neutral effect Effects 0.000 description 4
- 230000007613 environmental effect Effects 0.000 description 3
- 150000002431 hydrogen Chemical class 0.000 description 3
- 230000001131 transforming effect Effects 0.000 description 3
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N CCc1ccccc1 Chemical compound CCc1ccccc1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 description 2
- 101710198884 GATA-type zinc finger protein 1 Proteins 0.000 description 2
- DTHNMHAUYICORS-KTKZVXAJSA-N Glucagon-like peptide 1 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](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=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 DTHNMHAUYICORS-KTKZVXAJSA-N 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 102100040918 Pro-glucagon Human genes 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000008103 glucose Substances 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
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 150000003053 piperidines Chemical class 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- ZJMWRROPUADPEA-VIFPVBQESA-N CC[C@H](C)c1ccccc1 Chemical compound CC[C@H](C)c1ccccc1 ZJMWRROPUADPEA-VIFPVBQESA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000051325 Glucagon Human genes 0.000 description 1
- 108060003199 Glucagon Proteins 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- ZSBOMTDTBDDKMP-OAHLLOKOSA-N alogliptin Chemical compound C=1C=CC=C(C#N)C=1CN1C(=O)N(C)C(=O)C=C1N1CCC[C@@H](N)C1 ZSBOMTDTBDDKMP-OAHLLOKOSA-N 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 230000002068 genetic effect Effects 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
- 229940126904 hypoglycaemic agent Drugs 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 230000003914 insulin secretion Effects 0.000 description 1
- 208000028280 polygenic inheritance Diseases 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- BXHWWPNRUOHACS-MRVPVSSYSA-N tert-butyl (3r)-1-aminopiperidine-3-carboxylate Chemical class CC(C)(C)OC(=O)[C@@H]1CCCN(N)C1 BXHWWPNRUOHACS-MRVPVSSYSA-N 0.000 description 1
- 238000003809 water extraction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/56—Nitrogen atoms
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
The invention discloses a preparation method of (R)-3-Boc-aminopiperidine and relates to the technical field of preparation of piperidine heterocyclic compounds. The preparation method includes following steps: (1) with N-Cbz-3-piperidinecarboxylic acid as a raw material, performing chiral resolution with R-phenylethylamine to obtain a compound I; (2) performing an acid-amide condensation reaction to the compound I and ammonia gas to obtain a compound II; (3) performing a Hofmann degradation reaction to the compound II to obtain a compound III; (4) performing protection to the compound III with di-tert-butyl dicarbonate to obtain a compound IV; and (5) performing a hydrogenation and Cbz-removal reaction to the compound IV to prepare the (R)-3-Boc-aminopiperidine. The method is mild in reaction conditions, is safe and reliable, is excellent in process stability, is low in energy consumption, is high in yield, is green and environment-protective and is suitable for industrial production.
Description
Technical field
The present invention relates to the preparing technical field of piperidines heterogeneous ring compound.
Background technology
Diabetes B is a kind of polygenic inheritance disease, and be the coefficient result of environmental factors and inherited genetic factors, the cause of disease is relevant with insulin resistant and hypoinsulinism.Clinical statistics shows, and diabetic subject more than 90% is diabetes B.The treatment of diabetes B is mainly to control blood sugar, and general treatment is all the medicine by some hypoglycemics or stabilizing blood sugar.
BI 1356 is a kind of selective d PP-4 inhibitor, the activity of this enzyme is suppressed by being combined with DPP-4 reversibility, delay GLP-1 degraded, strengthen the activity of GLP-1, stimulate insulin secretion in the mode of glucose dependency, and reduce Plasma Glucagon Level in circulation, thus regulate the glucose level of diabetes B patient.
(R)-3-Boc-amino piperidine is also known as (R)-3-t-butoxycarbonyl amino piperidines, (R)-3-(N-Boc-is amino) piperidines; English name: (R)-3-(Boc-Amino) piperidine; No. CAS: 309956-78-3; Molecular formula: C
10h
20n
2o
2; Molecular weight: 200.28.(R)-3-Boc-amino piperidine is white sprills, is the important intermediate of synthesis BI 1356, is also the important intermediate of synthesis diabetes B medicine SYR-322.
