CN105085310A - New synthesis method of telaprevir intermediate - Google Patents

New synthesis method of telaprevir intermediate Download PDF

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CN105085310A
CN105085310A CN201410204863.0A CN201410204863A CN105085310A CN 105085310 A CN105085310 A CN 105085310A CN 201410204863 A CN201410204863 A CN 201410204863A CN 105085310 A CN105085310 A CN 105085310A
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李子清
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Chongqing Co Ltd Of Hui Zhi Drug Research Institute
Chongqing Shenghuaxi Pharmaceutical Co Ltd
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Chongqing Co Ltd Of Hui Zhi Drug Research Institute
Chongqing Shenghuaxi Pharmaceutical Co Ltd
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Abstract

The invention discloses a method for preparing (3S)-3-amino-2-hydroxyl-N-cyclopropylhexanamide. The compound can be used as an important intermediate for preparing telaprevir. According to the invention, ethyl butyrylacetate is used as a starting raw material, and through steps of helogenation, substitution, amination, reduction, hydrolysis, deprotection, resolution and the like, (3S)-3-amino-2-hydroxyl-N-cyclopropylhexanamide is prepared. The method provided by the invention has advantages as follows: raw materials are cheap and easily available; reaction yield is high; and costs are high.

Description

A kind of new synthetic method of TVR intermediate
Technical field
The present invention relates to medication chemistry technology, more specifically to a kind of synthesis technique preparing TVR key intermediate.
Background technology
TVR (telaprevir); chemistry (1S by name; 3aR; 6aS)-(2S) valyl-N-of-2-cyclohexyl-N-(pyrazoyl) glycyl-3-methyl-L-[(1S)-1-[(cyclopropyl amino) oxygen base ethanoyl] butyl] octahydro ring penta [c] pyrroles-1-methane amide; it is the novel hepatitis C protease inhibitors of VertexPharms company of U.S. research and development; on May 23rd, 2011, FDA official approval is for La Puwei listing.
Universal Chinese character name: TVR
English popular name: Telaprevir
Trade(brand)name: Incivek
Another name: LY-570310; MP-424; VX-950;
No. CAS: 402957-28-2
Molecular formula: C 36h 53n 7o 6
Molecular weight: 679.8
Structural formula:
English name: (3aR, 6aS)-2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-
carboxamido)acetamido)-3,3-dimethylbutanoyl)-N-((S)-1-(cyclopropyl
amino)-1,2-dioxohexan-3-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide
Formulation and specification: film coating tablet, 375mg/ sheet
Indication: chronic hepatitis C (with Peg-IFN alpha-2b α and ribavirin coupling).
Hepatitis C virus (hepatitisCvirus, HCV) is a kind of Yeast Nucleic Acid (ribonucleicacid, RNA) virus, can cause acute and chronic hepatopathy, and then develop into liver cirrhosis, liver cancer.In global range, HCV infection number is about 200,000,000 people, accounts for nearly 3% of total number of people, and wherein 1 type the infected accounts for and infects 40% ~ 80% of total number of persons.In China, although the attention rate of hepatitis C is far away from hepatitis B, the morbidity of hepatitis C is not low, and HCV infection person about 4,000 ten thousand, and wherein 69% is the infection of l type, and 13% is that 2 types infect, and 18% is that other types infect.The infected of HCV about has 60% ~ 80% can develop into chronic hepatitis, wherein has an appointment again 20% to develop into liver cirrhosis, and have the patient of 2% ~ 5% to die from liver cirrhosis that HCV infection causes and liver cancer.Therefore, HCV infection has become serious global public health problem.
