CN104478877B - The method preparing Lei Dipawei intermediate - Google Patents
The method preparing Lei Dipawei intermediate Download PDFInfo
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- CN104478877B CN104478877B CN201410609225.7A CN201410609225A CN104478877B CN 104478877 B CN104478877 B CN 104478877B CN 201410609225 A CN201410609225 A CN 201410609225A CN 104478877 B CN104478877 B CN 104478877B
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- tertbutyloxycarbonyl
- azabicyclo
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- 239000002904 solvent Substances 0.000 claims abstract description 12
- -1 Boc acid anhydrides Chemical class 0.000 claims abstract description 11
- ZSWFCLXCOIISFI-UHFFFAOYSA-N Cyclopentadiene Chemical compound C1C=CC=C1 ZSWFCLXCOIISFI-UHFFFAOYSA-N 0.000 claims abstract description 9
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims abstract description 9
- 150000002148 esters Chemical class 0.000 claims abstract description 8
- 239000007864 aqueous solution Substances 0.000 claims abstract description 7
- 150000001298 alcohols Chemical class 0.000 claims abstract description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 14
- IFAMSTPTNRJBRG-YIZRAAEISA-N (1S,2S,4R)-3-[(2-methylpropan-2-yl)oxycarbonyl]-3-azabicyclo[2.2.1]heptane-2-carboxylic acid Chemical compound C1C[C@@H]2[C@@H](C(O)=O)N(C(=O)OC(C)(C)C)[C@H]1C2 IFAMSTPTNRJBRG-YIZRAAEISA-N 0.000 claims description 13
- 239000007787 solid Substances 0.000 claims description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 239000000706 filtrate Substances 0.000 claims description 8
- 239000000243 solution Substances 0.000 claims description 8
- 238000003756 stirring Methods 0.000 claims description 8
- DBPFRRFGLYGEJI-UHFFFAOYSA-N ethyl glyoxylate Chemical compound CCOC(=O)C=O DBPFRRFGLYGEJI-UHFFFAOYSA-N 0.000 claims description 7
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 6
- 239000000284 extract Substances 0.000 claims description 5
- 239000012065 filter cake Substances 0.000 claims description 5
- 239000002808 molecular sieve Substances 0.000 claims description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L na2so4 Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 4
- 239000012074 organic phase Substances 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 claims description 3
- 235000011152 sodium sulphate Nutrition 0.000 claims description 3
- 238000007792 addition Methods 0.000 claims description 2
- 238000005984 hydrogenation reaction Methods 0.000 claims description 2
- 239000000376 reactant Substances 0.000 claims description 2
- 238000010792 warming Methods 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 abstract description 28
- 239000000654 additive Substances 0.000 abstract description 5
- 230000000996 additive Effects 0.000 abstract description 5
- 150000007529 inorganic bases Chemical class 0.000 abstract description 5
- 239000012024 dehydrating agents Substances 0.000 abstract description 4
- 125000004429 atoms Chemical group 0.000 abstract description 3
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 238000003541 multi-stage reaction Methods 0.000 abstract description 3
- 238000001953 recrystallisation Methods 0.000 abstract description 3
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 abstract description 3
- OBETXYAYXDNJHR-UHFFFAOYSA-N 2-Ethylhexanoic acid Chemical compound CCCCC(CC)C(O)=O OBETXYAYXDNJHR-UHFFFAOYSA-N 0.000 abstract description 2
- BHHGXPLMPWCGHP-UHFFFAOYSA-N 2-Phenethylamine Chemical compound NCCC1=CC=CC=C1 BHHGXPLMPWCGHP-UHFFFAOYSA-N 0.000 abstract 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 abstract 1
- 150000001875 compounds Chemical class 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 208000005176 Hepatitis C Diseases 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical compound N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 description 4
