CN104478791B - (S) preparation method of-5-R-5-azaspiro [2,4] heptane-6-carboxylic acid - Google Patents
(S) preparation method of-5-R-5-azaspiro [2,4] heptane-6-carboxylic acid Download PDFInfo
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- CN104478791B CN104478791B CN201410657803.4A CN201410657803A CN104478791B CN 104478791 B CN104478791 B CN 104478791B CN 201410657803 A CN201410657803 A CN 201410657803A CN 104478791 B CN104478791 B CN 104478791B
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- 0 COC([C@](CC1(CCN)CC1)**)=O Chemical compound COC([C@](CC1(CCN)CC1)**)=O 0.000 description 2
- LQBXUNZLAVQJTR-JTQLQIEISA-N CC(C)(C)OC(N(CCCCCC1)[C@@H]1C(O)=O)=O Chemical compound CC(C)(C)OC(N(CCCCCC1)[C@@H]1C(O)=O)=O LQBXUNZLAVQJTR-JTQLQIEISA-N 0.000 description 1
- DWEHOFAVJQOKSM-VSRNMKFJSA-N C[C@@H](CC[C@@H]1C(C)(C)c2ccccc2)CC1/C=N/CC(OC)=[U] Chemical compound C[C@@H](CC[C@@H]1C(C)(C)c2ccccc2)CC1/C=N/CC(OC)=[U] DWEHOFAVJQOKSM-VSRNMKFJSA-N 0.000 description 1
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The present invention relates to one (S) 5 R 5 azaspiro [2; 4] heptane 6 carboxylic acid; the preparation method of compound shown in formula (III); comprising: compound 5 is dissolved in atent solvent; add alkali to carry out reacting (5); wherein LG is leaving group, and R is amino protecting group.Reaction of the present invention can chirality synthesis, productivity more than 75%, total recovery about 50%.Product efficient liquid phase (HPLC) purity is more than 99%, and ee is more than 98%, it is not necessary to chiral separation, is greatly improved yield, reduces cost.
Description
Technical field
The present invention relates to medicinal chemistry art, be specifically related to the preparation method of (S)-5-R-5-azaspiro [2,4] heptane-6-carboxylic acid.
Background technology
Lei Dipawei, also referred to as GS5885, shown in its structure such as formula (I), Lei Dipawei is hepatitis C virus NS 5 A protein on NS inhibitor.Clinical
The III phase is studied and shows that it has preferable therapeutical effect to various hepatitis C, will be the choice drug of hepatitis C treatment in the coming years
PCT application WO2013184698 and WO2013184702 report the synthetic route of Lei Dipawei, wherein (S)-5-Boc-5-azaspiro [2.4]
Heptane-6-carboxylic acid formula (IIIa) or its potassium salt are the crucial intermediate in route:
PCT application WO2013184702 reports the preparation method of compound shown in formula (IIIa), its course of reaction as shown in Scheme 1:
Route 1
The method uses chiral separation, though title intermediate can be obtained smoothly, but needs to use chiral separation, and splitting step yield only has 33%,
It is substantially reduced total recovery.
Summary of the invention
A kind of method that it is an object of the invention to provide brand-new synthesis (S)-5-R-5-azaspiro [2,4] heptane-6-carboxylic acid, this method High level of stereoselectivity
Selectivity, it is not necessary to chiral separation.
A kind of (S)-5-R-5-azaspiro [2,4] heptane-6-carboxylic acid, the preparation method of compound shown in formula (III),
Comprising: compound 5 is dissolved in atent solvent, adds alkali and react
Wherein LG is leaving group, and R is amino protecting group.
Described leaving group LG can be any pharmaceutically acceptable leaving group such as-OSO2CH3,-OSO2Ph,-OSO2Ph-Me or Br or Cl
Or I；In certain embodiments, LG is Br or I.
