CN109988126A - A kind of 3- amino-oxetane derivative and its preparation method and application - Google Patents
A kind of 3- amino-oxetane derivative and its preparation method and application Download PDFInfo
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Abstract
The invention discloses a kind of 3- amino-oxetane derivatives and its preparation method and application, using compound II and compound III as raw material, under the conditions of existing for the alkali 1, compound IV is prepared, compound IV is under reducing agent effect, compound V is prepared, for compound V under the action of 30%~98% sulfuric acid or alkali and cyclization reagent, reaction generates compound VI:3- amino-oxetane derivative；Reduction reaction occurs under the conditions of compound VI is existing for hydrogen source, hydrogen source/catalyst or hydrogen source/deprotection reagent, obtains compound I.
Description
Technical field
The invention belongs to pharmaceutical synthesis fields, and in particular to a kind of 3- amino-oxetane derivative and its preparation side
Method and application.
Background technique
3- amino-oxetane derivative is a kind of very important, extensive application pharmaceutical intermediate, such as
The MGLUR1 receptor antagonist of Astellas pharmacy group company exploitation, non-opioid analgesic agents all include 3- amino-oxa- ring
Butane fragments molecules.
The PRMT5 receptor antagonist of GlaxoSmithKline PLC company exploitation similarly uses 3- amino-oxetanes segment:
It is conventionally synthesized 3- amino-oxetanes method, generally there are following three kinds:
1. passing through sulphonic acid ester from corresponding hydroxyl, then react to obtain nitrine with Sodium azide, be obtained by reduction；
2. being made into oxime from corresponding ketone and hydroxylamine hydrochloride, obtained using reduction；
3. being obtained from corresponding carboxylic acid by Ku Ertisi rearrangement reaction.
All there is raw material and be not readily available in three of the above approach, expensive, synthetic route is long, uneconomic disadvantage.
Summary of the invention
The technical problem to be solved in the present invention is to provide a kind of 3- amino-oxetane derivative and preparation method thereof,
And its application in pharmaceutical chemistry.
In order to solve the above technical problems, The technical solution adopted by the invention is as follows:
A kind of 3- amino-oxetane derivative of structural formula VI:
Wherein: R and R1Separately selected from C1~C6 linear or branched alkyl group, C3~C6 naphthenic base or Heterocyclylalkyl,
Benzyl, α-methylbenzyl, to methoxy-benzyl, 2,4- dimethoxy-benzyl, benzhydryl or R and R1Collectively constitute adjacent benzene two
Formoxyl；
R3And R4Separately it is selected from H, C1~C6 linear or branched alkyl group, phenyl, substituted-phenyl or R3And R4Jointly
The cycloalkanes and heterocycle alkane of C4~C6 are formed, wherein atom adjacent with spiro-atom in heterocycle alkane is C；Wherein, R3And R4It does not select simultaneously
From H.
Said derivative can be with are as follows:
A kind of 3- amino-oxetane derivative preparation method of structural formula VI:
Using compound V as raw material
Under the action of sulfuric acid or alkali/cyclization reagent, reaction generates compound VI,
Wherein: R and R1Separately selected from C1~C6 linear or branched alkyl group, C3~C6 naphthenic base or Heterocyclylalkyl,
Benzyl, α-methylbenzyl, to methoxy-benzyl, 2,4- dimethoxy-benzyl, benzhydryl or R and R1Collectively constitute adjacent benzene two
Formoxyl；
R3And R4Separately it is selected from H, C1~C6 linear or branched alkyl group, phenyl, substituted-phenyl or R3And R4Jointly
The cycloalkanes and heterocycle alkane of C4~C6 are formed, wherein atom adjacent with spiro-atom in Heterocyclylalkyl is C；Wherein, R3And R4When different
Selected from H；
Above-mentioned cyclization reagent is selected from triphenylphosphine, diethyl carbonate, paratoluensulfonyl chloride or mesyl chloride.