- 229960000329 Ribavirin Drugs 0.000 description 4
- CHQMHPLRPQMAMX-UHFFFAOYSA-L Sodium persulfate Chemical compound [Na+].[Na+].[O-]S(=O)(=O)OOS([O-])(=O)=O CHQMHPLRPQMAMX-UHFFFAOYSA-L 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 4
- 230000001225 therapeutic Effects 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 210000004185 Liver Anatomy 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 229920000160 (ribonucleotides)n+m Polymers 0.000 description 2
- WTEOIRVLGSZEPR-UHFFFAOYSA-N Boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N Di-tert-butyl dicarbonate Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 2
- 238000005698 Diels-Alder reaction Methods 0.000 description 2
- 241000711549 Hepacivirus C Species 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 239000007791 liquid phase Substances 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L mgso4 Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N n-butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 230000003612 virological Effects 0.000 description 2
- MVZVDAGWAAZJPE-UHFFFAOYSA-N 1,2-xylene;1,3-xylene;1,4-xylene Chemical compound CC1=CC=C(C)C=C1.CC1=CC=CC(C)=C1.CC1=CC=CC=C1C MVZVDAGWAAZJPE-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- BTANRVKWQNVYAZ-UHFFFAOYSA-N 2-Butanol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 1
- 208000007502 Anemia Diseases 0.000 description 1
- IFAMSTPTNRJBRG-HACHORDNSA-N CC(C)(C)OC(N(C1CC2CC1)[C@@H]2C(O)=O)=O Chemical compound CC(C)(C)OC(N(C1CC2CC1)[C@@H]2C(O)=O)=O IFAMSTPTNRJBRG-HACHORDNSA-N 0.000 description 1
- 0 CC(C)(C)OC(N1[C@](*)C2CC1CC2)=O Chemical compound CC(C)(C)OC(N1[C@](*)C2CC1CC2)=O 0.000 description 1
- KOPOQZFJUQMUML-UHFFFAOYSA-N Chlorosilane Chemical compound Cl[SiH3] KOPOQZFJUQMUML-UHFFFAOYSA-N 0.000 description 1
- 239000005046 Chlorosilane Substances 0.000 description 1
- 208000000419 Chronic Hepatitis B Diseases 0.000 description 1
- 208000006154 Chronic Hepatitis C Diseases 0.000 description 1
- HHLFWLYXYJOTON-UHFFFAOYSA-N Glyoxalate, Glyoxylate Chemical compound OC(=O)C=O HHLFWLYXYJOTON-UHFFFAOYSA-N 0.000 description 1
- 208000006454 Hepatitis Diseases 0.000 description 1
- 208000002672 Hepatitis B Diseases 0.000 description 1
- 206010019799 Hepatitis viral Diseases 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- SKRDXYBATCVEMS-UHFFFAOYSA-N Isopropyl nitrite Chemical compound CC(C)ON=O SKRDXYBATCVEMS-UHFFFAOYSA-N 0.000 description 1
- 101700019282 MRL7 Proteins 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- PMJHHCWVYXUKFD-SNAWJCMRSA-N Piperylene Chemical compound C\C=C\C=C PMJHHCWVYXUKFD-SNAWJCMRSA-N 0.000 description 1
- 206010061920 Psychotic disease Diseases 0.000 description 1
- 210000002966 Serum Anatomy 0.000 description 1
- IJOOHPMOJXWVHK-UHFFFAOYSA-N Trimethylsilyl chloride Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 201000005794 allergic hypersensitivity disease Diseases 0.000 description 1
- 238000010009 beating Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000010523 cascade reaction Methods 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000022534 cell killing Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- DCFKHNIGBAHNSS-UHFFFAOYSA-N chloro(triethyl)silane Chemical compound CC[Si](Cl)(CC)CC DCFKHNIGBAHNSS-UHFFFAOYSA-N 0.000 description 1
- ACTAPAGNZPZLEF-UHFFFAOYSA-N chloro(tripropyl)silane Chemical compound CCC[Si](Cl)(CCC)CCC ACTAPAGNZPZLEF-UHFFFAOYSA-N 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000001684 chronic Effects 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 230000000875 corresponding Effects 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 230000000994 depressed Effects 0.000 description 1
- XUCJHNOBJLKZNU-UHFFFAOYSA-M dilithium;hydroxide Chemical compound [Li+].[Li+].[OH-] XUCJHNOBJLKZNU-UHFFFAOYSA-M 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000000977 initiatory Effects 0.000 description 1