Present stage prepare this intermediate Problems existing be mainly reflected in following some: reaction scheme is longer, and overall yield is low; Technological operation is harsher; Post-processing operation operation is more loaded down with trivial details, and is difficult to purifying.
Summary of the invention
The technical problem to be solved in the present invention is to provide the preparation method of one (R)-3-Boc-amino piperidine, and the method reaction conditions is gentle, safe and reliable, and technology stability is good, and energy consumption is low, and yield is high, and environmental protection is suitable for suitability for industrialized production.
For solving the problems of the technologies described above, the technical solution used in the present invention is: a kind of preparation method of (R)-3-Boc-amino piperidine, comprises the following steps:
(1) with N-Cbz-3-piperidine carboxylic acid for raw material, obtain chemical compounds I by R-phenylethylamine chiral separation;
(2) chemical compounds I and ammonia carry out acid amide condensation reaction, obtain compound ii;
(3) compound ii obtains compound III through hoffman degradation reaction;
(4) on compound III tert-Butyl dicarbonate, protection obtains compounds Ⅳ;
(5) de--Cbz of compounds Ⅳ hydrogenation obtains (R)-3-Boc-amino piperidine; Total reaction equation is:
Wherein, Cbz is carbobenzoxy-(Cbz), and Boc is tertbutyloxycarbonyl.
Preferably, in the synthesis of step (1), chemical compounds I: the mol ratio of R-phenylethylamine and N-Cbz-3-piperidine carboxylic acid is 0.7 ~ 0.9.
Preferably, in the synthesis of step (1), chemical compounds I: N-Cbz-3-piperidine carboxylic acid is dissolved in organic solvent, be heated with stirring to 40 ~ 50 DEG C, slowly drip the above-mentioned organic solvent solution of R-phenylethylamine at such a temperature, drip and finish, insulated and stirred to reacting complete, cooling, suction filtration, dry carboxylate salt
; Then by carboxylate salt
purify to ee value and be greater than 99%; Finally by carboxylate salt
dissociate with acid, extraction, concentrates to obtain chemical compounds I.
Preferred further, in the synthesis of step (1), chemical compounds I: organic solvent is methyl alcohol, acetone or ethyl acetate.
Preferred further, in the synthesis of step (1), chemical compounds I: N-Cbz-3-piperidine carboxylic acid is dissolved in organic solvent, be heated with stirring to 40 ~ 50 DEG C, slowly drip the above-mentioned organic solvent solution of R-phenylethylamine at such a temperature, drip and finish, insulated and stirred 20 ~ 30min, slowly cools to 10 ~ 15 DEG C, suction filtration, dry carboxylate salt
; Then by carboxylate salt
add in ethanol, be heated to 70 ~ 75 DEG C, insulation 15 ~ 20min, is slowly down to 10 ~ 15 DEG C, suction filtration, dry carboxylate salt
, repeat this and be operated to ee value and be greater than 99%; Finally by carboxylate salt
dissociate with concentrated hydrochloric acid, pH is adjusted to 1 ~ 2, extraction into ethyl acetate, concentrates to obtain chemical compounds I.
Preferably, in the synthesis of step (2), compound ii: chemical compounds I and Methanesulfonyl chloride are formed
after, pass into ammonia and obtain compound ii.
Preferred further, in the synthesis of step (2), compound ii: chemical compounds I is dissolved in tetrahydrofuran (THF), add DIPEA, be cooled to-10 ~-5 DEG C, slow dropping Methanesulfonyl chloride, drip and finish, slowly pass into ammonia at such a temperature, after reaching capacity, system is warming up to 20 ~ 25 DEG C of reactions, reacts complete and obtain compound ii; The mol ratio of Methanesulfonyl chloride and N, N-diisopropylamine and chemical compounds I is respectively 1.05 ~ 1.25, and 1.1 ~ 1.4.