When using 30%~98% sulfuric acid, solvent is methylene chloride, 1,2- dichloroethanes, chloroform or carbon tetrachloride；
Reaction temperature is 0~60 DEG C；Compound V: the molar ratio of sulfuric acid is 1: 0.01~1: 1.
When cyclization reagent is triphenylphosphine, alkali is selected from diisopropyl azodiformate or diethyl azodiformate；
Solvent is tetrahydrofuran, benzene,toluene,xylene, ether, dioxane, glycol dimethyl ether, diethylene glycol dimethyl ether, positive heptan
Alkane, n-hexane, hexamethylene, pentane or pentamethylene；Reaction temperature is -20~50 DEG C；Compound V: triphenylphosphine: alkali rubs
You are than being 1: 1~2: 1~2.
When cyclization reagent is diethyl carbonate, alkali is potassium hydroxide；Reaction temperature is 100~200 DEG C；In reaction system
Ethyl alcohol can also be added, compound V: potassium hydroxide: the molar ratio of ethyl alcohol is 1: 0.01~0.1: 0~0.5；Diethyl carbonate is
Quantity of solvent.
When cyclization reagent is paratoluensulfonyl chloride or mesyl chloride, alkali is selected from potassium tert-butoxide or n-BuLi；Solvent
Selected from tetrahydrofuran, benzene,toluene,xylene, ether, dioxane, glycol dimethyl ether, diethylene glycol dimethyl ether, normal heptane,
N-hexane, hexamethylene, pentane or pentamethylene；Temperature is selected from -80~50 DEG C；Compound V: cyclization reagent: the molar ratio of alkali
It is 1: 1~1.5: 2~5.
Further, compound V can be prepared by the following method to obtain:
Using compound IV as raw material
Under reducing agent effect, compound V is prepared,
Above-mentioned reducing agent is selected from Lithium Aluminium Hydride, sodium borohydride, lithium borohydride, potassium borohydride/lithium chloride, red aluminum, hydroboration
Sodium/aluminium chloride, sodium borohydride/zinc chloride, aluminum hydride, lithium aluminium hydride reduction/boron trifluoride ether, tri-tert lithium aluminium hydride reduction or two
Isobutylaluminiumhydride；Solvent is selected from tetrahydrofuran, benzene,toluene,xylene, ether, dioxane, glycol dimethyl ether, diethyl
Glycol dimethyl ether, normal heptane, n-hexane, hexamethylene, pentane or pentamethylene；Reaction temperature is -80~60 DEG C；Compound IV
: the molar ratio of reducing agent is 1: 0.5~1: 5.
Further, compound IV can be prepared by the following method to obtain:
Using compound II and compound III as raw material
Under the conditions of existing for the alkali 1, compound IV is prepared,
Above-mentioned alkali 1 is selected from lithium diisopropylamine, sodium hexamethyldisilazide, hexamethyldisilazide lithium, pregnancy
Two silicon substrate amido potassium of base or 2,2,6,6- tetramethyl piperidine lithium salts；Solvent is selected from tetrahydrofuran, benzene,toluene,xylene, second
Ether, dioxane, glycol dimethyl ether, diethylene glycol dimethyl ether, normal heptane, n-hexane, hexamethylene, pentane or ring penta
Alkane；Reaction temperature is -80~10 DEG C；Compound II: compound III: the molar ratio of alkali 1 is 1: 1~3: 1~3.
The present invention also provides the preparation methods of compound I a kind of:
Using compound VI as raw material
Reduction reaction occurs under the conditions of existing for hydrogen source, hydrogen source/catalyst or hydrogen source/deprotection reagent, is changed
Object I-1 or I-2 are closed,
Wherein: R is selected from C1~C6 linear or branched alkyl group, C3~C6 naphthenic base or Heterocyclylalkyl, benzyl, Alpha-Methyl benzyl
Base, to methoxy-benzyl, 2,4- dimethoxy-benzyl or benzhydryl；
R1Selected from benzyl, α-methylbenzyl, to methoxy-benzyl, 2,4- dimethoxy-benzyl, benzhydryl or R and R1
Collectively constitute phthalyl；
R3And R4Separately it is selected from H, C1~C6 linear or branched alkyl group, phenyl, substituted-phenyl or R3And R4Jointly
The cycloalkanes and heterocycle alkane of C4~C6 are formed, wherein atom adjacent with spiro-atom in heterocycle alkane is C；Wherein, R3And R4It does not select simultaneously
From H.
