CN106554301A - A kind of preparation method of BMS-477118 key intermediate - Google Patents
A kind of preparation method of BMS-477118 key intermediate Download PDFInfo
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Abstract
The present invention relates to a kind of preparation method of (1S, 3S, 5S) -3- (amino carbonyl) -2- azabicyclos [3.1.0] hexane -2- t-butyl formates, which comprises the following steps：1) Boc-L- pyroglutamic acids methyl ester is reduced by lithium triethylborohydride, then obtains (S) -1-N- tertbutyloxycarbonyl -2,3- dihydro -2- pyrrole carboxylic acid ethyl esters with trifluoroacetic anhydride dehydration；2) by (S) -1-N- tertbutyloxycarbonyls -2,3- dihydro -2- pyrrole carboxylic acids ethyl ester hydrolysis in the basic conditions, plus DIPEA (S) -1-N- tertbutyloxycarbonyls -2 are obtained into after salt, 3- dihydro -2- pyrrole carboxylic acid N, N- diisopropylethylamine salt；3) by step 2) obtained by (S) -1-N- tertbutyloxycarbonyl -2,3- dihydro -2- pyrrole carboxylic acid N, N- diisopropylethylamine salt obtains (S) -1-N- tertbutyloxycarbonyl -2,3- dihydro -2- methylpyrrol carboxamides after carrying out amidatioon；4) by (S) -1-N- tertbutyloxycarbonyls -2,3- dihydro -2- methylpyrrol carboxamides obtain the target product (1S of single configuration with the reaction of Chiral Nickel catalyst ciprofloxacin eye drops, 3S, 5S) -3- (amino carbonyl) -2- azabicyclos [3.1.0] hexane -2- t-butyl formates (SM1).
Description
Technical field
The present invention relates to a kind of preparation method of compound intermediate, and in particular to BMS-477118 key intermediate
Preparation method.
Background technology
BMS-477118 is the competitive suppression of a kind of dipeptidyl peptidase-4 (DPP-4) researched and developed by Bristol-Myers Squibb Co.
Preparation, by the deactivation rate that can reduce intestinal insulinotropic hormone, increases its haemoconcentration, so as to dependence on the glucose
Property mode reduce patients with NIDDM on an empty stomach and blood sugar concentration after the meal.On July 31st, 2009 is in the U.S.
City.
Chemical entitled (1S, 3S, 5S) -2- { (2S) -2- amino -2- (3- hydroxyadamantane -1- bases) acetyl of BMS-477118
Base } -2- azabicyclics [3.1.0] hexane -3- formonitrile HCN monohydrates.At present, which is mainly by (1S, 3S, 5S) -3- (amino carbonyls
Base) -2- azabicyclos [3.1.0] hexane -2- t-butyl formates (SM1), 3- hydroxyadamantane-Boc-S- glycine (SM2)
Two key intermediates be initiation material by deprotection reaction, condensation reaction, dehydration, again deprotection it is anti-
Should obtain.BMS-477118 and two key intermediate structure such as reaction equation 1：
Compound (1S, 3S, 5S) -3- (amino carbonyl) -2- azabicyclos [3.1.0] hexane -2- t-butyl formates are (as reacted
SM1 in formula 1) used as the key intermediate of BMS-477118, patent WO2004052850 discloses the intermediate
Preparation method (such as reaction equation 2).First, compound 1 passes through trifluoroacetic acid Jing after lithium triethylborohydride reduction
Acid anhydride dehydration obtains compound 2；Simmons-Smith ciprofloxacin eye drops are carried out by diethyl zinc and diiodomethane further
Reaction obtains compound 3 and compound 4；Compound 3 is obtained through column chromatography for separation；Compound 3 is dissolved in methanol
Compound 5 is obtained with lithium hydrate afterwards；Compound 5 is obtained with ammonia reaction in the presence of butyl chloroformate
Carry out amidatioon and obtain target compound (1S, 3S, 5S) -3- (amino carbonyl) -2- azabicyclos [3.1.0] hexane -2- formic acid
The tert-butyl ester (SM1)
In said synthesis route, compound 4 is reacted by classical Simmons-Smith, i.e., by diethyl
Zinc and diiodomethane effect carry out cyclization and obtain compound 3 and compound 4, and the method is according to document Bioorg.
