CN107188894B - Tert-butyl 7- hydroxyl hexahydro furyl simultaneously [3,2-b] pyridine -4 (2H)-carboxylate preparation method - Google Patents
Tert-butyl 7- hydroxyl hexahydro furyl simultaneously [3,2-b] pyridine -4 (2H)-carboxylate preparation method Download PDFInfo
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- CN107188894B CN107188894B CN201710512773.1A CN201710512773A CN107188894B CN 107188894 B CN107188894 B CN 107188894B CN 201710512773 A CN201710512773 A CN 201710512773A CN 107188894 B CN107188894 B CN 107188894B
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- butyl
- pyridine
- hexahydro furyl
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 title claims abstract description 20
- 125000002541 furyl group Chemical group 0.000 title claims abstract description 18
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- DGLFDUYUBFYJJK-UHFFFAOYSA-N 1,2-dihydropyridine-4-carboxylic acid Chemical compound OC(=O)C1=CCNC=C1 DGLFDUYUBFYJJK-UHFFFAOYSA-N 0.000 title claims abstract description 9
- 150000001875 compounds Chemical class 0.000 claims abstract description 36
- 239000012279 sodium borohydride Substances 0.000 claims abstract description 7
- 229910000033 sodium borohydride Inorganic materials 0.000 claims abstract description 7
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 claims abstract description 5
- 229940125797 compound 12 Drugs 0.000 claims abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims description 53
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Natural products OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 25
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 23
- 239000002994 raw material Substances 0.000 claims description 21
- 239000001257 hydrogen Substances 0.000 claims description 20
- 229910052739 hydrogen Inorganic materials 0.000 claims description 20
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 15
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 claims description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 12
- 235000019441 ethanol Nutrition 0.000 claims description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 10
- 238000003756 stirring Methods 0.000 claims description 9
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 claims description 8
- 229940125898 compound 5 Drugs 0.000 claims description 8
- 238000000926 separation method Methods 0.000 claims description 8
- 238000004440 column chromatography Methods 0.000 claims description 7
- 229940125773 compound 10 Drugs 0.000 claims description 7
- 229940126214 compound 3 Drugs 0.000 claims description 7
- 238000005984 hydrogenation reaction Methods 0.000 claims description 7
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 claims description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 235000019445 benzyl alcohol Nutrition 0.000 claims description 4
- 229960004217 benzyl alcohol Drugs 0.000 claims description 4
- 230000003197 catalytic effect Effects 0.000 claims description 4
- 229940125904 compound 1 Drugs 0.000 claims description 4
- 229940125782 compound 2 Drugs 0.000 claims description 4
- 150000002431 hydrogen Chemical class 0.000 claims description 4
- 230000007062 hydrolysis Effects 0.000 claims description 4
- 238000006460 hydrolysis reaction Methods 0.000 claims description 4
- -1 methanol Compound Chemical class 0.000 claims description 4
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 claims 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 description 4
- IBYHHJPAARCAIE-UHFFFAOYSA-N 1-bromo-2-chloroethane Chemical class ClCCBr IBYHHJPAARCAIE-UHFFFAOYSA-N 0.000 claims description 3
- JMQGGPRJQOQKRT-UHFFFAOYSA-N diphenyl hydrogen phosphate;azide Chemical compound [N-]=[N+]=[N-].C=1C=CC=CC=1OP(=O)(O)OC1=CC=CC=C1 JMQGGPRJQOQKRT-UHFFFAOYSA-N 0.000 claims description 3
- OVEHNNQXLPJPPL-UHFFFAOYSA-N lithium;n-propan-2-ylpropan-2-amine Chemical compound [Li].CC(C)NC(C)C OVEHNNQXLPJPPL-UHFFFAOYSA-N 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 238000007792 addition Methods 0.000 claims description 2