Preferably, in the synthesis of step (2), compound ii: aftertreatment is, reacts complete, filter, filtrate is concentrated into dry, and add methylene dichloride and water extraction, concentrated organic phase obtains crude product, and crude product sherwood oil and methylene dichloride force crystalline substance to obtain compound ii.
Preferably, in the synthesis of step (3), compound III: compound ii, under the condition of clorox and aqueous sodium hydroxide solution, at 35 ~ 40 DEG C, obtains compound III through hoffman degradation reaction.
Preferred further, in the synthesis of step (3), compound III: the mol ratio of the sodium hydroxide in aqueous sodium hydroxide solution and clorox and compound ii is respectively 15 ~ 17,1.4 ~ 2.
Preferred further, in the synthesis of step (3), compound III: added to by compound ii in 40wt% aqueous sodium hydroxide solution, drip aqueous sodium hypochlorite solution, 35 ~ 40 DEG C of insulated and stirred, complete to feedstock conversion; Adjust pH to neutral, extraction into ethyl acetate, concentrated organic phase obtains compound III.
Preferably, in the synthesis of step (4), compounds Ⅳ: add in water by compound III and sodium carbonate, ice bath is cooled to 0 ~ 5 DEG C, drips the methanol solution of tert-Butyl dicarbonate, drips and finishes, being back to 20 ~ 25 DEG C of reactions, to reacting complete, obtaining compounds Ⅳ; The mol ratio of tert-Butyl dicarbonate and sodium carbonate and compound III is respectively 1.1 ~ 1.3, and 1.5 ~ 2.5.
Preferably, in the synthesis of step (4), compounds Ⅳ: aftertreatment is, reacts complete, adds dichloromethane extraction, concentrated organic phase, process of lowering the temperature again after using sherwood oil and ethyl acetate hot breakdown obtains compounds Ⅳ.
Preferably, in the synthesis of step (5), (R)-3-Boc-amino piperidine: by compounds Ⅳ, palladium charcoal and methyl alcohol add in autoclave, nitrogen replacement 3 ~ 4 times, under the hydrogen pressure of 0.3 ~ 0.4MPa, 35 ~ 40 DEG C of reactions, to reacting complete, obtain (R)-3-Boc-amino piperidine.
Preferably, in the synthesis of step (5), (R)-3-Boc-amino piperidine: aftertreatment is, reacts complete, filter, concentrated, methylene dichloride and sherwood oil force crystalline substance to obtain (R)-3-Boc-amino piperidine.
Further preferred, in the synthesis of step (5), (R)-3-Boc-amino piperidine: when palladium charcoal selects 10% wet palladium charcoal (water ratio 50%), 10% wet palladium charcoal (water ratio 50%) is 3% ~ 7% with the mass ratio of compounds Ⅳ.
The beneficial effect adopting technique scheme to produce is: the inventive method reaction conditions is gentle, safe and reliable, and technology stability is good, and energy consumption is low, and yield is high, and environmental protection is suitable for suitability for industrialized production.
Embodiment
Embodiment 1-17 is described in further detail the preparation method of the present invention (R)-3-Boc-amino piperidine.
The synthesis of step (1), chemical compounds I:
Embodiment 1
26.3gN-Cbz-3-piperidine carboxylic acid is dissolved in 55mL methyl alcohol, is heated with stirring to 40 ~ 50 DEG C, slowly drip the 13.5mL methanol solution of 9.7gR-phenylethylamine at such a temperature, drip and finish, insulated and stirred 20 ~ 30min, slowly cools to 10 ~ 15 DEG C, suction filtration, dry carboxylate salt
16g; Then by 16g carboxylate salt
add in 32mL ethanol, be heated to 70 ~ 75 DEG C, insulation 15 ~ 20min, is slowly down to 10 ~ 15 DEG C, suction filtration, dry carboxylate salt
15.2g, repeats this operation 2 times, obtains carboxylate salt
13.5g, ee value 99.7%; Finally by 13.5g carboxylate salt
add in 40mL water, with concentrated hydrochloric acid, pH is adjusted to 1 ~ 2, add 30mL extraction into ethyl acetate twice, merge organic phase and be concentrated into without cut, obtain chemical compounds I 9.2g.