Med.Chem.22 (2014) report ciprofloxacin eye drops conversion ratios are relatively low (45%), cause target product yield relatively low
(10%-20%) it is, relatively costly；Meanwhile, substantial amounts of waste water and dregs can be produced during industrial production, to environment
Cause greatly pollution[1,2]。
For the problems referred to above, a kind of new preparation (1S, 3S, 5S) -3- (amino carbonyl) -2- azabicyclos are we provided
[3.1.0] hexane -2- t-butyl formate methods, the method reaction condition are gentle, and enantioselectivity is high, can have
The conversion ratio of ciprofloxacin eye drops reaction is improve effect, so as to be effectively improved (1S, 3S, 5S) -3- (amino carbonyl) -2- nitrogen
The yield of miscellaneous bicyclic [3.1.0] hexane -2- t-butyl formates, reduces production cost.And efficiently solve environment
The problem of pollution.
The content of the invention
The concrete synthetic method such as reaction equation 3 of the present invention：
First, Boc-L- pyroglutamic acids methyl ester is reduced by lithium triethylborohydride, then is dehydrated with trifluoroacetic anhydride
Obtain (S) -1-N- tertbutyloxycarbonyl -2,3- dihydro -2- pyrrole carboxylic acid ethyl esters；Then water in the basic conditions
Solution reacts, adds DIPEA that (S) -1-N- tertbutyloxycarbonyl -2,3- dihydro -2- pyrrole carboxylic acid N, N- are obtained into after salt
Diisopropylethylamine salt；Further (S) -1-N- tertbutyloxycarbonyl -2,3- dihydro -2- pyrrolylcarbonyls are obtained after amidatioon
Amine；The target product of single configuration is obtained with commercially available Chiral Nickel catalyst ciprofloxacin eye drops reaction finally
(1S, 3S, 5S) -3- (amino carbonyl) -2- azabicyclos [3.1.0] hexane -2- t-butyl formates (SM1).
Specifically, the invention provides a kind of (1S, 3S, 5S) -3- (amino carbonyl) -2- azabicyclos [3.1.0] hexane
The preparation method of -2- t-butyl formates, which comprises the following steps：
1) Boc-L- pyroglutamic acids methyl ester is reduced by lithium triethylborohydride, then is obtained with trifluoroacetic anhydride dehydration
(S) -1-N- tertbutyloxycarbonyls -2,3- dihydros -2- pyrrole carboxylic acid ethyl esters；
2) hydrolysis by (S) -1-N- tertbutyloxycarbonyl -2,3- dihydro -2- pyrrole carboxylic acids ethyl ester in the basic conditions is anti-
, should add DIPEA that (S) -1-N- tertbutyloxycarbonyl -2,3- dihydro -2- pyrrole carboxylic acid N, N- diisopropyls are obtained into after salt
Ethylamine salt；
3) by step 2) obtained by (S) -1-N- tertbutyloxycarbonyl -2,3- dihydro -2- pyrrole carboxylic acid N, N- diisopropyl second
Amine salt obtains (S) -1-N- tertbutyloxycarbonyl -2,3- dihydro -2- methylpyrrol carboxamides after carrying out amidatioon；
4) (S) -1-N- tertbutyloxycarbonyl -2,3- dihydro -2- methylpyrrol carboxamides are acted in chiral Raney nickel and highly basic
Lower and trifluoroacetic acid tetramethyl ammonium carries out the target product that ciprofloxacin eye drops reaction obtains single configuration
(1S, 3S, 5S) -3- (amino carbonyl) -2- azabicyclos [3.1.0] hexane -2- t-butyl formates (SM1)；
The structure of hand-type Raney nickel therein is as follows
Chiral Raney nickel.