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 2
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 2
- 125000004494 ethyl ester group Chemical group 0.000 claims description 2
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 2
- 125000006239 protecting group Chemical group 0.000 claims description 2
- 238000006462 rearrangement reaction Methods 0.000 claims description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 238000001308 synthesis method Methods 0.000 abstract description 2
- 239000000543 intermediate Substances 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 52
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 39
- 239000012074 organic phase Substances 0.000 description 22
- 239000012043 crude product Substances 0.000 description 15
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 239000007864 aqueous solution Substances 0.000 description 8
- 230000006837 decompression Effects 0.000 description 8
- 239000012071 phase Substances 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 238000005406 washing Methods 0.000 description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 244000248349 Citrus limon Species 0.000 description 4
- 235000005979 Citrus limon Nutrition 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 238000010189 synthetic method Methods 0.000 description 3
- DZAHXNNEQCZPGJ-UHFFFAOYSA-N CCCCOC(OC)=O.COC(O)=O Chemical compound CCCCOC(OC)=O.COC(O)=O DZAHXNNEQCZPGJ-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000012266 salt solution Substances 0.000 description 2
- QMSVNDSDEZTYAS-UHFFFAOYSA-N 1-bromo-1-chloroethane Chemical compound CC(Cl)Br QMSVNDSDEZTYAS-UHFFFAOYSA-N 0.000 description 1
- UHBXGHADNVDXMM-UHFFFAOYSA-N C(C)(C)N(C(C)C)CC[Li] Chemical compound C(C)(C)N(C(C)C)CC[Li] UHBXGHADNVDXMM-UHFFFAOYSA-N 0.000 description 1
- 238000007445 Chromatographic isolation Methods 0.000 description 1
- 241000254173 Coleoptera Species 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 238000011097 chromatography purification Methods 0.000 description 1
- 239000002027 dichloromethane extract Substances 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 150000002240 furans Chemical class 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The present invention relates to a kind of (3aR, 7S, 7aR)-tert-butyl 7- hydroxyl hexahydro furyl simultaneously [3,2-b] pyridine -4 (2H)-carboxylate preparation methods, the technical issues of mainly solution currently without suitable Industrialized synthesis method.The present invention is divided into nine steps: the 9th step obtains a pair of of compound 12 and 12A under sodium borohydride effect.
Description
Technical field
The present invention relates to tert-butyl 7- hydroxyl hexahydro furyl simultaneously [3,2-b] pyridine -4 (2H)-carboxylate preparation method,
I.e. (3aR, 7S, 7aR)-tert-butyl 7- hydroxyl hexahydro furyl simultaneously [3,2-b] pyridine -4 (2H)-carboxylate (MDL:
MFCD28122595 synthetic method).
Background technique
(3aR, 7S, 7aR)-tert-butyl 7- hydroxyl hexahydro furyl simultaneously [3,2-b] pyridine -4 (2H)-carboxylate and relevant
Derivative has in pharmaceutical chemistry and organic synthesis to be widely applied.At present about (3aR, 7S, 7aR)-tert-butyl 7- hydroxyl six
Hydrogen furans simultaneously [3,2-b] pyridine -4 (2H)-carboxylate synthesis report seldom, similar document reaction there are certain risk and
Route is long, and yield is lower.Therefore it needs to develop a raw material to be easy to get, it is easy to operate, react easily controllable, what overall yield was suitble to
Synthetic method.
Summary of the invention
It is easy to operate the purpose of the present invention is developing one kind to be easy to get with raw material, react easily controllable, yield is higher
(3aR, 7S, 7aR)-tert-butyl 7- hydroxyl hexahydro furyl simultaneously [3,2-b] pyridine -4 (2H)-carboxylate synthetic method.Main solution
Certainly currently without suitable Industrialized synthesis method the technical issues of.