Described amino protecting group R is trityl group, tertbutyloxycarbonyl, benzyloxycarbonyl group, 2-xenyl-2-the third oxygen carbonyl, formoxyl or trifluoro second
Acyl group；In certain embodiments, R is tertbutyloxycarbonyl.
In certain embodiments, described alkali is highly basic, weak base or a combination thereof.In further embodiments, described alkali be sodium, potassium, hydrofining,
The alkali of sodium hydride, lithium hydride, calcium hydride or shares activity or a combination thereof.In certain embodiments, described alkali be potassium tert-butoxide, sodium tert-butoxide,
Feldalat NM, sodium isopropylate or shares activity alkali or a combination thereof.In certain embodiments, described alkali is Lithium hydrate, sodium hydroxide, potassium hydroxide
Or a combination thereof.In certain embodiments, described alkali is alkali or a combination thereof of potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate or shares activity.
In certain embodiments, described alkali be sodium, potassium, hydrofining, sodium hydride, lithium hydride, calcium hydride, potassium tert-butoxide, sodium tert-butoxide, Feldalat NM,
Sodium isopropylate, Lithium hydrate, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate or potassium bicarbonate or a combination thereof.
In certain embodiments, described atent solvent is aprotic solvent, the alcoholic solvent of weakly nucleophilic or a combination thereof.
In certain embodiments, described atent solvent be aprotic solvent oxolane, dioxane, methyl tertiary butyl ether(MTBE), dimethoxy, two
Glycol dimethyl ether, triethylene glycol dimethyl ether. or a combination thereof.
In certain embodiments, described atent solvent is aprotic solvent DMF (DMF), dimethyl sulfoxide (DMSO), tetramethyl
Base sulfone, dimethyl sulfone or a combination thereof.
In further embodiments, described atent solvent is aprotic solvent benzene,toluene,xylene or a combination thereof.
In certain embodiments, this reaction can carried out to atent solvent reflux temperature for 0 DEG C.In certain embodiments reaction temperature be 10 DEG C extremely
Atent solvent reflux temperature.Reaction temperature is 50 DEG C in certain embodiments.
One prepares the method for compound (3),
It includes, in aprotic solvent, in the presence of highly basic, compound (2) reacts with compound (2a)
Wherein the definition of LG is identical with compound (5).
In certain embodiments, LG is halogen such as Br or I.
In certain embodiments, described aprotic solvent be N,N-dimethylacetamide (DMAc), DMF (DMF), DMSO,
Tetramethyl sulfone, dimethyl sulfone or a combination thereof.
In certain embodiments, described highly basic is alkali or a combination thereof of sodium, potassium, hydrofining, sodium hydride, lithium hydride, calcium hydride or shares activity.
In certain embodiments, described highly basic is potassium tert-butoxide, sodium tert-butoxide, Feldalat NM, sodium isopropylate or shares activity alkali or a combination thereof.
In certain embodiments, described reaction is carried out about 10 DEG C or less than 10 DEG C；In certain embodiments, reaction is at about 0 DEG C or 0 DEG C
Hereinafter carry out.
On compound 3 after amino protecting group, then hydroxyl is converted into leaving group LG i.e. obtains compound (5).
A kind of (S)-5-Boc-5-azaspiro [2,4] heptane-6-carboxylic acid, the preparation method of compound shown in formula (IIIa),
It comprises the following steps:
1) annulation: be dissolved in atent solvent by compound (5a), adds alkali and carries out
Wherein LG is Cl, Br or I；
2) halogenation: in halogenated hydrocarbon solvent, compound (4) and halide reagent generation halogenation prepare compound (5a)
3) upper amino protecting group reaction: compound (3) reacts prepared compound (4) in a solvent in the presence of a base with Bis(tert-butoxycarbonyl)oxide
Step 1) described in atent solvent is oxolane, dioxane, methyl tertiary butyl ether(MTBE), toluene or dimethylbenzene one or more；Described
Alkali be sodium, potassium, hydrofining, sodium hydride, lithium hydride, calcium hydride, potassium tert-butoxide, sodium tert-butoxide, Feldalat NM, sodium isopropylate or shares activity
Alkali or a combination thereof.