Further, step 4) in chiral Raney nickel in R1 be methyl, ethyl, isopropyl, phenyl
In one kind, preferably methyl or phenyl；R2 be methyl, ethyl, isopropyl, the one kind in phenyl but and with
R1 is different, preferably methyl or phenyl；R3 be triphenylphosphinyl, tri-tert phosphino-, triethyl group phosphino-, three
Methyl phosphino-, thricyclohexyl phosphino-, three cyclopenta phosphino-s, (1- phenylpyrrole bases)-di-t-butyl phosphino-, positive fourth
One kind in base-two (1- adamantyls) phosphino-, preferably triphenylphosphinyl or tri-tert phosphino-；R4 is triphen
Base phosphino-, tri-tert phosphino-, triethyl group phosphino-, trimethyl phosphino-, thricyclohexyl phosphino-, three cyclopenta phosphines
One kind in base, (1- phenylpyrrole bases)-di-t-butyl phosphino-, normal-butyl-two (1- adamantyls) phosphino-, preferably
For triphenylphosphinyl or tri-tert phosphino-, the chiral Raney nickel is more preferably
Further, step 4) reaction temperature is -50-50 DEG C, preferably -10-10 DEG C or is 0-25 DEG C.……
Further, step 4) reaction dissolvent be non-protonic solvent, preferably tetrahydrofuran, dimethyl sulfoxide,
Dimethylformamide, dioxanes, hexamethyl phosphoramide, acetone, ether, acetonitrile, carbon tetrachloride, curing
Carbon, benzene, toluene, hexane, chloroform, ethyl acetate, dichloromethane.
Further, step 4) the used highly basic of reaction selected from n-BuLi, tert-butyl lithium, s-butyl lithium,
Isobutyl group lithium, ethyl-lithium or phenyl lithium, preferably n-BuLi.
Further, step 4) response time is 6-26 hours, preferably 10-20 hours, more preferably 16
Hour.
Further, step 4) reacted under an inert gas, it is preferable that the noble gases be nitrogen,
Argon.
Further, step 4) also include the step of being extracted with solvent after the completion of reaction, the solvent is ten
One alkane, pentane water mixed solution (after pentane and the mixing of isopyknic water, stratification, takes obtained by intermediate layer).
Further, after extraction step also include column chromatography purification step, the column chromatography purification be with normal hexane/
Ethyl acetate (20:1) eluent carries out eluting.
Beneficial effect
1. the synthetic reaction yield is than former synthetic route high income, the conversion ratio of ciprofloxacin eye drops reaction 45% improve to
90%, reduce production cost.
2. reaction selectivity is high, obtains single configuration product.
3. the problem of environmental pollution of diethyl zinc and diiodomethane is avoided.
Specific embodiment
Embodiment 1：(S) preparation of -1-N- tertbutyloxycarbonyls -2,3- dihydros -2- pyrrole methyl formates
In the there-necked flask of 500mL, nitrogen protection adds Boc- pyroglutamic acid methyl ester (21.8g), toluene
(144mL).Stirring is molten clear, and system temperature is cooled to -60 DEG C～-70 DEG C.Maintain the temperature at -60 DEG C～-70 DEG C bars
Under part, the tetrahydrofuran solution (1mol/L, 91.6mL) of lithium triethylborohydride is slowly added dropwise, after dripping
Continue stirring 3 hours.DIPEA, DMAP, TFAA are sequentially added in reactant liquor, control temperature is less than
-60℃.Naturally it is warmed to room temperature, continues stirring 3 hours.0-5 DEG C is cooled to, add water (200mL), stirring 20
Minute.A point liquid is stood, organic faciess use 3mol/L dilute hydrochloric acid (200mL), saturated sodium bicarbonate solution successively
(200mL), saturated common salt aqueous solution is washed successively.Collect organic faciess, the concentrating under reduced pressure under 45 DEG C of temperature conditionss
To dry, grease is obtained.On grease in silicagel column, and make grease even in silica gel, with just oneself
Alkane/ethyl acetate (5:1) eluent carries out eluting, and eluting is finished, and collects to product point terminating substantially, 45
DEG C concentrating under reduced pressure eluent, obtains pale yellow oil, i.e. compound (S) -1-N- tertbutyloxycarbonyl -2,3- dihydro -2- pyrroles
(20.3g, yield is 99.7%) to cough up methyl formate.