Embodiment 2
26.3gN-Cbz-3-piperidine carboxylic acid is dissolved in 105mL acetone, is heated with stirring to 40 ~ 50 DEG C, slowly drip the 50mL acetone soln of 10.3gR-phenylethylamine at such a temperature, drip and finish, insulated and stirred 20 ~ 30min, slowly cools to 10 ~ 15 DEG C, suction filtration, dry carboxylate salt
15.4g; Then by 15.4g carboxylate salt
add in 30mL ethanol, be heated to 70 ~ 75 DEG C, insulation 15 ~ 20min, is slowly down to 10 ~ 15 DEG C, suction filtration, dry carboxylate salt
14.6g, repeats this operation 2 times, obtains carboxylate salt
12.9g, ee value 99.5%; Finally by 12.9g carboxylate salt
add in 40mL water, with concentrated hydrochloric acid, pH is adjusted to 1 ~ 2, add 25mL extraction into ethyl acetate twice, merge organic phase and be concentrated into without cut, obtain chemical compounds I 8.8g.
Embodiment 3
26.3gN-Cbz-3-piperidine carboxylic acid is dissolved in 150mL ethyl acetate, is heated with stirring to 40 ~ 50 DEG C, slowly drip the 50mL ethyl acetate solution of 9.2gR-phenylethylamine at such a temperature, drip and finish, insulated and stirred 20 ~ 30min, slowly cools to 10 ~ 15 DEG C, suction filtration, dry carboxylate salt
15.7g; Then by 15.7g carboxylate salt
add in 30mL ethanol, be heated to 70 ~ 75 DEG C, insulation 15 ~ 20min, is slowly down to 10 ~ 15 DEG C, suction filtration, dry carboxylate salt
14.9g, repeats this operation 2 times, obtains carboxylate salt
13.2g, ee value 99.5%; Finally by 13.2g carboxylate salt
add in 40mL water, with concentrated hydrochloric acid, pH is adjusted to 1 ~ 2, add 25mL extraction into ethyl acetate twice, merge organic phase and be concentrated into without cut, obtain chemical compounds I 9.0g.
Embodiment 4
26.3gN-Cbz-3-piperidine carboxylic acid is dissolved in 55mL methyl alcohol, is heated with stirring to 40 ~ 50 DEG C, slowly drip the 13.5mL methanol solution of 8.5gR-phenylethylamine at such a temperature, drip and finish, insulated and stirred 20 ~ 30min, slowly cools to 10 ~ 15 DEG C, suction filtration, dry carboxylate salt
15.5g; Then by 15.5g carboxylate salt
add in 30mL ethanol, be heated to 70 ~ 75 DEG C, insulation 15 ~ 20min, is slowly down to 10 ~ 15 DEG C, suction filtration, dry carboxylate salt
14.7g, repeats this operation 2 times, obtains carboxylate salt
13.0g, ee value 99.4%; Finally by 13.0g carboxylate salt
add in 40mL water, with concentrated hydrochloric acid, pH is adjusted to 1 ~ 2, add 26mL extraction into ethyl acetate twice, merge organic phase and be concentrated into without cut, obtain chemical compounds I 8.9g.