A kind of technical solution of the present invention: (3aR, 7S, 7aR)-tert-butyl 7- hydroxyl hexahydro furyl simultaneously [3,2-b] pyridine-
The preparation method of 4 (2H)-carboxylates, includes the following steps, the present invention divides 9 steps, the first step, by compound 1 and compound 2 third
Reaction generates compound 3 in ketone, and second step, compound 4, triethylamine, di-tert-butyl dicarbonate and palladium carbon hydrogenate instead in ethanol
It should obtain compound 5, third step, compound 5 and bromochloroethane and generate chemical combination under the action of sodium hydrogen and lithium diisopropylamine
Hydrogenation generates compound 7 in ethanol for object 6, the 4th step compound 6 and palladium carbon, and the 5th step, compound 7 is in first alcohol and water
Compound 8 is obtained by sodium hydroxide hydrolysis, the 6th step, compound 8, triethylamine, benzylalcohol reacts to obtain in toluene through Ke Disi
Hydrogenation obtains compound 10, the 8th step, compound 10, chemical combination in methyl alcohol for compound 9, the 7th step, compound 9 and palladium carbon
Object 3 and DBU react in methylene chloride and dimethylformamide, obtain compound 11, the 9th step, and compound 11 is used in methyl alcohol
Sodium borohydride reduction, column chromatography for separation obtain compound 12 and 12A.Reaction equation is as follows:
In above-mentioned reaction: first step return stirring is stayed overnight；Second step palladium carbon catalytic hydrogen reduction reacts four hours；Third step
Subzero 60 DEG C of additions raw material, warms naturally to be stirred overnight at room temperature；4th step palladium carbon catalytic hydrogen reduction in high pressure hydrogen is anti-
It answers four hours；5th step sodium hydroxide hydrolysis ethyl ester reacts four hours；6th step Ke Disi rearrangement reaction, reaction are refluxed overnight；
7th step palladium carbon catalytic hydrogenation deviates from benzyloxycarbonyl protecting group；The reaction of 8th step is stirred overnight at room temperature；9th step sodium borohydride is also
Original reacts half an hour.
Beneficial effects of the present invention: the present invention provides a kind of synthesis (3aR, 7S, 7aR)-tert-butyl 7- hydroxyl hexahydro furans
It mutters simultaneously [3,2-b] pyridine -4 (2H)-carboxylate method, this method synthetic route is reliable, and reaction is easy to amplify, and it is easy to operate,
With industrial applications prospect.
Specific embodiment
Reaction equation of the present invention is as follows:
Embodiment 1:a, compound 1 (53 g, 0.5 mol) and compound 2 (86 g, 0.5 mol) are dissolved
Be heated in acetone (300 milliliters) 60 DEG C be stirred overnight .TLC show raw material completely disappear.Solution, which is concentrated under reduced pressure, removes solvent
Obtain yellow solid compound 3 (132 g), yield 95%.
B, by compound 4 (12.5 g, 0.042 mol), palladium carbon (3 g), triethylamine (6.5 mL, 0.044
Mol) and dimethyl dicarbonate butyl ester (12g, 0.046 mol) is dispersed in ethyl alcohol (200 milliliters), then in hydrogen (55
Psi) pressure is stirred at room temperature 4 hours.TLC shows that raw material completely disappears.Reaction solution is depressurized and is filtered, filtrate decompression concentration.Slightly
Product is dissolved in ethyl acetate (200 milliliters) and water (150 milliliters).Separate organic phase, organic phase saturated salt solution (200
Milliliter) it washes twice, it is concentrated to get orange oily compound 5 (13 g) after anhydrous sodium sulfate is dry, crude product is directly used in next
Step reaction.
C, compound 5(10 g is added portionwise at 30-50 DEG C for sodium hydrogen (1 g, 25 mmol)) and hexamethyl phosphinylidyne three
In the anhydrous tetrahydrofuran solution of amine (9 g).Half an hour is stirred at room temperature in reaction solution after charging.By reaction solution in nitrogen
Subzero 50 DEG C to subzero 60 DEG C are cooled under protection.Then lithium diisopropylamine solution (37 mL) is dripped at subzero 60 DEG C
It is added in reaction solution, half an hour is stirred in continuation at this temperature.By the bromo- 2- chloroethanes of 1- (137 g, 0.958 mol) subzero
60 DEG C are added drop-wise in reaction solution, and reaction warms naturally to room temperature after being added dropwise, and are stirred overnight.TLC shows that most of raw material is anti-
It should finish.Reaction solution is poured into saturated lemon aqueous solution (100 mL), organic phase is separated.Water phase ethyl acetate (100
ML X 2) extraction, merge organic phase, organic phase saturated common salt water washing, anhydrous sodium sulfate drying.Organic phase is concentrated under reduced pressure
Obtain crude product.It is solid that crude product column chromatography for separation (eluant, eluent: petrol ether/ethyl acetate volume ratio=100/1-5/1) obtains white
Body compound 6(5 g), yield 45%.