- 238000009114 investigational therapy Methods 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 238000011031 large scale production Methods 0.000 description 1
- 229910001947 lithium oxide Inorganic materials 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 201000004044 liver cirrhosis Diseases 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 108010092851 peginterferon alfa-2b Proteins 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propanol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 231100000486 side effect Toxicity 0.000 description 1
- TTZHDVOVKQGIBA-IQWMDFIBSA-N sofosbuvir Chemical compound N1([C@@H]2O[C@@H]([C@H]([C@]2(F)C)O)CO[P@@](=O)(N[C@@H](C)C(=O)OC(C)C)OC=2C=CC=CC=2)C=CC(=O)NC1=O TTZHDVOVKQGIBA-IQWMDFIBSA-N 0.000 description 1
- 229960002063 sofosbuvir Drugs 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000002194 synthesizing Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 201000001862 viral hepatitis Diseases 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/08—Bridged systems
Abstract
The present invention relates to the method that one prepares (1R, 3S, 4S) N tertbutyloxycarbonyl 2 azabicyclo [2,2,1] heptane 3 carboxylic acid (Formula V),
Description
Technical field
The present invention relates to medicinal chemistry art, be specifically related to (1R, 3S, 4S)-N-tertbutyloxycarbonyl-2-azabicyclo [2,
2,1] preparation method of heptane-3-carboxylic acid.
Background technology
Viral hepatitis type C, is called for short hepatitis C, is the one viral liver that has that HCV (HCV) causes
Scorching.Estimating according to the World Health Organization, whole world hepatitis C infections rate is about 3%, estimates that there are about 100,000,000 7 million people carries hepatitis C virus.
Hepatitis C may result in the necrosis of liver chronic inflammation and fibrillatable, and some patients may develop into cirrhosis even liver cancer, to trouble
The health and lives of person brings threat greatly.
The therapeutic purpose of chronic hepatitis C is to remove virus, thus the generation of complication can be restricted or prevented, and success
The standard for the treatment of is defined as 24 weeks after stopping treatment, can't detect the RNA of hepatitis C virus in patients serum.And current third type liver
Scorching standard treatment is Peg-IFN alpha-2b and ribavirin combination scheme, but the method may cause anaemia, allergy
With the side effect such as depressed sample psychosis, therefore study novel anti-chronic hepatitis C viral's medicine and always study popular domain.
Lucky Deco (Gilead Siences) (on November 14th, 2012) recently discloses II phase ELECTRON research
Positive interim data, the research carries out in just controlling (treatment-naive) I type chronic hepatitis B patient, investigation
The curative effect of 12 weeks by a definite date noiseless elements combination treatment (Suo Feibuwei+Lei Dipawei+Ribavirin (ribavirin)).Research
Result shows, in 4 weeks after completing treatment (SVR4), patient (n=25/25) the internal HCV rna level of 100% cannot be examined
Measure.Result of study shows, adds GS-5885 to therapeutic scheme based on sofosbuvir, can improve SVR and lead, be expected to as I
Type HCV patient provides the oral therapies of 12 weeks by a definite date easily.On October 10th, 2014, Suo Feibuwei+Lei Dipawei is multiple
Square piece agent has been approved by the FDA in the United States, and becomes the first in the world therapeutic gene 1 type and becomes the complete oral of human C type hepatitis, without dry
Disturb the therapeutic scheme of element and Ribavirin, shown in the chemical constitution of Lei Dipawei such as formula (1):
The synthetic route of Lei Dipawei mainly has:
Wherein key intermediate (1R, 3S, 4S)-N-tertbutyloxycarbonyl-2-azabicyclo [2,2,1] heptane-3-carboxylic acid is (i.e.