Embodiment 2：(S) -1-N- tertbutyloxycarbonyls -2,3- dihydros -2- pyrrole carboxylic acid N, the preparation of N- diisopropylethylamine salt
In 500mL there-necked flasks, (S) -1-N- tertbutyloxycarbonyl -2,3- dihydro -2- pyrrole methyl formates are added
(20.3g), methanol (100mL).Reacting liquid temperature is cooled to into 0-5 DEG C, lithium hydroxide aqueous solution is slowly added dropwise
(0.1g/mL, 70.7mL).After dripping, continuation stirring 2 hours is warmed to room temperature.Reactant liquor is under the conditions of 40 DEG C
After being concentrated into half volume, water (100mL) and methyl tertiary butyl ether(MTBE) (100ml) are added, continue stirring 10 minutes.
A point liquid is stood, water phase is collected, methyl tertiary butyl ether(MTBE) (100mL) is added.Mixed liquor is cooled down into 5-10 DEG C, phosphorus is used
Sour 85%- water (1:4) mixed solution (1:4) adjust pH=2.3.5-10 DEG C is maintained the temperature at, stratification,
Organic faciess are collected, water is mutually extracted with methyl tertiary butyl ether(MTBE) (100mL) again.Merge organic faciess, add DIPEA (16.3g),
Stirring 30 minutes.Under 30 DEG C of temperature conditionss, organic faciess are concentrated to dryness.Obtain target compound (S) -1-N- uncles
Butoxy carbonyl -2, (26.5g, yield is 92%) for 3- dihydro -2- pyrrole carboxylic acids DIPEA salt
Embodiment 3：(S) preparation of -1-N- tertbutyloxycarbonyls -2,3- dihydros -2- methylpyrrol carboxamides
In 500mL there-necked flasks, (S) -1-N- tertbutyloxycarbonyl -2,3- dihydro -2- pyrrole carboxylic acid N, N- are added
Diisopropylethylamine salt (26.5g), tetrahydrofuran (150mL), stir molten clear.System temperature is down to into -20 DEG C,
It is slowly added dropwise into mesyl chloride (13.2g), control temperature is less than 0 DEG C, after dripping, adds DIPEA (36mL).
After stirring 3 hours, control temperature is less than 0 DEG C.Ammonium carbonate (13.0g), room temperature is added to continue to be stirred overnight.
Reaction is filtered, filter cake is rinsed with appropriate tetrahydrofuran, collect filtrate, be concentrated to dryness under the conditions of 40 DEG C.It is dense
Contracting thing is molten clear with dichloromethane (150mL), adds water (150mL) washing, stands a point liquid, collects organic faciess,
Water is mutually extracted twice with dichloromethane (150mL × 2) again.Merge organic faciess, be concentrated to dryness under the conditions of 25 DEG C.
Obtain pale yellow oil (S) -1-N- tertbutyloxycarbonyl -2,3- dihydro -2- methylpyrrol carboxamides (14.8g, yield
90%).
Embodiment 4：Trifluoroacetic acid tetramethyl ammonium (NMe4OTf preparation)
In 2L single-necked flasks, argon protection adds iodomethane (20g), benzene (280mL), water-bath keeping body
Be temperature at 25 DEG C, trimethylamine tetrahydrofuran solution (0.8mol/L, 700mL) is slowly added to into reaction bulb,
After adding, reactant liquor continues stirring 15 hours at ambient temperature, and off-white powder is obtained after concentrating under reduced pressure.Keep away
After light, methanol (600mL), water (140mL) are added, reactant liquor is warming up to into 60 DEG C.Add silver trifluoroacetate
Methanol solution (15.42g silver trifluoroacetates/40mL methanol).Continue stirring 10 minutes.Room temperature is cooled to, is continued
Stirring 15 minutes.Filter, filtrate reduced in volume obtains crude product to dry.The anhydrous isopropyl alcohol that crude product is seethed with excitement is molten
Solution, under -20 DEG C of temperature conditionss, crystallize overnight, is filtered, and filter cake is rinsed with cold isopropanol.It is vacuum dried smart
(9.1g, yield is 66%) for product.