(3S)-3-amino-2-hydroxy-n-cyclopropyl hexanamide is the key intermediate preparing TVR, CAS:402960-19-4(free alkali).The chemical synthesis process reported has following several:
JournalofMedicinalChemistry, 2009,52,7993-8001 and patent WO2007109023 report a kind of synthesis technique (shown in route one) of this intermediate.With 1-hydroxyl-2-hexin for starting raw material, anti-form-1-hydroxyl-2-hexene is obtained through red aluminium reducing, acid is oxidized to twice again through Manganse Dioxide, clorox, acid and cyclopropylamine condensation, double bond obtains the racemic intermediate of target compound through trifluoacetic anhydride epoxidation, azide, catalytic hydrogenation, then obtain target product by Septochol chiral separation, then become hydrochloride purifying, finally free.This route is longer, total recovery only about 2%.
Document OrganicLetters, 2000,2 (18), 2769-2772 and patent WO2007022459, WO2007109023 report a kind of synthesis technique (route two shown in) of this intermediate.With L-norvaline for raw material; Cbz protects amino; then under EDCI and NMM effect with N; O-dimethyl hydroxylamine reacts to obtain acid amides; acid amides obtains aldehyde through lithium aluminium hydride reduction; aldehyde obtains acid amides with cyclopropyl isonitrile reaction under the effect of acetic acid, sloughs protecting group and obtain target product after then alkaline hydrolysis, Pd/C catalytic hydrogen reduction.This method step is relatively simple, and total recovery is about 30%, can suitability for industrialized production, but starting raw material is expensive, and aldehyde radical intermediate is unstable, apt to deteriorate under room temperature preservation, the cyclopropyl isocyanide wherein used has irritating smell and unstable, limits the industrial applications of this technique.
Another route (shown in route three) of patent WO0218369, WO2005058821, WO2005087730, WO2008086053, WO2007005838, WO2009055467 report; L-norvaline is protected with Boc; then with N; O-dimethyl hydroxylamine reacts; then aldehyde is obtained with lithium aluminium hydride reduction; aldehyde obtains acid amides with cyclopropyl isonitrile reaction under the effect of acetic acid, and then alkaline hydrolysis is sloughed protecting group under acidic conditions and obtained target product.This technique comparatively Cbz protects cost to decrease, and same cyclopropyl isocyanide has irritating smell and unstable, and starting raw material is the bottleneck of deindustrialization equally.
Patent WO0218369, WO2007022459, WO2007109023 report with L-norvaline as starting raw material simultaneously; amino through Cbz protection; then with N; O-dimethyl hydroxylamine reacts; then be aldehyde with lithium aluminium hydride reduction, then under Sulfothiorine effect, obtain prussiate with potassium cyanide generation aldehyde radical nucleophilic reaction, prussiate is hydrolyzed to obtain alpha hydroxy acid; alpha hydroxy acid and cyclopropylamine condensation, then hydrogenation deprotection obtains target product (shown in route four).The operation of this method is relatively loaded down with trivial details, and total recovery is about 15%, employs severe poisonous chemicals potassium cyanide.
WO2009114633 reports another kind of new synthetic process (shown in route five).With L-norvaline for starting raw material; change protecting group into benzyl; under benzyl chloride effect, generate the benzyl ester of benzyl protection, then through steps such as hydrolysis, amidation, reduction, cyano group addition, hydrolysis, amidation, fractionation, hydrogenation deprotections, obtain target product.This technique has easy purification of products, chiral purity is a little high, but processing step is complicated, cost height is shortcoming.
In sum, (3S)-3-amino-2-hydroxy-n-cyclopropyl hexanamide is the key intermediate preparing TVR, all there is certain defect in all synthetic methods reported, causes suitability for industrialized production difficulty comparatively large, urgently develops one and be easy to industrialized preparation technology.
Summary of the invention
It is long that the present invention mainly solves existing (3S)-3-amino-2-hydroxy-n-cyclopropyl hexanamide synthetic route, the problems such as production cost is high, intermediate is unstable, reagent toxicity is large.
The object of this invention is to provide the new preparation process of one (3S)-3-amino-2-hydroxy-n-cyclopropyl hexanamide.