Compound shown in formula (V)) synthetic method be mainly initiation material by glyoxylic acid ethyl ester and (R)-phenyl ethylamine, anti-through multistep
Should prepare.Wherein there is Diels-Alder reacting generating compound II with cyclopentadiene in imines I, mainly uses boron trifluoride
Being additive with trifluoroacetic acid, carry out under the conditions of-78 DEG C, the method condition is harsh, should not mass produce,
Corresponding patent and document is had to report Diels-Alder reaction, such as: PCT application WO the most successively
2011091532 and PCT application WO 20120923 report under trifluoroacetic acid effect, DMF is solvent,
This reaction can be carried out in room temperature；Organic Process Research & Development 2005,9,105-109 reports
Road is with methyl alcohol and toluene for solvent trim,ethylchlorosilane as additive, and this reaction can carry out at-10～0 DEG C.PCT application WO
2011091532 change synthetic route, its first Hydrolysis of compound III, then prepare compound (V) with Boc anhydride reaction, but this
A little reports are all that the production cycle is long, post-processes loaded down with trivial details, even needs to pass through post through multistep reaction synthesis key intermediate (V)
Chromatography refined product, these schemes all cannot embody Atom economy.
Summary of the invention
One prepares the side of (1R, 3S, 4S)-N-tertbutyloxycarbonyl-2-azabicyclo [2,2,1] heptane-3-carboxylic acid (Formula V)
Method,
Comprising: be dissolved in solvent by glyoxylic ester, it is cooled to-10～0 DEG C, adds dehydrating agent and (R)-phenyl ethylamine, then
Within the spacer unit time, it is sequentially added into alcohols solvent and additive, cyclopentadiene, palladium carbon, inorganic base aqueous solution, Boc acid anhydrides enter
Row reaction.
In certain embodiments, described dehydrating agent isMolecular sieve, anhydrous sodium sulfate, colourless magnesium sulfate or a combination thereof.
In certain embodiments, described solvent is toluene or dichloromethane or a combination thereof.
In certain embodiments, described additive is trim,ethylchlorosilane, chlorotriethyl silane, tripropyl chlorosilane etc. three
Alkylchlorosilane or a combination thereof, the glyoxylic ester relative to 1 mole, the amount of described edittrialkyl chlorosilane is about 1.0 moles extremely
1.5 mole.
In certain embodiments, the glyoxylic ester relative to 1 mole, the amount of cyclopentadiene is about 1.1 to 2.5 moles,
In certain embodiments, about 1.5 to 2.0 moles.
In certain embodiments, described alcohols solvent is the alcohol of C1-C5, selected from methyl alcohol, ethanol, normal propyl alcohol, isopropanol, just
One or more in butanol or sec-butyl alcohol.
In certain embodiments, the glyoxylic ester that amount is 5 to 10%wt of described palladium carbon.
In certain embodiments, the solute inorganic base in described inorganic base aqueous solution is potassium hydroxide, NaOH or hydrogen
One or more in lithia；In certain embodiments, the concentration of described inorganic base aqueous solution is 1-2mol/L.
In certain embodiments, described glyoxylic ester is glyoxalic acid methylester, glyoxylic acid ethyl ester or glyoxalic acid isopropyl ester.
In certain embodiments, the described unit interval is 30 minutes to 48 hours, and within preferably 1 hour, to 24, more preferably 2 is little
Up to 6 hours.
In certain embodiments, preparation (1R, 3S, 4S)-N-tertbutyloxycarbonyl-2-azabicyclo [2,2,1] heptane-3-carboxylic
The method of acid (Formula V) includes procedure below: 1. glyoxylic acid ethyl ester is dissolved in toluene and is cooled to-10～0 DEG C, addsMolecular sieve and
(R)-phenyl ethylamine stirs 3 hours；2. in-10～0 DEG C, add methyl alcohol and trim,ethylchlorosilane, stir 2 hours, add ring penta 2
Alkene stirs 3 hours；3. in-10～0 DEG C, palladium carbon, normal pressure hydrogenation 3 hours are added；4. add sodium hydrate aqueous solution, be warming up to 50
DEG C stirring 2 hours；5. in 0 DEG C, add Boc acid anhydrides and stir 4 hours to obtain reactant liquor.