Embodiment 5：Key intermediate (1S, 3S, 5S) -3- (amino carbonyl) -2- azabicyclos [3.1.0] hexane -2- t-butyl formates
(SM1) preparation
In dry there-necked flask, argon protection.Add NMe4OTf (2.2g), chiral Raney nickel
[(Ph3P)((tBu)3P)Ni(CH2(Ph)(Me)CH2)] (0.074g), anhydrous tetrahydro furan (20mL), be cooled to 0
DEG C, add (S) -1-N- tertbutyloxycarbonyl -2,3- dihydros -2- methylpyrrol carboxamides (2.1g).Then protect in argon
Under the conditions of, it is slowly added dropwise into n-BuLi hexane solution (1.6mol/L, 6.6mL), after dripping, rises naturally
Continue stirring 16 hours to room temperature.(10mL, should to add hendecane (1.0mL), pentane water mixed solution
Solution is taken obtained by the 10mL of intermediate layer by stratification after 200mL pentanes and the mixing of 200mL water), stirring 1
After hour, stratification, organic faciess are dried overnight with magnesium sulfate.Filter, after concentration, obtain colorless oil.Oil
On shape thing in silicagel column, and in making grease even into silica gel, with n-hexane/ethyl acetate (20:1) wash
De- liquid carries out eluting, and eluting is finished, and collects to product point terminating substantially, 45 DEG C of concentrating under reduced pressure eluents,
White solid, i.e., (1S, 3S, 5S) -3- (amino carbonyl) -2- azabicyclos [3.1.0] hexane -2- t-butyl formates (2.1g,
Yield is 93%).ee>99%, de>99%. [α]D 2535.1(c 0.72,CH3OH).1H NMR(400
MHz,DMSO-D6):7.49 (s, 2H), 4.72 (dd, J=11.5,3.5Hz, 1H), 3.83 (td, J=6.3,2.4Hz,
1H), 2.47 (ddd, J=12.0,1H), 1.82 (dd, J=13.5,1H), 1.75-1.71 (m, 1H), 1.55 (s,
9H), 1.00 (dd, J=14.4,6.1Hz, 1H), 0.75 (dd, J=14.2,5.5Hz, 1H) ..ESI-MS m/z 227
[M+H]+.
Embodiment 6：Key intermediate (1S, 3S, 5S) -3- (amino carbonyl) -2- azabicyclos [3.1.0] hexane -2- t-butyl formates
(SM1) preparation
In dry there-necked flask, argon protection.Add NMe4OTf (2.2g), chiral Raney nickel
[(Ph3P)2Ni(CH2(Ph)(Me)CH2)] (0.105g), anhydrous tetrahydro furan (20mL), be cooled to 0 DEG C, plus
Enter (S) -1-N- tertbutyloxycarbonyls -2,3- dihydros -2- methylpyrrol carboxamides (2.1g).Then under argon protective condition,
Be slowly added dropwise into n-BuLi hexane solution (1.6mol/L, 6.6mL), after dripping, be warmed to room temperature naturally after
Continuous stirring 16 hours.Add hendecane (1.0mL), (10mL, the solution is by 200mL for pentane water mixed solution
Stratification after pentane and the mixing of 200mL water, takes obtained by the 10mL of intermediate layer), after stirring 1 hour, stand
Layering, organic faciess are dried overnight with magnesium sulfate.Filter, after concentration, obtain colorless oil.In silica gel on grease
In post, and in making grease even into silica gel, with n-hexane/ethyl acetate (20:1) eluent carries out eluting,
Eluting is finished, and is collected to product point terminating substantially, 45 DEG C of concentrating under reduced pressure eluents, obtains white solid, i.e.,
(2.0g, yield is 86%) for (1S, 3S, 5S) -3- (amino carbonyl) -2- azabicyclos [3.1.0] hexane -2- t-butyl formates.