Embodiment 5
26.3gN-Cbz-3-piperidine carboxylic acid is dissolved in 55mL methyl alcohol, is heated with stirring to 40 ~ 50 DEG C, slowly drip the 13.5mL methanol solution of 11gR-phenylethylamine at such a temperature, drip and finish, insulated and stirred 20 ~ 30min, slowly cools to 10 ~ 15 DEG C, suction filtration, dry carboxylate salt
15.3g; Then by 15.3g carboxylate salt
add in 30mL ethanol, be heated to 70 ~ 75 DEG C, insulation 15 ~ 20min, is slowly down to 10 ~ 15 DEG C, suction filtration, dry carboxylate salt
14.5g, repeats this operation 2 times, obtains carboxylate salt
12.8g, ee value 99.6%; Finally by 12.8g carboxylate salt
add in 38mL water, with concentrated hydrochloric acid, pH is adjusted to 1 ~ 2, add 25mL extraction into ethyl acetate twice, merge organic phase and be concentrated into without cut, obtain chemical compounds I 8.7g.
The synthesis of step (2), compound ii:
Embodiment 6
30g chemical compounds I is dissolved in 200mL tetrahydrofuran (THF), add 16.2gN, N-diisopropylethylamine, be cooled to-10 ~-5 DEG C, slowly drip 13.7g Methanesulfonyl chloride, drip and finish, slowly pass into ammonia at such a temperature, after reaching capacity, system is warming up to 20 ~ 25 DEG C, it is complete to transforming that HPLC follows the tracks of raw material.After completion of the reaction, filter, filtrate is concentrated into dry, add 150mL methylene dichloride and the extraction of 120mL water, aqueous phase uses 60mL dichloromethane extraction twice more respectively, merges organic phase, be concentrated into without cut, crude product added 90mL methylene dichloride, be warming up to 30 ~ 35 DEG C, drip 180mL sherwood oil, insulation 1h, slow cooling to 0 ~ 5 DEG C, suction filtration, obtain 26.3g compound ii, yield 87.1%.
Embodiment 7
30g chemical compounds I is dissolved in 200mL tetrahydrofuran (THF), add 18.4gN, N-diisopropylethylamine, be cooled to-10 ~-5 DEG C, slowly drip 14.4g Methanesulfonyl chloride, drip and finish, slowly pass into ammonia at such a temperature, after reaching capacity, system is warming up to 20 ~ 25 DEG C, it is complete to transforming that HPLC follows the tracks of raw material.After completion of the reaction, filter, mother liquor contracting is dry, add 150mL methylene dichloride and the extraction of 120mL water, aqueous phase uses 60mL dichloromethane extraction twice more respectively, merges organic phase, be concentrated into without cut, crude product added 90mL methylene dichloride, be warming up to 30 ~ 35 DEG C, drip 180mL sherwood oil, insulation 1h, slow cooling to 0 ~ 5 DEG C, suction filtration, obtain 26.9g compound ii, yield 89.7%.
Embodiment 8
30g chemical compounds I is dissolved in 200mL tetrahydrofuran (THF), add 20.6gN, N-diisopropylethylamine, be cooled to-10 ~-5 DEG C, slowly drip 16.3g Methanesulfonyl chloride, drip and finish, slowly pass into ammonia at such a temperature, after reaching capacity, system is warming up to 20 ~ 25 DEG C, it is complete to transforming that HPLC follows the tracks of raw material.After completion of the reaction, filter, mother liquor contracting is dry, add 150mL methylene dichloride and the extraction of 120mL water, aqueous phase uses 60mL dichloromethane extraction twice more respectively, merges organic phase, be concentrated into without cut, crude product added 90mL methylene dichloride, be warming up to 30 ~ 35 DEG C, drip 180mL sherwood oil, insulation 1h, slow cooling to 0 ~ 5 DEG C, suction filtration, obtain 26.5g compound ii, yield 88.5%.
The synthesis of step (3), compound III:
Embodiment 9
By 42.7g(0.163) compound ii adds in 245mL40% aqueous sodium hydroxide solution (wherein containing sodium hydroxide 2.50mol), be warming up to 25 ~ 30 DEG C, drip 330mL5% aqueous sodium hypochlorite solution (wherein containing clorox 0.25mol) at such a temperature, drip and finish, be warming up to 35 ~ 40 DEG C, insulated and stirred, complete to feedstock conversion.Adjust pH to neutral, add 300mL extraction into ethyl acetate, aqueous phase uses 85mL extracting twice respectively again, merges organic phase, is concentrated into without cut, obtains 35.8 compound III, crude yield 93.8%.