Present invention employs following technical proposal, provide the easy synthesis technique of one (3S)-3-amino-2-hydroxy-n-cyclopropyl hexanamide, comprise the steps: that operational path is as follows:
1) take ethyl butyrylacetate as starting raw material, through carbonyl α position, halo obtains compound 2;
2) substitution reaction is carried out to compound 2 and obtain compound 3;
3) compound 3 obtains compound 4 through carbonyl amination reaction;
4) compound 4 reduces to obtain compound 5 under the existence of amino protecting agent;
5) compound 5 obtains compound 6 through amidation, deprotection;
6) compound 6 obtains compound 7 through acidolysis;
7) compound 7 is through splitting to obtain compound 1.
In step 1), ethyl butyrylacetate under the effect of halogenating agent, alpha-position generation halogenating reaction.Solvent be selected from methyl tertiary butyl ether, methylene dichloride, ethylene dichloride, THF, 2-methyltetrahydrofuran, toluene one or more; Preferred solvent is methyl tertiary butyl ether, methylene dichloride; Halogenating agent is selected from SULPHURYL CHLORIDE, N-chlorosuccinimide, N-bromosuccinimide, bromine, trichlorine isocyanic acid; Preferred SULPHURYL CHLORIDE.
Selection process data statistics is as follows.
In step 2) in, under the catalysis of alkali, the halogen atom of compound 2 replaces.Replace reagent and be selected from phenylformic acid, anisic acid, preferred anisic acid; Reaction solvent is selected from DMF, DMA, N-Methyl pyrrolidone, acetonitrile, preferred DMF; Alkali is selected from organic bases triethylamine, diisopropylethylamine, N-methylmorpholine etc., inorganic bases sodium carbonate, salt of wormwood, sodium hydroxide, potassium hydroxide, sodium phosphate, potassiumphosphate etc., preferred salt of wormwood.
Selection process data statistics is as follows.
In step 3), the carbonyl generation amination reaction of compound 3, one or more in solvent selected from methanol, ethanol, 1-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, tetrahydrofuran (THF), preferred solvent is Virahol; Amination reagent is selected from ammonium acetate, ammonium chloride, ammoniacal liquor, ammonium sulfate, ammonium formiate etc., is preferably Ammoniom-Acetate.
Selection process data statistics.
In step 4), compound 4 is under the existence of amino protecting agent, and reduction obtains compound 5; Reductive agent is selected from sodium borohydride, POTASSIUM BOROHYDRIDE, lithium borohydride, sodium cyanoborohydride, preferred sodium borohydride; One or more in solvent selected from methanol, ethanol, 1-propyl alcohol, 2-propyl alcohol, propyl carbinol, isopropylcarbinol, tetrahydrofuran (THF), acetonitrile, preferred solvent is methyl alcohol; Described amido protecting agent is selected from tert-Butyl dicarbonate, isobutylchloroformate, chloroformic acid benzyl ester, is preferably tert-Butyl dicarbonate.Also can hydro-reduction be compound 5 under the catalysis of noble metal catalyst.
Selection process data statistics is as follows.
In step 5), by compound 5 first amination under the effect of cyclopropylamine, then under Luwis acid catalysis, hydrolysis obtains compound 6; In solvent selected from acetone, methyl alcohol, ethanol, THF, dioxane one or more, preferred dioxane; Catalyzer is selected from lithium hydroxide, lithium chloride, calcium chloride, magnesium chloride, preferred lithium hydroxide.
Selection process data statistics is as follows.
In step 6), compound 6 is hydrolyzed under acid catalysis and obtains compound 7; Solvent to be selected from water, methyl alcohol, ethanol, acetone, Virahol one or more, preferred acetone; Acid is selected from hydrochloric acid, sulfuric acid, acidic alcohol, hydrochloric acid acetone, hydrochloric acid Virahol, preferred hydrochloric acid acetone.
Selection process data statistics.
In step 7), compound 7 is split and obtains target compound 1; In solvent selected from acetone, Virahol, tetrahydrofuran (THF) one or more, preferred tetrahydrofuran (THF); Resolving agent is selected from Septochol.
Selection process data statistics.