Embodiment 7：Key intermediate (1S, 3S, 5S) -3- (amino carbonyl) -2- azabicyclos [3.1.0] hexane -2- t-butyl formates
(SM1) preparation
In dry there-necked flask, argon protection.Add NMe4OTf (2.2g), chiral Raney nickel
[((tBu)3)2Ni(CH2(Ph)(Me)CH2)] (0.515g), anhydrous tetrahydro furan (20mL), be cooled to 0 DEG C, plus
Enter (S) -1-N- tertbutyloxycarbonyls -2,3- dihydros -2- methylpyrrol carboxamides (2.1g).Then under argon protective condition,
Be slowly added dropwise into n-BuLi hexane solution (1.6mol/L, 6.6mL), after dripping, be warmed to room temperature naturally after
Continuous stirring 16 hours.Add hendecane (1.0mL), (10mL, the solution is by 200mL for pentane water mixed solution
Stratification after pentane and the mixing of 200mL water, takes obtained by the 10mL of intermediate layer), after stirring 1 hour, stand
Layering, organic faciess are dried overnight with magnesium sulfate.Filter, after concentration, obtain colorless oil.In silica gel on grease
In post, and in making grease even into silica gel, with n-hexane/ethyl acetate (20:1) eluent carries out eluting,
Eluting is finished, and is collected to product point terminating substantially, 45 DEG C of concentrating under reduced pressure eluents, obtains white solid, i.e.,
(1.7g, yield is 75%) for (1S, 3S, 5S) -3- (amino carbonyl) -2- azabicyclos [3.1.0] hexane -2- t-butyl formates.
Embodiment 8：Key intermediate (1S, 3S, 5S) -3- (amino carbonyl) -2- azabicyclos [3.1.0] hexane -2- t-butyl formates
(SM1) preparation
In dry there-necked flask, argon protection.Add NMe4OTf (2.2g), chiral Raney nickel
[(Ph3P)((tBu)3P)Ni(CH2(Ph)(Me)CH2)] (0.074g), anhydrous tetrahydro furan (20mL), be cooled to 0
DEG C, add (S) -1-N- tertbutyloxycarbonyl -2,3- dihydros -2- methylpyrrol carboxamides (2.1g).Then protect in argon
Under the conditions of, it is slowly added dropwise into tert-butyl lithium hexane solution (1.0mol/L, 11.0mL), after dripping, it is natural
It is warmed to room temperature continuation stirring 16 hours.Add hendecane (1.0mL), pentane water mixed solution (10mL,
The solution is taken obtained by the 10mL of intermediate layer by stratification after 200mL pentanes and the mixing of 200mL water), stir
After mixing 1 hour, stratification, organic faciess are dried overnight with magnesium sulfate.Filter, after concentration, obtain colorless oil.
On grease in silicagel column, and in making grease even into silica gel, with n-hexane/ethyl acetate (20:1)
Eluent carries out eluting, and eluting is finished, and collects to product point terminating substantially, 45 DEG C of concentrating under reduced pressure eluents,
Obtain white solid, i.e. (1S, 3S, 5S) -3- (amino carbonyl) -2- azabicyclos [3.1.0] hexane -2- t-butyl formates (1.8
G, yield is 80%).
Embodiment 9：Key intermediate (1S, 3S, 5S) -3- (amino carbonyl) -2- azabicyclos [3.1.0] hexane -2- t-butyl formates
(SM1) preparation
In dry there-necked flask, argon protection.Add NMe4OTf (2.2g), chiral Raney nickel
[(Ph3P)((tBu)3P)Ni(CH2(Ph)(Me)CH2)] (0.074g), anhydrous tetrahydro furan (20mL), be cooled to 0
DEG C, add (S) -1-N- tertbutyloxycarbonyl -2,3- dihydros -2- methylpyrrol carboxamides (2.1g).Then in argon ceiling
Under part, it is slowly added dropwise into phenyl lithium tetrahydrofuran solution (1.7mol/L, 6.5mL), after dripping, rises to naturally
Room temperature continues stirring 16 hours.Add hendecane (1.0mL), (10mL, this is molten for pentane water mixed solution
Liquid is taken obtained by the 10mL of intermediate layer by stratification after 200mL pentanes and the mixing of 200mL water), stirring 1
After hour, stratification, organic faciess are dried overnight with magnesium sulfate.Filter, after concentration, obtain colorless oil.Oil
On shape thing in silicagel column, and in making grease even into silica gel, with n-hexane/ethyl acetate (20:1) wash
De- liquid carries out eluting, and eluting is finished, and collects to product point terminating substantially, 45 DEG C of concentrating under reduced pressure eluents,
Obtain white solid, i.e. (1S, 3S, 5S) -3- (amino carbonyl) -2- azabicyclos [3.1.0] hexane -2- t-butyl formates (1.3
G, yield is 58%).