Embodiment 10
42.7g compound ii is added in 260mL40% aqueous sodium hydroxide solution (wherein containing sodium hydroxide 2.65mol), be warming up to 25 ~ 30 DEG C, drip 375mL5% aqueous sodium hypochlorite solution (wherein containing clorox 0.28mol) at such a temperature, drip and finish, be warming up to 35 ~ 40 DEG C, insulated and stirred, complete to feedstock conversion.Adjust pH to neutral, add 350mL extraction into ethyl acetate, aqueous phase uses 95mL extracting twice respectively again, merges organic phase, is concentrated into without cut, obtains 36.5 compound III, crude yield 95.7%.
Embodiment 11
42.7g compound ii is added in 275mL40% aqueous sodium hydroxide solution (wherein containing sodium hydroxide 2.80mol), be warming up to 25 ~ 30 DEG C, drip 420mL5% aqueous sodium hypochlorite solution (wherein containing clorox 0.32mol) at such a temperature, drip and finish, be warming up to 35 ~ 40 DEG C, insulated and stirred, complete to feedstock conversion.Adjust pH to neutral, add 400mL extraction into ethyl acetate, aqueous phase uses 100mL extracting twice respectively again, merges organic phase, is concentrated into without cut, obtains 35.1 compound III, crude yield 92.1%.
The synthesis of step (4), compounds Ⅳ:
Embodiment 12
35g compound III and 23.7g sodium carbonate are added in 245mL water, ice bath is cooled to 0 ~ 5 DEG C, the 18mL methanol solution of slow dropping 35.9g tert-Butyl dicarbonate, drip and finish, be back to 20 ~ 25 DEG C of reactions, it is complete that HPLC tracks to feedstock conversion, add 175mL dichloromethane extraction, aqueous phase uses 70mL dichloromethane extraction twice more respectively, merge organic phase, be concentrated into without cut, add 10.5mL ethyl acetate and 70mL, be warming up to 60 ~ 65 DEG C, slow dropping 190mL sherwood oil, insulation 30min, slow cooling to 0 ~ 5 DEG C again, filter, 45 ~ 50 DEG C of oven dry, obtain 41.8g compounds Ⅳ, yield 83.6%.
Embodiment 13
35g compound III and 31.7g sodium carbonate are added in 245mL water, ice bath is cooled to 0 ~ 5 DEG C, the 18mL methanol solution of slow dropping 39.1g tert-Butyl dicarbonate, drip and finish, be back to 20 ~ 25 DEG C of reactions, it is complete that HPLC tracks to feedstock conversion, add 175mL dichloromethane extraction, aqueous phase uses 70mL dichloromethane extraction twice more respectively, merge organic phase, be concentrated into without cut, add 10.5mL ethyl acetate and 70mL, be warming up to 60 ~ 65 DEG C, slow dropping 190mL sherwood oil, insulation 30min, slow cooling to 0 ~ 5 DEG C again, filter, 45 ~ 50 DEG C of oven dry, obtain 42.4g compounds Ⅳ, yield 84.9%.
Embodiment 14
35g compound III and 39.6g sodium carbonate are added in 245mL water, ice bath is cooled to 0 ~ 5 DEG C, the 18mL methanol solution of slow dropping 42.4g tert-Butyl dicarbonate, drip and finish, be back to 20 ~ 25 DEG C of reactions, it is complete that HPLC tracks to feedstock conversion, add 175mL dichloromethane extraction, aqueous phase uses 70mL dichloromethane extraction twice more respectively, merge organic phase, be concentrated into without cut, add 10.5mL ethyl acetate and 70mL, be warming up to 60 ~ 65 DEG C, slow dropping 190mL sherwood oil, insulation 30min, slow cooling to 0 ~ 5 DEG C again, filter, 45 ~ 50 DEG C of oven dry, obtain 42.0g compounds Ⅳ, yield 84.2%.