Compared to the prior art, the present invention has following Advantageous Effects:
1) yield is high, 7 step total recoverys 23%, and compare with the technique of bibliographical information, yield increases substantially;
2) production cost reduces greatly, improves labor productivity;
Get rid of poisonous and harmful reagent in existing method, there is industrial production value.
Embodiment
Further describe technical scheme of the present invention below by embodiment, for the ordinary skill in the art, the following example does not form the restriction to protection scope of the present invention.
embodiment 1:
2-chloro-3-oxo ethyl hexanoate (compound 2):
Ethyl butyrylacetate 15.8g (100mmol) is added in reaction flask, methylene dichloride 200ml, be cooled to 0 ~ 10 DEG C, drip SULPHURYL CHLORIDE 16.2g(120mmol), room temperature is risen to after adding, insulation reaction 4h, TLC monitor reactant and are converted into product (developping agent: ethyl acetate: normal hexane=1:3) completely.React complete, be cooled to about 0 DEG C, add 150mL1MK 3pO 4the aqueous solution, be separated which floor has, water layer add methylene chloride 50ml extract secondary, merge organic layer, be washed to neutrality, 20g anhydrous magnesium sulfate drying, filters siccative, is evaporated to without till slipping out thing, obtain oily matter 19.2g, yield 100%, need not refine and be directly used in the next step.ESI-MS(m/z):193[M+1] +。
The synthesis (compound 3) of 1-oxyethyl group-1,3-dioxo hexane-2-base anisic acid ester:
The oily matter 19.2g (100mmol) of compound 2 is added, dry DMF 50ml, anisic acid 18.2g(120mmol) in reaction flask, salt of wormwood 9.66g(70mmol), be warming up to 55 ~ 60 DEG C of reactions 16 hours, frozen water is cooled to less than 10 DEG C, add isopropyl ether 100ml, water 50ml, be separated organic layer, water layer isopropyl ether extracts secondary, merges organic layer, is washed to neutrality, anhydrous magnesium sulfate drying, suction filtration, is spin-dried for obtain oily matter 27.2g, yield 88%.ESI-MS(m/z):309[M+1] +。
The synthesis (compound 4) of 3-amino-1-ethoxy carbonyl-1-pentenyl anisic acid ester:
Compound 320g (65mmol) is added, Virahol 80mL, Ammoniom-Acetate 20g (260mmol) in reaction flask, finish, be warming up to 50 ~ 55 DEG C of reaction 2h, decompression steams partial solvent, and constantly supplement new Virahol, three times so repeatedly, solvent evaporated, add methylene dichloride 100ml and water 50mL, separatory, water layer methylene dichloride 50mL extracts secondary, merge organic layer, 100mL washes, anhydrous sodium sulfate drying, remove solvent under reduced pressure, obtain solid 18.9g, yield 95%.ESI-MS(m/z):308[M+1] +。
The synthesis (compound 5) of 3-t-butoxycarbonyl amino-1-ethoxy carbonyl-1-pentenyl anisic acid ester:
Compound 420g (65mmol) is added in reaction flask, methyl alcohol 120mL, tert-Butyl dicarbonate 21.2g (97.5mmol), sodium borohydride 3.7g(97.5mmol), holding temperature 20 ~ 25 DEG C, by oxyacetic acid 5.4g(71.5mmol) be dissolved in 22ml methyl alcohol, drip in above-mentioned reaction solution, dropwise rear insulation reaction 12h, decompression steams solvent, add methylene dichloride 100ml and water 50mL, separatory, water layer methylene dichloride 50mL extracts secondary, merge organic layer, 100mL washes, anhydrous sodium sulfate drying, remove solvent under reduced pressure, obtain solid 23.4g, yield 88%.ESI-MS(m/z):410[M+1] +。