List of references：
[1] M, Pasco, N.Gilbon, T.Mejuch, Organometallics 2013,32,942-950
[2]“Cyclopropanation mediated by zinc Organometallics”:A.B.Cha‐rette in The
Chemistry of Organzinc
Compounds,Vol.1(Eds.:Z.Rappoport,I.Marek),Wiley,Chichester,2006,pp.237‐286.
Abbreviation and English implication in the present invention
| Abbreviation and English | Implication |
| DIPEA | DIPEA |
| DMAP | DMAP |
| TFAA | Trifluoroacetic anhydride |
| DCM | Dichloromethane |
| DME | Glycol dimethyl ether |
| LiEt3BH, | Lithium triethylborohydride |
| MsCl | Mesyl chloride |
| NMM | N-methylmorpholine |
| THF | Tetrahydrofuran |
| ClCOOBu | Solid acid n-butyl chloroacete |
| ZnEt2 | Diethyl zinc |
| n-BuLi | N-BuLi |
| NMe4OTf | Trifluoroacetic acid tetramethyl ammonium |
Claims (6)
1. a kind of preparation side of (1S, 3S, 5S) -3- (amino carbonyl) -2- azabicyclos [3.1.0] hexane -2- t-butyl formates
Method, which comprises the following steps：
1) Boc-L- pyroglutamic acids methyl ester is reduced by lithium triethylborohydride, then is obtained with trifluoroacetic anhydride dehydration
(S) -1-N- tertbutyloxycarbonyls -2,3- dihydros -2- pyrrole carboxylic acid ethyl esters；
2) hydrolysis by (S) -1-N- tertbutyloxycarbonyl -2,3- dihydro -2- pyrrole carboxylic acids ethyl ester in the basic conditions is anti-
, should add DIPEA that (S) -1-N- tertbutyloxycarbonyl -2,3- dihydro -2- pyrrole carboxylic acid N, N- diisopropyls are obtained into after salt
Ethylamine salt；
3) by step 2) obtained by (S) -1-N- tertbutyloxycarbonyl -2,3- dihydro -2- pyrrole carboxylic acid N, N- diisopropyl second
Amine salt obtains (S) -1-N- tertbutyloxycarbonyl -2,3- dihydro -2- methylpyrrol carboxamides after carrying out amidatioon；
4) (S) -1-N- tertbutyloxycarbonyl -2,3- dihydro -2- methylpyrrol carboxamides are acted in chiral Raney nickel and highly basic
Lower and trifluoroacetic acid tetramethyl ammonium carries out the target product that ciprofloxacin eye drops reaction obtains single configuration
(1S, 3S, 5S) -3- (amino carbonyl) -2- azabicyclos [3.1.0] hexane -2- t-butyl formates (SM1)；
The structure of hand-type Raney nickel therein is as follows
Chiral Raney nickel.