Work as R1Selected from benzyl, α-methylbenzyl, to methoxy-benzyl, 2,4- dimethoxy-benzyl or benzhydryl when,
The hydrogen source is hydrogen, hydrazine, formic acid or ammonium formate；The catalyst is palladium carbon, hydroxide palladium carbon or palladium chloride；Temperature is
0~60 DEG C；Compound VI: the mass ratio of catalyst is 1: 0.01~1: 1.
As R and R1When collectively constituting phthalyl, the hydrogen source is hydrazine hydrate or methylamine solution；Temperature is -10
~50 DEG C；Hydrogen source is quantity of solvent.
Work as R1When selected to methoxy-benzyl or 2,4- dimethoxy-benzyl:
Deprotection reagent is p-methyl benzenesulfonic acid, hydrochloric acid, sulfuric acid, nitric acid, trifluoroacetic acid, formic acid, acetic acid or phosphoric acid；Hydrogen source
For the water being added during solvent or post-reaction treatment；Solvent is methanol, ethyl alcohol, isopropanol, methylene chloride, bis- chloroethene of 1,2-
Alkane, chloroform, carbon tetrachloride, benzene, toluene, tetrahydrofuran, ether, dioxane, dimethylbenzene, glycol dimethyl ether, diethylene glycol
Dimethyl ether or acetonitrile；
Deprotecting reagent is the chloro- 5,6- dicyanoquinone of 2,3- bis-, ammonium ceric nitrate or means of samarium iodide；Hydrogen source be solvent or
The water being added during post-reaction treatment；Solvent is methylene chloride, 1,2- dichloroethanes, chloroform, carbon tetrachloride, benzene, toluene, four
Hydrogen furans, ether, dioxane, dimethylbenzene, glycol dimethyl ether, diethylene glycol dimethyl ether, acetonitrile or water；Temperature is -10
~60 DEG C；Compound VI: the molar ratio for deprotecting reagent is 1: 1~1: 10.
Beneficial effect
3- amino-oxetanes is the pharmaceutical intermediate of extensive application, and the present invention provides a series of 3- ammonia
Base-oxetane derivative can provide more alternatives for new drug development, to improve the success rate of new medicament screen,
Preparation method, total three-step reaction, step is short, process stabilizing, and easy to operate, raw material market is in liberal supply, and total recovery is reachable
29.1%.
The abbreviation for the reaction reagent being related in specification is as follows:
MsCl: methylsufonyl chloride；
TsCl: paratoluensulfonyl chloride；
MTBE: methyl tertiary butyl ether(MTBE)；
EA: ethyl acetate；
THF: tetrahydrofuran；
LDA: lithium diisopropylamine；
NaHMDS: sodium hexamethyldisilazide；
LiHMDS: lithium hexamethyldisilazide；
KHMDS: potassium hexamethyldisilazide；
DIBAL-H: diisobutyl aluminium hydride；
The chloro- 5,6- dicyanoquinone of DDQ:2,3- bis-；
DEAD: diethyl azodiformate；
DIAD: diisopropyl azodiformate.
Specific embodiment
According to following embodiments, the present invention may be better understood.However, as it will be easily appreciated by one skilled in the art that real
It applies content described in example and is merely to illustrate the present invention, without sheet described in detail in claims should will not be limited
Invention.
Embodiment 1
The preparation of compound IV-1:
Diisopropylamine (56.0g, 0.55mol, 1.25eq.) is dissolved in THF, is cooled to -78 DEG C, n-BuLi is added dropwise
(212mL, 0.53mol, 1.2eq.) after being added dropwise, reacts 30min, the LDA solution for later use that will be prepared.