Post processing after reaction terminates includes: filtering reacting liquid, removing solid, and filtrate adds 2mol/L hydrochloric acid and is adjusted to acid
Property, concentrate, recrystallization, obtain pure (1R, 3S, 4S)-N-tertbutyloxycarbonyl-2-azabicyclo [2,2,1] heptane-3-carboxylic acid.
Post processing after more specifically reaction terminates includes: solids removed by filtration, filtrate stratification, it is molten that separatory obtains alcohols
Agent, decompression is distilled off solvent, and raffinate adds 2mol/L hydrochloric acid solution regulation pH value and extracts 4 times to 3-4, addition ethyl acetate,
Merging organic phase, colourless sodium sulphate is dried, and filters, and filtrate decompression is distilled to obtain faint yellow solid, added acetone, then at 27-
29 DEG C are stirred 1 to 3 hour, separate out solid, filter, and filter cake acetone washs, and is dried, obtains the pure tertiary fourth of (1R, 3S, 4S)-N-
Oxygen carbonyl-2-azabicyclo [2,2,1] heptane-3-carboxylic acid.
Reaction of the present invention, uses efficient liquid phase (HPLC) to monitor what reaction end, reaction raw materials or period produced
It is considered as reaction when the HPLC peak area of compound shown in each intermediate is less than or equal to 0.5% to terminate, before obtaining end-product
Need not any separation process, after reaction terminates, i.e. add next reaction mass.
The present invention is with glyoxylic acid ethyl ester and (R)-phenyl ethylamine as raw material, and cyclopentadiene and Boc acid anhydrides are main reaction thing,Point
Son sieve is for dehydrating agent, and trim,ethylchlorosilane (TMSCl) and palladium carbon (Pd/C) are catalyst, and need not before obtaining end-product any
Separation process, it is achieved that " one kettle way ".
What the present invention compared with prior art had is clearly advantageous that: operation is simple, and multistep reaction is improved to " one
Pot method ", the production cycle shortens, and isolated and purified simply, only need to can be obtained by the target product of single configuration at recrystallization；Produce
Rate is high, and reaction efficiently, embodies Atom economy, and has abandoned-78 DEG C and wait harsh reaction condition, is conducive to extensive life
Produce.
The present invention uses " one kettle way ", multistep cascade reaction asymmetric syntheses Lei Dipawei key intermediate (1R, 3S,
4S)-N-tertbutyloxycarbonyl-2-azabicyclo [2,2,1] heptane-3-carboxylic acid, obtains the compound of single configuration by making beating, pure
Degree reaches 99.7%, ee > 99%, and total recovery is 40%, reacts and detects through efficient liquid phase HPLC, does not find other three configurations
Isomers (VIII to Ⅹ)；The method post processing is simple, decreases the use of solvent, and experiment condition is gentle, simple to operate, can
Large-scale production,
Detailed description of the invention
In order to make those skilled in the art be more fully understood that technical scheme, disclose some further below non-
The present invention is described in further detail to limit embodiment.
Reagent used in the present invention all can be buied from the market or can be by method system described in the invention
Standby and obtain.
In the present invention, Boc represents that tertbutyloxycarbonyl, g represent gram, and mL represents milliliter.