δ(CDCl3)= 1.31 (t, J=7.28 Hz, 3 H) 1.50 (s, 9 H) 1.82 - 1.96 (m, 1 H)
2.11 - 2.23 (m, 1 H) 2.66 - 2.88 (m, 3 H) 4.02 (d, J=11.91 Hz, 1 H) 4.17 -
4.45 (m, 4 H) 4.52 (t, J=8.82 Hz, 1 H)。
D, compound 6(40 g, 1.35mol) and palladium carbon (8 g) are dispersed in ethyl alcohol (0.8 L), hydrogen is replaced 3 times.
Then reaction solution is heated to 70 DEG C in the autoclave of hydrogen (5 MPa) and is stirred overnight.TLC shows that raw material disappears.By reaction solution
It is cooled to room temperature decompression to filter, filtrate decompression is concentrated to get yellow oily compound 7(41 g), yield 99%.
E, compound 7(23 g will be added to dissolved with the aqueous solution room temperature of sodium hydroxide (6.2 g)) ethyl alcohol (200
ML) in solution, reaction is stirred at room temperature 4 hours after charging.TLC shows that raw material completely disappears.Reaction solution is concentrated and is removed
Solvent.Residue is dissolved into water (300 mL), and liquid separation is extracted with ethyl acetate, and retains water phase.Water phase diluted hydrochloric acid aqueous solution
(1 M) adjusts pH=3-4, and water phase is extracted with ethyl acetate 3 times, the organic phase saturated common salt water washing after merging, anhydrous slufuric acid
Compound as white solid 8(21 g is concentrated under reduced pressure to give after sodium is dry), yield: 99%.
F, diphenyl phosphate azide (14g) room temperature is added to compound 8(10 g) and triethylamine (12 g) without water beetle
In benzene (100 mL) solution, reaction solution is heated to reflux to no gas and generates after charging.Then benzylalcohol (13g) is added to instead
It answers in liquid, continues return stirring and stay overnight.TLC shows that raw material completely disappears.Water (100 mL) is added after being cooled to room temperature in reaction solution,
Organic phase is separated, organic phase saturated common salt water washing is concentrated under reduced pressure to give crude product after anhydrous sodium sulfate is dry.Crude product column
Chromatography purifying (eluant, eluent: petrol ether/ethyl acetate volume ratio=100/1-5/1) obtains yellow oily compound 9(6 g),
Yield 40%.
G, compound 9(8 g, 1.35mol) and palladium carbon (2 g) are dispersed in methanol (200 mL), hydrogen is replaced 3 times.
Then reaction solution is stirred at room temperature 2 hours in the hydrogenation bottle of hydrogen (50 psi).TLC shows that raw material disappears.Reaction solution is depressurized
Filter, filtrate decompression is concentrated to get yellow oily compound 10(4 g), yield 80%.
H, compound 10(7 g) and compound 3(6.8 g) methylene chloride (60 mL) and dimethylformamide (20 mL)
Solution is stirred at room temperature 1 hour.TLC shows that raw material completely disappears.Then DBU(5 g) is added in reaction solution at room temperature,
Saturated lemon aqueous solution is added in reaction solution after continuing stirring 1 hour, continues to be stirred overnight at room temperature.Reaction solution dichloro
Methane extracts three times.Organic phase saturated common salt water washing after merging is concentrated under reduced pressure to give brown after anhydrous sodium sulfate is dry
Oily compound 11(3 g).
I, compound 11(5 g is added portionwise in sodium borohydride (0.8 g) at 0-10 DEG C) methanol (50 mL) solution
In.Reaction solution continues to stir half an hour after charging.TLC shows that raw material completely disappears.Reaction is depressurized dense after being quenched with acetone
Contracting.Residue is extracted 3 times after being diluted with water with ethyl acetate (100 mL).Organic phase after merging is concentrated under reduced pressure to give crude product.
Crude product column chromatography for separation obtains yellow solid compound 12(1.6g) and yellow solid compound 12A(0.3 g).