The synthesis (compound 6) of 3-t-butoxycarbonyl amino-N-cyclopropyl-2-hydroxyl hexanamide:
Compound 523.4g(57mmol is added) in there-necked flask, dioxane 100ml, cyclopropylamine 9.7g(171mmol), stirring is warming up to 50 DEG C of reactions 20 hours, be cooled to about 30 DEG C, lithium hydroxide 2.74g(114mmol is added) in reaction mixture, continue stirring reaction 4 hours, decompression steams solvent after completion of the reaction, in residue, add 50% acetone 50ml, be warming up to 50 DEG C of stirring and dissolving, be cooled to 0-5 DEG C of growing the grain 2 hours, suction filtration dries to obtain off-white color solid 14g, yield 86%.ESI-MS(m/z):287[M+1] +。
The synthesis (compound 7) of 3-amino-N-cyclopropyl-2-hydroxyl hexanamide hydrochloride:
Compound 614g(49mmol is added) in there-necked flask, acetone 56ml, 6M hydrochloric acid acetone 50ml, stirring is warming up to 50 DEG C of reactions 6 hours, is cooled to about 30 DEG C, adds normal hexane 106ml in reaction mixture, continue stirring and be cooled to about 0 DEG C, insulated and stirred 2 hours, suction filtration dries to obtain the hydrochloride 8.5g of compound 7, yield 78%.ESI-MS(m/z):187[M+1] +。
The synthesis (compound 1) of 3-S-3-amino-N-cyclopropyl-2-hydroxyl hexanamide:
Compound 78.5g(38mmol is added in there-necked flask), methyl tertiary butyl ether 50ml, water 20ml, stir the lower 5%NaOH of dropping solution and regulate pH value to 9-10, layering, water layer methyl tertiary butyl ether extracts, and merges organic layer, is washed to neutrality, drying, suction filtration, is spin-dried for obtain oily matter.
Above-mentioned oily matter is added successively, tetrahydrofuran (THF) 71ml, Septochol 11.2g(28.5mmol) in there-necked flask, be warming up to about 60 DEG C insulated and stirred 2 hours, then be cooled to about 10 DEG C and continue stirring 4 hours, suction filtration dries to obtain off-white color solid 10.3g, yield 47%.ESI-MS(m/z):187[M+1] +。
Namely above-mentioned solid obtains target compound 1 through conventional processing.
embodiment 2:
2-chloro-3-oxo ethyl hexanoate (compound 2):
Ethyl butyrylacetate 15.8g (100mmol) is added in reaction flask, methyl tertiary butyl ether 100ml, be cooled to 0 ~ 10 DEG C, by N-chlorosuccinimide 14.6g(110mmol) be dissolved in 100ml methyl tertiary butyl ether, drip in above-mentioned reaction solution, add rear insulation reaction 6h, TLC monitoring reactant and be converted into product (developping agent: ethyl acetate: normal hexane=1:3) completely.React complete, be cooled to about 0 DEG C, add 70mL1MK 3pO 4the aqueous solution, be separated organic layer, water layer methylate tertbutyl ether 50ml extracts secondary, merges organic layer, be washed to neutrality, 20g anhydrous magnesium sulfate drying, filters siccative, is evaporated to without till slipping out thing, obtain oily matter 18.6g, yield 97%, need not refine and be directly used in the next step.ESI-MS(m/z):193[M+1] +。
The synthesis (compound 3) of 1-oxyethyl group-1,3-dioxo hexane-2-base anisic acid ester:
The oily matter 19.2g (100mmol) of compound 2 is added, dry DMF 50ml, phenylformic acid 14.6g(120mmol) in reaction flask, triethylamine 12.1g(120mmol), be warming up to 55 ~ 60 DEG C of reactions 22 hours, frozen water is cooled to less than 10 DEG C, add isopropyl ether 100ml, water 50ml, be separated organic layer, water layer isopropyl ether extracts secondary, merges organic layer, is washed to neutrality, anhydrous magnesium sulfate drying, suction filtration, is spin-dried for obtain oily matter 25.9g, yield 84%.ESI-MS(m/z):309[M+1] +。