The preparation of embodiment 1 (1R, 3S, 4S)-N-tertbutyloxycarbonyl-2-azabicyclo [2,2,1] heptane-3-carboxylic acid
Under the conditions of-10 DEG C to 0 DEG C, (R)-phenyl ethylamine (47.5g) is slowly dropped to containing glyoxylic acid ethyl ester (80g),
In the toluene (80g) of molecular sieve (30g), dripping and finish ,-10 DEG C to 0 DEG C are reacted 3 hours, add methyl alcohol (63.3g), the most slowly drip
Adding trim,ethylchlorosilane (85.02g), drip and finish ,-10 DEG C to 0 DEG C are reacted 2 hours, then are slowly added dropwise freshly prepd cyclopentadiene
(50.0g), dripping and finish ,-10 DEG C to 0 DEG C are reacted 3 hours, are subsequently adding 10% palladium carbon (5.3g), are passed through hydrogen, room in reaction bulb
React 3 hours at temperature about 27 DEG C, add sodium hydroxide solution (0.8mL, 2mol/L), drip and finish, room temperature reaction 2 hours, will be anti-
Answer system to be down to-5 DEG C to 0 DEG C, add Boc acid anhydrides (102g), finish, react 4 hours under the conditions of-10 DEG C to 0 DEG C, reaction knot
Bundle, is filtered to remove filter residue, and filtrate adds 2mol/L hydrochloric acid solution pH value and is adjusted to 2-3, and ethyl acetate (300mL × 4) extracts, and merges
Organic phase, is dried, and faint yellow solid (47g) is distilled to obtain in decompression, adds acetone (35mL), stirs 30 minutes, filters, and filter cake is with third
Ketone washs, and obtains (1R, 3S, 4S)-N-tertbutyloxycarbonyl-2-azabicyclo [2,2,1] heptane-3-carboxylic acid, white solid, yield
Being 40%, purity is 97.5%, ee > 99%.1H NMR (400MHz, DMSO) δ 4.13 (s, 0.56H), 4.05 (d, J=
8.6Hz, 0.48H), 3.61 (d, J=4.2Hz, 1H), 2.59 (s, 1H), 1.78 1.45 (m, 5H), 1.39 (s, 4H), 1.32
(s, 5H), 1.24 (t, J=9.3Hz, 1H).
The preparation of embodiment 2 (1R, 3S, 4S)-N-tertbutyloxycarbonyl-2-azabicyclo [2,2,1] heptane-3-carboxylic acid
Under the conditions of-10 DEG C to 0 DEG C, (R)-phenyl ethylamine (47.5g) is slowly dropped to containing glyoxalic acid methylester (80g), nothing
In the dichloromethane (80g) of aqueous sodium persulfate (40g), dripping and finish ,-10 DEG C to 0 DEG C are reacted 3 hours, add methyl alcohol (63.3g), then
Being slowly added dropwise trim,ethylchlorosilane (85.02g), drip and finish ,-10 DEG C to 0 DEG C are reacted 2 hours, then are slowly added dropwise freshly prepd ring penta
Diene (50.0g), drips and finishes, and-10 DEG C to 0 DEG C are reacted 3 hours, are subsequently adding 5% palladium carbon (10.6g), are passed through hydrogen in reaction bulb
Gas, reacts 3 hours at room temperature about 27 DEG C, adds sodium hydroxide solution (0.8L, 2mol/L), drips and finishes, room temperature reaction 2 hours,
Reaction system is down to-5 DEG C to 0 DEG C, adds Boc acid anhydrides (102g), finish, react 4 hours under the conditions of-10 DEG C to 0 DEG C, reaction
Terminating, be filtered to remove filter residue, filtrate adds 2mol/L hydrochloric acid solution pH value and is adjusted to 2-3, and ethyl acetate (300mL × 4) extracts, and closes
And organic phase, it being dried, faint yellow solid (47g) is distilled to obtain in decompression, adds acetone (35mL), stirs 30 minutes, filters, and filter cake is used
Acetone washs, and obtains (1R, 3S, 4S)-N-tertbutyloxycarbonyl-2-azabicyclo [2,2,1] heptane-3-carboxylic acid, white solid, receives
Rate is 37%, and purity is 97.2%, ee > 99%.