12: δ(CDCl3)= 1.49 (s, 9 H) 1.57 - 1.68 (m, 1 H) 1.84 - 1.96 (m, 1 H)
2.02 - 2.17 (m, 2 H) 2.39 (br. s., 1 H) 3.22 (t, J=12.13 Hz, 1 H) 3.74 (d, J=
12.35 Hz, 1 H) 3.81 - 4.00 (m, 3 H) 4.15 (t, J=7.94 Hz, 1 H) 4.59 (d, J=7.06
Hz, 1 H)
12A: δ(CDCl3)= 1.42 - 1.67 (m, 9 H) 1.73 - 1.92 (m, 2 H) 2.15 (br.
s., 1 H) 2.35 (br. s., 1 H) 2.85 (t, J=12.35 Hz, 1 H) 3.55 - 3.70 (m, 2 H)
3.89 - 3.98 (m, 1 H) 3.99 - 4.09 (m, 2 H) 4.69 (br. s., 1 H)。
Embodiment 2:a, compound 1 (53 g, 0.5 mol) and compound 2 (86 g, 0.5 mol) are dissolved
Be heated in acetone (300 milliliters) 60 DEG C be stirred overnight .TLC show raw material completely disappear.Solution, which is concentrated under reduced pressure, removes solvent
Obtain yellow solid compound 3 (132 g), yield 95%.
B, by compound 4 (125 g, 0.42 mol), palladium carbon (17 g), triethylamine (65 mL, 0.44 mol)
And dimethyl dicarbonate butyl ester (115 g, 0.46 mol) is dispersed in ethyl alcohol (1.5 liters), is then pressed at hydrogen (55 psi)
Power is stirred at room temperature 4 hours.TLC shows that raw material completely disappears.Reaction solution is depressurized and is filtered, filtrate decompression concentration.Crude product is molten
Solution is in ethyl acetate (500 milliliters) and water (250 milliliters).Organic phase is separated, organic phase is washed with saturated salt solution (200 milliliters)
It washs twice, orange oily compound 5 (128 g) is concentrated to get after anhydrous sodium sulfate is dry, crude product is directly used in anti-in next step
It answers.
C, compound 5(200 g, 0.737 mol are added portionwise at 30-50 DEG C for sodium hydrogen (10 g, 0.25 mol))
In the anhydrous tetrahydrofuran solution of hexamethylphosphoramide (172 g, 0.958 mol).Reaction solution is in room temperature after charging
Lower stirring half an hour.Reaction solution is cooled to subzero 50 DEG C to subzero 60 DEG C under nitrogen protection.Then by diisopropylaminoethyl
Lithium solution (737 mL, 1.47 mol) is added drop-wise in reaction solution at subzero 60 DEG C, and half an hour is stirred in continuation at this temperature.
The bromo- 2- chloroethanes of 1- (137 g, 0.958 mol) is added drop-wise in reaction solution at subzero 60 DEG C, reacts nature after being added dropwise
It is warming up to room temperature, is stirred overnight.TLC shows most of raw material end of reaction.Reaction solution is poured into saturated lemon aqueous solution (2
L in), organic phase is separated.Water phase is extracted with ethyl acetate (0.5 L X 2), merges organic phase, and organic phase is washed with saturated common salt
It washs, anhydrous sodium sulfate is dry.Organic phase is concentrated under reduced pressure to give crude product.Crude product column chromatography for separation (washing and dehydrating integrated machine: petroleum ether/
Ethyl acetate volume ratio=100/1-5/1) obtain compound as white solid 6(98 g), yield 45%.
δ(CDCl3)= 1.31 (t, J=7.28 Hz, 3 H) 1.50 (s, 9 H) 1.82 - 1.96 (m, 1 H)
2.11 - 2.23 (m, 1 H) 2.66 - 2.88 (m, 3 H) 4.02 (d, J=11.91 Hz, 1 H) 4.17 -
4.45 (m, 4 H) 4.52 (t, J=8.82 Hz, 1 H)。
D, compound 6(400 g, 1.35mol) and palladium carbon (80 g) are dispersed in ethyl alcohol (8 L), hydrogen is replaced 3 times.
Then reaction solution is heated to 70 DEG C in the autoclave of hydrogen (5 MPa) and is stirred overnight.TLC shows that raw material disappears.By reaction solution
It is cooled to room temperature decompression to filter, filtrate decompression is concentrated to get yellow oily compound 7(400 g), yield 99%.
E, it will be added to compound 7(230 g dissolved with the aqueous solution room temperature of sodium hydroxide (62 g, 1.54 mol),
0.768 mol) ethyl alcohol (1 L) solution in, after charging reaction be stirred at room temperature 4 hours.TLC shows that raw material disappears completely
It loses.Reaction solution is concentrated and removes solvent.Residue is dissolved into water (1.5 L), and liquid separation is extracted with ethyl acetate, and retains water phase.