The synthesis (compound 4) of 3-amino-1-ethoxy carbonyl-1-pentenyl anisic acid ester:
Compound 320g (65mmol) is added, propyl carbinol 80mL, ammonium formiate 16.4g (260mmol) in reaction flask, finish, be warming up to 50 ~ 55 reaction 5h, decompression steams solvent bank water, and constantly supplement novel solvent, three times so repeatedly, solvent evaporated, add methylene dichloride 100ml and water 50mL, separatory, water layer methylene dichloride 50mL extracts secondary, merge organic layer, 100mL washes, anhydrous sodium sulfate drying, remove solvent under reduced pressure, obtain solid 18.7g, yield 94%.ESI-MS(m/z):308[M+1] +。
The synthesis (compound 5) of 3-t-butoxycarbonyl amino-1-ethoxy carbonyl-1-pentenyl anisic acid ester:
Compound 420g (65mmol) is added in autoclave, methyl alcohol 120mL, 5%Pd/C2g(moisture 50%) tert-Butyl dicarbonate 21.2g (97.5mmol), nitrogen replacement three times, hydrogen exchange three times, be warming up to 50 DEG C, pressure 0.5MPa, insulation reaction 10h, filtration catalizer, decompression steams solvent, add methylene dichloride 100ml and water 50mL, separatory, water layer methylene dichloride 50mL extracts secondary, merge organic layer, 100mL washes, and anhydrous sodium sulfate drying, removes solvent under reduced pressure, obtain solid 24.2g, yield 91%.ESI-MS(m/z):410[M+1] +。
The synthesis (compound 6) of 3-t-butoxycarbonyl amino-N-cyclopropyl-2-hydroxyl hexanamide:
Compound 520g(49mmol is added in there-necked flask), methyl alcohol 100ml, cyclopropylamine 11.2g(196mmol), stirring is warming up to 50 DEG C of reactions 20 hours, be cooled to about 30 DEG C, in reaction mixture, add lithium hydroxide 2.74g(114mmol), continue stirring reaction 4 hours, decompression steams solvent after completion of the reaction, in residue, add 50% acetone 50ml, be warming up to 50 DEG C of stirring and dissolving, be cooled to 0-5 DEG C of growing the grain 2 hours, suction filtration dries to obtain off-white color solid 12g, yield 86%.ESI-MS(m/z):287[M+1] +。
The synthesis (compound 7) of 3-amino-N-cyclopropyl-2-hydroxyl hexanamide hydrochloride:
Compound 612g(42mmol is added) in there-necked flask, Virahol 48ml, 6M hydrochloric acid Virahol 42ml, stirring is warming up to 50 DEG C of reactions 6 hours, is cooled to about 30 DEG C, adds normal hexane 90ml in reaction mixture, continue stirring and be cooled to about 0 DEG C, insulated and stirred 2 hours, suction filtration dries to obtain the hydrochloride 7g of compound 7, yield 75%.ESI-MS(m/z):187[M+1] +。
The synthesis (compound 1) of 3-S-3-amino-N-cyclopropyl-2-hydroxyl hexanamide:
Compound 77g(31mmol is added in there-necked flask), methyl tertiary butyl ether 50ml, water 20ml, stir the lower 5%NaOH of dropping solution and regulate pH value to 9-10, layering, water layer methyl tertiary butyl ether extracts, and merges organic layer, is washed to neutrality, drying, suction filtration, is spin-dried for obtain oily matter.
Above-mentioned oily matter is added successively, acetone 35ml, Septochol 9.1g(23mmol in there-necked flask), be warming up to about 50 DEG C insulated and stirred 2 hours, be then cooled to about 10 DEG C and continue stirring 4 hours, suction filtration dries to obtain off-white color solid 5.7g, yield 32%.ESI-MS(m/z):187[M+1] +。
Namely above-mentioned solid obtains target compound 1 through conventional processing.