Step 2) described in halogenated hydrocarbon solvent be dichloromethane, chloroform, 1,2-dichloromethane or carbon tetrachloride or a combination thereof；Described halogen
Change reagent is bromine, N-bromo-succinimide (NBS), PBr3, N-chlorosuccinimide, sodium dichloro cyanurate, pyridinium tribromide or hydrogen
Iodic acid or a combination thereof.
Step 3) described in solvent do not specially require, as long as can dissolve to a certain extent reactant and not with reactant generation side reaction,
As in certain embodiments, described solvent is that conventional organic solvent is selected from oxolane, dichloromethane, toluene, dimethylformamide, acetonitrile
Deng.
Present invention also offers noval chemical compound (3) and noval chemical compound (5a)
Wherein LG is Cl, Br or I.
Reaction of the present invention, uses efficient liquid phase (HPLC) to monitor reaction end, when the HPLC purity of raw material is less than or equal to 0.5%
Being considered as reaction to terminate, the response time is generally below 12 hours.
The method of preparation provided by the present invention (S)-5-Boc-5-azaspiro [2,4] heptane-6-carboxylic acid, by building glycine α-C chirality, vertical
Body optionally obtains required configuration, it is not necessary to splitting, total recovery about 50%, product efficient liquid phase (HPLC) purity is more than 99%, and ee% is more than
98%, it is not necessary to chiral separation, it is greatly improved yield, reduces cost.
Detailed description of the invention
In order to make those skilled in the art be more fully understood that technical scheme, disclose some non-limiting embodiments further below to the present invention
It is described in further detail.
Reagent used in the present invention all can be buied from the market or can be prepared by method described in the invention.
In the present invention, mmol represents mM, and h represents hour, and g represents gram, and ml represents milliliter.
Embodiment 1 prepares compound 3
At 0 DEG C, in DMAc (110ml) liquid of NaH (12g, 300mmol) drip compound 2a (22.3g, 105mmol) and 2 (31.5g,
100mmol) DMAc (40ml) liquid.Dripping and finish, reactant liquor stirs 6 hours at such a temperature.After HPLC display compound 2 remains less than 0.5%,
Drip 2N HCl 230ml at a temperature of Gai, drip and finish, be warming up to room temperature, after stirring 4 hours, in reactant liquor, add ethyl acetate 300ml, separatory.
The saturated Na of aqueous phase2CO3Solution adjusts pH to alkalescence.It is added thereto to normal heptane 300ml, separatory again.Aqueous phase 200ml normal heptane extracts, and merges
Organic facies, is dried, concentrating under reduced pressure, obtains 13g grease, yield: 75%, and enantiomer excess rate (ee) is 99.2%.
1H NMR(400MHz,CDCl3): δ 5.10 (s, 2H), 4.09 (m, 1H), 3.68 (s, 3H), 3.54 (d, J=6.8Hz, 1H), 3.23
(d, J=6.8Hz, 1H), 2.03 (dd, J=8.4Hz, 4.8Hz, 1H), 1.92 (d, J=8.4Hz, 4.8Hz, 1H), 0.55 (m,
2H),0.45(m,2H)ppm.
Embodiment 2 prepares compound 4
At 0 DEG C, in DCM (100ml) liquid of compound 3 (13g, 75mmol), add potassium carbonate powder (20.7g, 150mmol), this temperature
After degree stirring 30min, dropping Bis(tert-butoxycarbonyl)oxide (35ml, 150mmol).Drip to finish and be warming up to room temperature, stir 2 hours, HPLC displayization
After compound 3 remains less than 0.5%, adding 100ml water, separate organic facies, organic facies is washed twice with 70ml saturated common salt again, anhydrous sodium sulfate
It is dried, is spin-dried for, obtains light grey solid 19.3g, yield: 94%.