2. the preparation method of preparation according to claim 1, wherein, step 4) in Chiral Nickel catalysis
R in agent1For the one kind in methyl, ethyl, isopropyl, phenyl, preferably methyl or phenyl；R2For methyl,
One kind and and R in ethyl, isopropyl, phenyl1Difference, preferably methyl or phenyl；R3For triphenylphosphinyl,
Tri-tert phosphino-, triethyl group phosphino-, trimethyl phosphino-, thricyclohexyl phosphino-, three cyclopenta phosphino-s, (1- benzene
Base pyrrole radicals)-di-t-butyl phosphino-, the one kind in normal-butyl-two (1- adamantyls) phosphino-, preferably triphenyl
Phosphino- or tri-tert phosphino-；R4For triphenylphosphinyl, tri-tert phosphino-, triethyl group phosphino-, trimethyl-phosphine
Base, thricyclohexyl phosphino-, three cyclopenta phosphino-s, (1- phenylpyrrole bases)-di-t-butyl phosphino- ,-two (1- of normal-butyl
Adamantyl) one kind in phosphino-, preferably triphenylphosphinyl or tri-tert phosphino-.
3. the preparation method of the preparation according to any one of claim 1-2, wherein, step 4) reaction temperature
Spend for -50-50 DEG C, preferably -10-10 DEG C, more preferably 0 DEG C.
4. the preparation method of the preparation according to any one of claim 1-3, wherein, step 4) reaction is molten
Agent is non-protonic solvent, preferably tetrahydrofuran, dimethyl sulfoxide, dimethylformamide, dioxanes, six
Methyl phosphamide, acetone, ether, acetonitrile, carbon tetrachloride, Carbon bisulfide, benzene, toluene, hexane, chloroform,
Ethyl acetate, dichloromethane or its combination.
5. the preparation method of the preparation according to any one of claim 1-4, wherein, step 4) reaction institute
The alkali for using is selected from n-BuLi, tert-butyl lithium, s-butyl lithium, isobutyl group lithium, ethyl-lithium or phenyl lithium, excellent
Elect n-BuLi as.
6. the preparation method of the preparation according to any one of claim 1-5, wherein, step 4) reaction when
Between be 6-26 hours, preferably 10-20 hours, more preferably 16 hours.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109761876A (en) * | 2019-01-17 | 2019-05-17 | 深圳市第二人民医院 | The preparation method for treating the drug saxagliptin of diabetes |
| CN111138341A (en) * | 2020-01-13 | 2020-05-12 | 天津民祥生物医药股份有限公司 | Preparation method of saxagliptin |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004052850A2 (en) * | 2002-12-09 | 2004-06-24 | Bristol-Myers Squibb Company | Methods and compounds producing dipeptidyl peptidase iv inhibitors and intermediates thereof |
| CN103215320A (en) * | 2004-04-14 | 2013-07-24 | 布里斯托尔-迈尔斯.斯奎布公司 | Process for preparing dipeptidyl IV inhibitors and intermediates therefor |
-
2015
- 2015-09-30 CN CN201510641004.2A patent/CN106554301B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004052850A2 (en) * | 2002-12-09 | 2004-06-24 | Bristol-Myers Squibb Company | Methods and compounds producing dipeptidyl peptidase iv inhibitors and intermediates thereof |
| CN103215320A (en) * | 2004-04-14 | 2013-07-24 | 布里斯托尔-迈尔斯.斯奎布公司 | Process for preparing dipeptidyl IV inhibitors and intermediates therefor |
Non-Patent Citations (3)
| Title |
|---|
| JIZHE DONG等: "Synthesis and biological evaluation of all eight stereoisomers of DPP-IV inhibitor saxagliptin", 《BIOORGANIC & MEDICINAL CHEMISTRY》 * |
| STEPHANE SENGMANY等: "Cyclopropane formation by nickel-catalyzed electroreductive coupling of activated olefins and unactivated gem-dibromo compounds", 《TETRAHEDRON》 * |
| 朱高峰等: "(1S,3S,5S)-2-氮杂二环[3.1.0]己烷-3-甲酰胺甲烷磺酸盐的合成", 《广州化工》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109761876A (en) * | 2019-01-17 | 2019-05-17 | 深圳市第二人民医院 | The preparation method for treating the drug saxagliptin of diabetes |
| CN109761876B (en) * | 2019-01-17 | 2021-11-16 | 深圳市第二人民医院 | Preparation method of medicine saxagliptin for treating diabetes |
| CN111138341A (en) * | 2020-01-13 | 2020-05-12 | 天津民祥生物医药股份有限公司 | Preparation method of saxagliptin |
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