Claims (8)

1. a new synthetic method for (3S)-3-amino-2-hydroxy-n-cyclopropyl hexanamide, it is characterized in that the method comprises the following steps, operational path is as follows:
1) take ethyl butyrylacetate as starting raw material, through carbonyl α position, halo obtains compound 2;
2) on compound 2, halogen atom anisic acid or phenylformic acid replace to obtain compound 3;
3) compound 3 obtains compound 4 through carbonyl amination reaction;
4) compound 4 reduces to obtain compound 5 under the existence of amino protecting agent;
5) compound 5 obtains compound 6 through amidate action, hydrolysis reaction;
6) compound 6 obtains compound 7 through acidolysis deprotection;
7) compound 7 is through splitting to obtain compound 1.
2. according to preparation method according to claim 1, it is characterized in that: in step 1), solvent be selected from methyl tertiary butyl ether, methylene dichloride, ethylene dichloride, THF, 2-methyltetrahydrofuran, toluene one or more, preferred solvent is methyl tertiary butyl ether, methylene dichloride; Halogenating agent is selected from SULPHURYL CHLORIDE, N-chlorosuccinimide, N-bromosuccinimide, bromine, trichlorine isocyanic acid; Preferred SULPHURYL CHLORIDE.
3. according to preparation method according to claim 1, it is characterized in that: in step 2) under the catalysis of alkali, during halogen atom replaces, replace reagent and be selected from, phenylformic acid, anisic acid, preferred anisic acid; Reaction solvent is selected from DMF, DMA, N-Methyl pyrrolidone, acetonitrile, preferred DMF; Alkali is selected from organic bases triethylamine, diisopropylethylamine, N-methylmorpholine etc., inorganic bases sodium carbonate, salt of wormwood, sodium hydroxide, potassium hydroxide, sodium phosphate, potassiumphosphate etc., preferred salt of wormwood.
4. according to preparation method according to claim 1, it is characterized in that: in step 3) carbonyl generation amination reaction, one or more in solvent selected from methanol, ethanol, 1-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, tetrahydrofuran (THF); Preferred solvent is Virahol; Amination reagent is selected from ammonium acetate, ammonium chloride, ammoniacal liquor, ammonium sulfate, ammonium formiate etc., is preferably Ammoniom-Acetate.
5. according to preparation method according to claim 1, it is characterized in that: under the existence of step 4) compound 4 at amino protecting agent, reduction obtains in compound 5, reductive agent is selected from sodium borohydride, POTASSIUM BOROHYDRIDE, lithium borohydride, sodium cyanoborohydride, preferred sodium borohydride; One or more in solvent selected from methanol, ethanol, 1-propyl alcohol, 2-propyl alcohol, propyl carbinol, isopropylcarbinol, tetrahydrofuran (THF), acetonitrile, preferred solvent is methyl alcohol; Described amido protecting agent is selected from tert-Butyl dicarbonate, isobutylchloroformate, chloroformic acid benzyl ester, and be preferably tert-Butyl dicarbonate, can hydro-reduction be also compound 5 under the catalysis of noble metal catalyst.
6. according to preparation method according to claim 1, it is characterized in that: in step 5) by amination under first for compound 5 effect in cyclopropylamine, then hydrolysis obtain in compound 6, in solvent selected from acetone, methyl alcohol, ethanol, THF, dioxane one or more, preferred dioxane; Catalyzer is selected from lithium hydroxide, lithium chloride, calcium chloride, magnesium chloride, preferred lithium hydroxide.
7. according to preparation method according to claim 1, it is characterized in that: in step 6) compound 6 is hydrolyzed under acid catalysis and obtains in compound 7; Solvent to be selected from water, methyl alcohol, ethanol, acetone, Virahol one or more, preferred acetone; Acid is selected from hydrochloric acid, sulfuric acid, acidic alcohol, hydrochloric acid acetone, hydrochloric acid Virahol, preferred hydrochloric acid acetone.
8. according to preparation method according to claim 1, it is characterized in that: in step 7), compound 7 fractionation is obtained in target compound 1; In solvent selected from acetone, Virahol, tetrahydrofuran (THF) one or more, preferred tetrahydrofuran (THF); Resolving agent is selected from Septochol.
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