1H NMR(400MHz,CDCl3): δ 8.10 (s, 1H), 4.09 (t, 4.8Hz, 1H), 3.68 (s, 3H), 3.54 (d, J=6.8Hz,
1H), 3.23 (d, J=6.8Hz, 1H), 2.03 (dd, J=8.4Hz, 4.8Hz, 1H), 1.92 (d, J=8.4Hz, 4.8Hz, 1H),
1.42(s,9H),0.55(m,2H),0.45(m,2H)ppm。
The preparation of embodiment 3 compound 5
At 0 DEG C, in the 60ml dichloromethane solution (150ml) of compound 4 (19.1g, 70mmol), it is slowly added dropwise PBr3(37.8g, 140mmol),
Drip and finish, stirred overnight at room temperature.Unsaturated carbonate potassium solution (100ml) is washed, and anhydrous sodium sulfate is dried, and obtains 22.5g faint yellow solid, yield: 97%.
1H NMR(400MHz,CDCl3): δ 8.10 (s, 1H), 4.09 (t, 4.8Hz, 1H), 3.68 (s, 3H), 3.24 (d, J=6.8Hz,
1H), 2.94 (d, J=6.8Hz, 1H), 2.03 (dd, J=8.4Hz, 4.8Hz, 1H), 1.92 (d, J=8.4Hz, 4.8Hz, 1H),
1.42(s,9H),0.55(m,2H),0.45(m,2H)ppm。
The preparation of embodiment 4 compound 6
At 0 DEG C, in toluene (100ml) liquid of compound 5 (20.1g, 60mmol), add potassium tert-butoxide (16g, 120mmol), heat up
To 50 DEG C, should at a temperature of stir 10 hours, HPLC display compound 5 content less than 0.5% after, drip in reactant liquor NaOH aqueous solution (2N,
60ml), stirring 5 hours is continued at a temperature of being somebody's turn to do.200ml ethyl acetate, separatory is added in reactant liquor.Aqueous phase 1N HCl adjusts pH to 5-6,
Again by 200ml ethyl acetate aqueous phase extracted, organic facies anhydrous sodium sulfate is dried, and is spin-dried for obtaining white solid 10.3g.
1H NMR(400MHz,CDCl3): δ 11.03 (s, 1H), 4.10 (t, 4.8Hz, 1H), 3.43 (d, J=6.8Hz, 1H), 3.12 (d,
J=6.8Hz, 1H), 2.03 (dd, J=8.4Hz, 4.8Hz, 1H), 1.92 (d, J=8.4Hz, 4.8Hz, 1H), 1.40 (s, 9H),
0.55(m,2H),0.45(m,2H)ppm。
The preparation of embodiment 5 compound 6
At 0 DEG C, in the tetrahydrochysene fluorine of compound 5 (20.1g, 60mmol) mutters (100ml) liquid, add NaH (10g, 120mmol), rise
Temperature, to 50 DEG C, stirs 10 hours at a temperature of being somebody's turn to do, and after HPLC display compound 5 content is less than 0.5%, drips the aqueous solution of NaOH in reactant liquor
(2N, 60ml), continues stirring 5 hours at a temperature of being somebody's turn to do.200ml ethyl acetate, separatory is added in reactant liquor.Aqueous phase 1N HCl adjusts pH
To 5-6, then by 200ml ethyl acetate aqueous phase extracted, organic facies anhydrous sodium sulfate is dried, and is spin-dried for obtaining white solid 13.3g, yield: 92%.
Embodiment 6
Under room temperature condition, in THF (90ml) liquid of compound 6 (13g, 54mmol), add potassium tert-butoxide powder (6.7g, 60mmol),
It is warming up to 40 DEG C, after stirring 2 hours, slow cooling to 10 DEG C, then stirring 4 hours at such a temperature, there is a large amount of solid to separate out, sucking filtration, dries
Dry, obtain white solid 13g, yield: 86%.