The synthesis of step (5), (R)-3-Boc-amino piperidine:
Embodiment 15
By 46.8g compounds Ⅳ, wet palladium charcoal (water ratio 50%) and 320mL methyl alcohol of 1.4g10% adds in autoclave, nitrogen replacement 3 ~ 4 times, under being filled with hydrogen 0.3 ~ 0.4MPa pressure, be warming up to 35 ~ 40 DEG C, insulation reaction 6h, it is complete that HPLC tracks to feedstock conversion, filter, be concentrated into without cut, add 23mL methylene dichloride and 46mL sherwood oil, be warming up to 35 ~ 40 DEG C, slowly drip 325mL sherwood oil at such a temperature, insulation 1h, slow cooling is to-5 ~ 0 DEG C again, filter, 40 ~ 45 DEG C of oven dry, obtain (R)-3-Boc-amino piperidine of 26.6g white, yield 95%.
Embodiment 16
By 46.8g compounds Ⅳ, wet palladium charcoal (water ratio 50%) and 320mL methyl alcohol of 2.3g10% adds in autoclave, nitrogen replacement 3 ~ 4 times, under being filled with hydrogen 0.3 ~ 0.4MPa pressure, be warming up to 35 ~ 40 DEG C, insulation reaction 2h, it is complete that HPLC tracks to feedstock conversion, filter, be concentrated into without cut, add 23mL methylene dichloride and 46mL sherwood oil, be warming up to 35 ~ 40 DEG C, slowly drip 325mL sherwood oil at such a temperature, insulation 1h, slow cooling is to-5 ~ 0 DEG C again, filter, 40 ~ 45 DEG C of oven dry, obtain (R)-3-Boc-amino piperidine of 26.7g white, yield 95.4%.
Embodiment 17
By 46.8g compounds Ⅳ, wet palladium charcoal (water ratio 50%) and 320mL methyl alcohol of 3.3g10% adds in autoclave, nitrogen replacement 3 ~ 4 times, under being filled with hydrogen 0.3 ~ 0.4MPa pressure, be warming up to 35 ~ 40 DEG C, insulation reaction 2h, it is complete that HPLC tracks to feedstock conversion, filter, be concentrated into without cut, add 23mL methylene dichloride and 46mL sherwood oil, be warming up to 35 ~ 40 DEG C, slowly drip 325mL sherwood oil at such a temperature, insulation 1h, slow cooling is to-5 ~ 0 DEG C again, filter, 40 ~ 45 DEG C of oven dry, obtain (R)-3-Boc-amino piperidine of 26.6g white, yield 95.2%.
Claims (10)
1. a preparation method for (R)-3-Boc-amino piperidine, is characterized in that, comprise the following steps:
(1) with N-Cbz-3-piperidine carboxylic acid for raw material, obtain chemical compounds I by R-phenylethylamine chiral separation;
(2) chemical compounds I and ammonia carry out acid amide condensation reaction, obtain compound ii;
(3) compound ii obtains compound III through hoffman degradation reaction;
(4) on compound III tert-Butyl dicarbonate, protection obtains compounds Ⅳ;
(5) compounds Ⅳ hydrogenation takes off Cbz and obtains (R)-3-Boc-amino piperidine; Total reaction equation is:
Wherein, Cbz is carbobenzoxy-(Cbz), and Boc is tertbutyloxycarbonyl.
2. the preparation method of (R)-3-Boc-amino piperidine according to claim 1, is characterized in that, in the synthesis of step (1), chemical compounds I: the mol ratio of R-phenylethylamine and N-Cbz-3-piperidine carboxylic acid is 0.7 ~ 0.9.