Water phase adjusts pH=3-4 with diluted hydrochloric acid aqueous solution (1 M), and water phase is extracted with ethyl acetate 3 times, the organic phase saturation after merging
Brine It is concentrated under reduced pressure to give compound as white solid 8(208 g after anhydrous sodium sulfate is dry), yield: 99%.
F, diphenyl phosphate azide (282g, 1.16mol) room temperature is added to compound 8(208 g, 0.767 mol)
In dry toluene (1.5 L) solution of triethylamine (235 g, 2.32mol), reaction solution is heated to reflux to nothing after charging
Gas generates.Then benzylalcohol (251g, 2.32 mol) is added in reaction solution, continues return stirring and stays overnight.TLC display is former
Material completely disappears.Water (1.5 L) is added after being cooled to room temperature in reaction solution, separates organic phase, organic phase saturated common salt water washing,
Crude product is concentrated under reduced pressure to give after anhydrous sodium sulfate is dry.Crude product column chromatographic isolation and purification (eluant, eluent: petroleum ether/acetic acid second
Ester volume ratio=100/1-5/1) obtain yellow oily compound 9(116 g), yield 40%.
G, compound 9(80 g, 1.35mol) and palladium carbon (15 g) are dispersed in methanol (1.2 L), hydrogen displacement 3
It is secondary.Then reaction solution is stirred at room temperature 2 hours in the hydrogenation bottle of hydrogen (50 psi).TLC shows that raw material disappears.Reaction solution is subtracted
Pressure filters, and filtrate decompression is concentrated to get yellow oily compound 10(41 g), yield 80%.
H, compound 10(70 g, 0.29mol) and compound 3(68 g, 0.43mol) methylene chloride (600 mL) and
Dimethylformamide (200 mL) solution is stirred at room temperature 1 hour.TLC shows that raw material completely disappears.Then by DBU(46 g,
It 0.3mol) is added in reaction solution, saturated lemon aqueous solution is added in reaction solution at room temperature after continuing stirring 1 hour,
Continue to be stirred overnight at room temperature.Reaction solution is extracted with dichloromethane three times.Organic phase saturated common salt water washing after merging, it is anhydrous
Brown oil compound 11(25 g is concentrated under reduced pressure to give after sodium sulphate is dry).
I, compound 11(30 g is added portionwise in sodium borohydride (4.7 g, 0.124mol) at 0-10 DEG C,
In methanol (300 mL) solution 0.124mol).Reaction solution continues to stir half an hour after charging.TLC shows that raw material is complete
It disappears.Reaction is concentrated under reduced pressure after being quenched with acetone.Residue is extracted 3 times after being diluted with water with ethyl acetate (100 mL).Merge
Organic phase afterwards is concentrated under reduced pressure to give crude product.Crude product column chromatography for separation obtains yellow solid compound 12(9g) and yellow solid
Compound 12A(2.2 g).
12: δ(CDCl3)= 1.49 (s, 9 H) 1.57 - 1.68 (m, 1 H) 1.84 - 1.96 (m, 1 H)
2.02 - 2.17 (m, 2 H) 2.39 (br. s., 1 H) 3.22 (t, J=12.13 Hz, 1 H) 3.74 (d, J=
12.35 Hz, 1 H) 3.81 - 4.00 (m, 3 H) 4.15 (t, J=7.94 Hz, 1 H) 4.59 (d, J=7.06
Hz, 1 H)
12A: δ(CDCl3)= 1.42 - 1.67 (m, 9 H) 1.73 - 1.92 (m, 2 H) 2.15 (br.