1H NMR(400MHz,CDCl3): δ 4.10 (t, 4.8Hz, 1H), 3.43 (d, J=6.8Hz, 1H), 3.12 (d, J=6.8Hz, 1H),
2.03 (dd, J=8.4Hz, 4.8Hz, 1H), 1.92 (d, J=8.4Hz, 4.8Hz, 1H), 1.40 (s, 9H), 0.55 (m, 2H),
0.45(m,2H)ppm。
The method of the present invention is described by preferred embodiment, and related personnel substantially can be to herein in present invention, spirit and scope
Described methods and applications are modified or suitably change and combine, and realize and apply the technology of the present invention.Those skilled in the art can use for reference herein
Content, is suitably modified technological parameter and realizes.Special needs to be pointed out is, all similar replacements and change be for a person skilled in the art aobvious and
Being clear to, they are considered as being included in the present invention.
Claims (10)
1. (S)-5-R-5-azaspiro [2.4] heptane-6-carboxylic acid preparation method of compound as shown in formula (III),
Comprising: compound (5) is dissolved in atent solvent, adds alkali and react
Wherein LG is leaving group, and R is amino protecting group.
2. the method for claim 1, described leaving group LG is-OSO2CH3,-OSO2Ph,-OSO2Ph-Me or Br or Cl or I；Described
Amino protecting group R is trityl group, tertbutyloxycarbonyl, benzyloxycarbonyl group, 2-xenyl-2-the third oxygen carbonyl, formoxyl or trifluoroacetyl group.
3. the method for claim 1, described alkali is hydrofining, sodium hydride, lithium hydride, calcium hydride or a combination thereof.
4. the method for claim 1, described atent solvent is aprotic solvent oxolane, dioxane, methyl tertiary butyl ether(MTBE), dimethoxy
Ethane, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether., DMF, DMSO, tetramethyl sulfone, dimethyl sulfone or a combination thereof.
5. (S)-5-Boc-5-azaspiro [2.4] heptane-6-carboxylic acid preparation method of compound as shown in formula (IIIa),
It comprises the following steps:
1) annulation: be dissolved in atent solvent by compound (5a), adds alkali and carries out
Wherein LG is Cl, Br or I；
2) halogenation: in halogenated hydrocarbon solvent, compound (4) and halide reagent generation halogenation prepare compound (5a)
3) upper amino protecting group reaction: compound (3) reacts prepared compound (4) in a solvent in the presence of a base with Bis(tert-butoxycarbonyl)oxide
6. method as claimed in claim 5, the atent solvent described in described step 1 is oxolane, dioxane, methyl tertiary butyl ether(MTBE), toluene
Or one or more of dimethylbenzene；Described alkali is hydrofining, sodium hydride, lithium hydride, calcium hydride, potassium tert-butoxide, sodium tert-butoxide, methanol
Sodium, sodium isopropylate or a combination thereof.
7. method as claimed in claim 5, the halogenated hydrocarbon solvent described in described step 2 be dichloromethane, chloroform, 1,2-dichloromethane or four
Chlorination carbon or a combination thereof；Described halide reagent is bromine, N-bromo-succinimide, PBr3, N-chlorosuccinimide, dichloro different
NaDCC, pyridinium tribromide or hydroiodic acid or a combination thereof.
8. method as claimed in claim 5, the solvent described in described step 3 be oxolane, dichloromethane, toluene, dimethylformamide or
Acetonitrile.
9. the method preparing compound (3),
It includes, in aprotic solvent, in the presence of highly basic, compound (2) reacts with compound (2a)
Wherein LG is Cl, Br or I.
10. compound (3) and noval chemical compound (5a)
Wherein LG is Cl, Br or I.
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