Compound II-1 (125.0g, 0.44mol, 1.0eq.) is dissolved in THF (2L), -78 DEG C of dropwise additions are above-mentioned homemade
LDA solution after being added dropwise, reacts 30min, is added dropwise acetone (31.0g, 0.53mol, 1.2eq.), reacts 2h, pour into saturation chlorine
Change in ammonium salt solution (1L), be layered liquid separation, the dry concentration of organic phase is added normal heptane (100mL), stirring has solid analysis under ice-water bath
Out, filter, solid it is dry white solid 81.0g, yield: 54.8%.1H-NMR (400MHz, CDCl3)δ(ppm)7.25-
7.41 (m, 10H), 4.30-4.44 (m, 2H), 4.23-4.28 (m, 2H), 3.41-3.47 (m, 3H), 3.15 (s, 1H), 1.46-
1.48 (m, 3H), 1.25 (s, 3H), 1.14 (s, 3H).
The preparation of compound V-1:
Lithium Aluminium Hydride (8.4g, 0.22mol, 1.0eq.) is dissolved in THF (600mL), control temperature is lower than 10 DEG C, is added dropwise
Compound IV-1 (75.0g, 0.22mol, 1.0eq.), reacts 20min after addition, TLC prosecution raw material fully reacting is added dropwise
Water (8.4g), 15% sodium hydroxide (8.4g) and water (8.4g), filtering, filter cake are washed (100mL × 2) with tetrahydrofuran, are concentrated,
Normal heptane (200mL) mashing is added, solid is precipitated, filters to obtain white solid 42.0g, yield: 64.6%.1H-NMR (400MHz,
CDCl3) δ (ppm) 7.26-7.35 (m, 10H), 4.00-4.06 (m, 4H), 3.77-3.81 (d, 2H), 3.01 (s, 1H), 2.79-
2.82 (m, 1H), 2.20-2.22 (m, 1H), 1.26 (s, 3H), 1.21 (s, 3H).
The preparation of compound VI-1:
Compound V-1 (46g, 0.153mol, 1.00eq.) is dissolved in tetrahydrofuran (1L), ice-water bath, the tert-butyl alcohol is added
Potassium (34.5g, 0.30mol, 2.0eq.) is added portionwise TsCl (30g, 0.153mol, 1.0eq.) in 28 DEG C of reaction 1h, water is added
(500mL) is layered liquid separation, and water phase extracts (250mL × 1) with methyl tertiary butyl ether(MTBE), and organic phase is dry, and concentration, column chromatographs (positive heptan
Alkane: ethyl acetate=20: 1), white solid 30.0g is obtained, yield: 69%.1HNMR (400MHz, CDCl3)δ(ppm)7.28-
7.34 (m, 10H), 4.15-4.23 (m, 2H), 3.49-3.59 (m, 3H), 3.25-3.28 (d, 2H), 1.60 (s, 3H), 1.41
(s, 3H).
Embodiment 2
The preparation of compound IV-2:
Compound II-2 (125.0g, 0.364mol, 1.0eq.) is dissolved in THF (2L), the LiHMDS of -78 DEG C of dropwise addition 1M
The THF solution of (364mL, 0.364mol, 1.0eq.) after being added dropwise, reacts 30min, compound III-2 is added dropwise at -78 DEG C
(41.56g, 0.364mol, 1.0eq.), adds and warms naturally to -5 DEG C, is stirred to react 2h, LC-MS detection display raw material reaction
It is complete, reaction solution is poured into saturated ammonium chloride solution (1L), liquid separation is layered, normal heptane is added in the dry concentration of organic phase
(100mL), stirring has solid precipitation under ice-water bath, filters, solid it is dry compound IV-2 white solid 111.2g, yield:
64.8%.