The preparation of embodiment 3 (1R, 3S, 4S)-N-tertbutyloxycarbonyl-2-azabicyclo [2,2,1] heptane-3-carboxylic acid
Under the conditions of-10 DEG C to 0 DEG C, (R)-phenyl ethylamine (47.5g) is slowly dropped to containing glyoxylic acid ethyl ester (80g), nothing
In the toluene (80g) of aqueous sodium persulfate (40g), dripping and finish ,-10 DEG C to 0 DEG C are reacted 3 hours, add methyl alcohol (63.3g), the most slowly
Dropping trim,ethylchlorosilane (85.02g), drips and finishes, and-10 DEG C to 0 DEG C are reacted 2 hours, then are slowly added dropwise freshly prepd cyclopentadiene
(50.0g), dripping and finish ,-10 DEG C to 0 DEG C are reacted 3 hours, are subsequently adding 5% palladium carbon (10.6g), are passed through hydrogen, room in reaction bulb
React 3 hours at temperature about 27 DEG C, add potassium hydroxide solution (0.8L, 2mol/L), drip and finish, room temperature reaction 2 hours, will reaction
System is down to-5 DEG C to 0 DEG C, adds Boc acid anhydrides (102g), finishes, and reacts 4 hours under the conditions of-10 DEG C to 0 DEG C, and reaction terminates,
Being filtered to remove filter residue, filtrate adds 2mol/L hydrochloric acid solution pH value and is adjusted to 2-3, and ethyl acetate (300mL × 4) extracts, and is associated with
Machine phase, is dried, and faint yellow solid (47g) is distilled to obtain in decompression, adds acetone (35mL), stirs 30 minutes, filters, filter cake acetone
Washing, obtains (1R, 3S, 4S)-N-tertbutyloxycarbonyl-2-azabicyclo [2,2,1] heptane-3-carboxylic acid, and white solid, yield is
38%, purity is 97.0%, ee > 99%.
The method of the present invention is described by preferred embodiment, related personnel substantially can present invention,
In spirit and scope, method described herein and application it is modified or suitably changes and combine, realize and apply the present invention
Technology.Those skilled in the art can use for reference present disclosure, is suitably modified technological parameter and realizes.Special needs to be pointed out is, institute
Having similar replacement and change apparent to those skilled in the art, they are considered as being included in the present invention
In.
Claims (1)
1. prepare the side of (1R, 3S, 4S)-N-tertbutyloxycarbonyl-2-azabicyclo [2,2,1] heptane-3-carboxylic acid (Formula V)
Method,
Comprising:
1. glyoxylic acid ethyl ester is dissolved in toluene, is cooled to-10～0 DEG C, addMolecular sieve and (R)-phenyl ethylamine stir 3 hours；
2. in-10～0 DEG C, add methyl alcohol and trim,ethylchlorosilane, stir 2 hours, add cyclopentadiene stirring 3 hours, wherein
Glyoxylic ester relative to 1 mole, the amount of described trim,ethylchlorosilane is about 1.0 moles to 1.5 moles, relative to 1 mole
Glyoxylic ester, the amount of described cyclopentadiene is 1.5 to 2.0 moles；
3. in-10～0 DEG C, palladium carbon, normal pressure hydrogenation 3 hours are added；
4. adding sodium hydrate aqueous solution, be warming up to 50 DEG C and stir 2 hours, the concentration of wherein said sodium hydrate aqueous solution is 1-
2mol/L；
5. in 0 DEG C, add Boc acid anhydrides and stir 4 hours, obtain reactant liquor；
6. filtering reacting liquid, removing solid, filtrate stratification, separatory obtains lower floor's alcohols solvent, and decompression is distilled off solvent, residual
Liquid adds 2mol/L hydrochloric acid solution regulation pH value and extracts 4 times to 3-4, addition ethyl acetate, and merging organic phase, anhydrous sodium sulfate is done
Dry, filter, filtrate decompression is distilled to obtain faint yellow solid, is added acetone, then stirs 1 to 3 hour at 27-29 DEG C, separates out solid
Body, filters, and filter cake acetone washs, and is dried, obtains pure (1R, 3S, 4S)-N-tertbutyloxycarbonyl-2-azabicyclo [2,2,1]
Heptane-3-carboxylic acid.
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