3. the preparation method of (R)-3-Boc-amino piperidine according to claim 1 and 2, it is characterized in that, in the synthesis of step (1), chemical compounds I: N-Cbz-3-piperidine carboxylic acid is dissolved in organic solvent, be heated with stirring to 40 ~ 50 DEG C, slowly drip the above-mentioned organic solvent solution of R-phenylethylamine at such a temperature, drip and finish, insulated and stirred to reacting complete, cooling, suction filtration, dry must carboxylate salt
; Then by carboxylate salt
purify to ee value and be greater than 99%; Finally by carboxylate salt
dissociate with acid, extraction, concentrates to obtain chemical compounds I.
4. the preparation method of (R)-3-Boc-amino piperidine according to claim 3, is characterized in that, in the synthesis of step (1), chemical compounds I: organic solvent is methyl alcohol, acetone or ethyl acetate.
5. the preparation method of (R)-3-Boc-amino piperidine according to claim 3, it is characterized in that, in the synthesis of step (1), chemical compounds I: N-Cbz-3-piperidine carboxylic acid is dissolved in organic solvent, be heated with stirring to 40 ~ 50 DEG C, slowly drip the above-mentioned organic solvent solution of R-phenylethylamine at such a temperature, drip and finish, insulated and stirred 20 ~ 30min, slowly cool to 10 ~ 15 DEG C, suction filtration, dry carboxylate salt
; Then by carboxylate salt
add in ethanol, be heated to 70 ~ 75 DEG C, insulation 15 ~ 20min, is slowly down to 10 ~ 15 DEG C, suction filtration, dry carboxylate salt
, repeat this and be operated to ee value and be greater than 99%; Finally by carboxylate salt
dissociate with concentrated hydrochloric acid, pH is adjusted to 1 ~ 2, extraction into ethyl acetate, concentrates to obtain chemical compounds I.
6. the preparation method of (R)-3-Boc-amino piperidine according to claim 1, is characterized in that, in the synthesis of step (2), compound ii: chemical compounds I and Methanesulfonyl chloride are formed
after, pass into ammonia and obtain compound ii.
7. the preparation method of (R)-3-Boc-amino piperidine according to claim 6, it is characterized in that, in the synthesis of step (2), compound ii: chemical compounds I is dissolved in tetrahydrofuran (THF), adds N, N-diisopropylethylamine, be cooled to-10 ~-5 DEG C, slowly drip Methanesulfonyl chloride, drip and finish, slowly pass into ammonia at such a temperature, after reaching capacity, system is warming up to 20 ~ 25 DEG C of reactions, reacts complete and obtain compound ii; The mol ratio of Methanesulfonyl chloride and N, N-diisopropylamine and chemical compounds I is respectively 1.05 ~ 1.25, and 1.1 ~ 1.4.
8. the preparation method of (R)-3-Boc-amino piperidine according to claim 1, it is characterized in that, in the synthesis of step (3), compound III: compound ii, under the condition of clorox and aqueous sodium hydroxide solution, at 35 ~ 40 DEG C, obtains compound III through hoffman degradation reaction.
9. the preparation method of (R)-3-Boc-amino piperidine according to claim 1, it is characterized in that, in the synthesis of step (4), compounds Ⅳ: compound III and sodium carbonate are added in water, ice bath is cooled to 0 ~ 5 DEG C, drip the methanol solution of tert-Butyl dicarbonate, drip and finish, be back to 20 ~ 25 DEG C of reactions, to reacting complete, obtain compounds Ⅳ; The mol ratio of tert-Butyl dicarbonate and sodium carbonate and compound III is respectively 1.1 ~ 1.3, and 1.5 ~ 2.5.
10. the preparation method of (R)-3-Boc-amino piperidine according to claim 1, it is characterized in that, in the synthesis of step (5), (R)-3-Boc-amino piperidine: by compounds Ⅳ, palladium charcoal and methyl alcohol add in autoclave, nitrogen replacement 3 ~ 4 times, under the hydrogen pressure of 0.3 ~ 0.4MPa, 35 ~ 40 DEG C of reactions, to reacting complete, obtain (R)-3-Boc-amino piperidine.
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