s., 1 H) 2.35 (br. s., 1 H) 2.85 (t, J=12.35 Hz, 1 H) 3.55 - 3.70 (m, 2 H)
3.89 - 3.98 (m, 1 H) 3.99 - 4.09 (m, 2 H) 4.69 (br. s., 1 H)。
Claims (10)
1. a kind of (3aR, 7S, 7aR)-tert-butyl 7- hydroxyl hexahydro furyl simultaneously [3,2-b] pyridine -4 (2H)-carboxylate preparation
Method, it is characterized in that compound 1 and compound 2 are reacted in acetone and generate compound 3 the following steps are included: the first step, the
Two steps, compound 4, triethylamine, di-tert-butyl dicarbonate and palladium carbon lead to hydrogen hydrogenation in ethanol and obtain compound 5, the
Three steps, compound 5 and the bromo- 2- chloroethanes of 1- are in tetrahydrofuran and sodium hydrogen and lithium diisopropylamine under the action of generate chemical combination
Object 6, the 4th step compound 6 and palladium carbon lead to hydrogen hydrogenation in ethanol and generate compound 7, and the 5th step, compound 7 is in methanol
Compound 8 is obtained by sodium hydroxide hydrolysis in water, the 6th step, compound 8, triethylamine, diphenyl phosphate azide, benzylalcohol is in first
It reacts to obtain compound 9, the 7th step through Ke Disi in benzene, compound 9 and palladium carbon lead to hydrogen hydrogenation in methyl alcohol
Conjunction object 10, the 8th step, compound 10, compound 3 and DBU react in methylene chloride and dimethylformamide, obtain compound
11, the 9th step, compound 11 uses sodium borohydride reduction in methyl alcohol, and column chromatography for separation obtains compound 12 and 12A, and reaction equation is such as
Under:
。
2. one kind (3aR, 7S, 7aR)-tert-butyl 7- hydroxyl hexahydro furyl according to claim 1 simultaneously [3,2-b] pyridine-
The preparation method of 4 (2H)-carboxylates, it is characterized in that first step return stirring is stayed overnight.
3. one kind (3aR, 7S, 7aR)-tert-butyl 7- hydroxyl hexahydro furyl according to claim 1 simultaneously [3,2-b] pyridine-
The preparation method of 4 (2H)-carboxylates, it is characterized in that second step palladium carbon catalytic hydrogen reduction reacts four hours.
4. one kind (3aR, 7S, 7aR)-tert-butyl 7- hydroxyl hexahydro furyl according to claim 1 simultaneously [3,2-b] pyridine-
The preparation method of 4 (2H)-carboxylates, it is characterized in that the subzero 60 DEG C of additions raw material of third step, warms naturally to be stirred overnight at room temperature.
5. one kind (3aR, 7S, 7aR)-tert-butyl 7- hydroxyl hexahydro furyl according to claim 1 simultaneously [3,2-b] pyridine-
The preparation method of 4 (2H)-carboxylates, it is characterized in that the 4th step palladium carbon catalytic hydrogen reduction in high pressure hydrogen reacts four hours.
6. one kind (3aR, 7S, 7aR)-tert-butyl 7- hydroxyl hexahydro furyl according to claim 1 simultaneously [3,2-b] pyridine-
The preparation method of 4 (2H)-carboxylates, it is characterized in that the 5th step sodium hydroxide hydrolysis ethyl ester, reacts four hours.
7. one kind (3aR, 7S, 7aR)-tert-butyl 7- hydroxyl hexahydro furyl according to claim 1 simultaneously [3,2-b] pyridine-
The preparation method of 4 (2H)-carboxylates, it is characterized in that the 6th step Ke Disi rearrangement reaction, reaction are refluxed overnight.
8. one kind (3aR, 7S, 7aR)-tert-butyl 7- hydroxyl hexahydro furyl according to claim 1 simultaneously [3,2-b] pyridine-
The preparation method of 4 (2H)-carboxylates, it is characterized in that the 7th step palladium carbon catalytic hydrogenation deviates from benzyloxycarbonyl protecting group.
9. one kind (3aR, 7S, 7aR)-tert-butyl 7- hydroxyl hexahydro furyl according to claim 1 simultaneously [3,2-b] pyridine-
The preparation method of 4 (2H)-carboxylates, it is characterized in that the reaction of the 8th step is stirred overnight at room temperature.
10. one kind (3aR, 7S, 7aR)-tert-butyl 7- hydroxyl hexahydro furyl according to claim 1 simultaneously [3,2-b] pyrrole
Pyridine -4 (2H)-carboxylate preparation method, it is characterized in that the 9th step sodium borohydride reduction, reacts half an hour.
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| CN105418620A (en) * | 2014-09-23 | 2016-03-23 | 天津药明康德新药开发有限公司 | Synthesis method for 4-(tert-butoxycarbonyl) octahydrofuro[3,2-b] pyridine-6-carboxylic acid |
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