The preparation of compound V-2:
Compound IV-2 (80.0g, 0.170mol, 1.0eq.), is dissolved in 600mL dioxane, under ice bath, is added portionwise
NaBH4(32.08g, 0.848mol, 5.0eq.), addition, which finishes to be warmed to room temperature, is stirred to react 3h, and TLC monitors raw material fully reacting,
MeOH quenching reaction is added dropwise, adds, by reaction solution down to down in ice water, EA extraction merges organic phase, and after dry, concentration adds
Enter normal heptane (100mL) mashing, be precipitated solid, filter compound V-2 be white solid 47.05g, yield: 66.6%.
The preparation of compound VI-2:
Compound V-2 (45g, 0.108mol, 1.0eq.) is dissolved in glycol dimethyl ether (1L), ice-water bath, uncle is added
Butanol potassium (24.24g, 0.216mol, 2.0eq.), MsCl (12.37g, 0.108mol, 1.0eq.) is added dropwise, and stirring is anti-at room temperature
1h is answered, is added water (500mL), liquid separation is layered, water phase extracts (250mL × 1) with MTBE, and organic phase is dry, concentration, column chromatography
(normal heptane: EA=20: 1), obtaining compound VI-2 is white solid 29.32g, yield: 68.3%.(ESI-TOF) m/z:[M+H
]+calcd for C25H35NO3: 397；Found:398.Purity: 98%.
Embodiment 3
The preparation of compound IV-3:
Compound II-3 (37.70g, 0.14mol, 1.0eq.) is dissolved in dioxane, under nitrogen protection, be cooled to-
80 DEG C, it is added dropwise to the THF solution of 2,2,6,6- tetramethyl piperidine lithium (420mL, 0.42mol, 3.0eq.) of 1M, after being added dropwise,
Insulation reaction 30min is added dropwise to compound III-3 (30.28g, 0.42mol, 3.0eq.), is stirred to react 2h, TLC at -50 DEG C
Showing that raw material disappears, reaction solution pours into the saturated ammonium chloride of 300mL, liquid separation, and organic phase is dry, it is concentrated to give yellow oil,
Be added 100mL normal heptane in stir, be precipitated solid, filter compound IV-3 be white solid 28.68g, yield 60%
。1HNMR(400MHz,CDCl3) δ (ppm): 7.26-7.35 (m, 10H), 4.28-4.43 (m, 2H), 3.86-3.93 (m, 3H),
3.43-3.47 (d, 2H), 3.32-3.35 (d, 1H), 2.13-2.21 (m, 2H), 1.43-1.47 (m, 3H), 0.94-0.96 (d,
3H), 0.35-0.37 (d, 3H).
The preparation of compound V-3:
Compound IV-3 (28.01g, 0.082mol, 1.0eq.), is dissolved in 100mL THF, addition LiCl (5.21g,
0.123mol, 1.5eq.), 10 DEG C or less are added portionwise KBH4(6.63g, 0.123mol, 1.5eq.), after addition, reaction
2h, TLC detection reacts, and by reaction solution down in ice water, EA extraction merges organic phase, is concentrated, with normal heptane/EA of 100mL
=10:1 stirring be precipitated solid, filter compound V-3 be white solid 17.00g, yield 66.14%.1H NMR
(400MHz, CDCl3) δ (ppm): 7.24-7.35 (m, 10H), 3.95-4.00 (m, 1H), 3.77-3.84 (m, 4H), 3.67-
3.71 (d, 2H), 2.78-2.83 (m, 2H), 1.99-2.03 (m.1H), 1.68-1.69 (m, 1H), 0.90-0.92 (d, 3H),
0.65-0.67 (d, 3H).
The preparation of compound VI-3:
Compound V-3 (17.00g, 0.0542mol, 1.0eq.) is dissolved in 200mL 1, in 2- dichloroethanes, under ice bath,
It is added dropwise to the 5mL concentrated sulfuric acid, is added and is heated to 60 DEG C and is stirred to react 5h, LC-MS shows that raw material has reacted, by reaction solution down to ice water
In, liquid separation, saturated sodium carbonate washs organic phase, after dry, sand processed is concentrated, column chromatographic purifying (normal heptane/EA elution) obtains chemical combination
Object VI-3 is colourless transparent liquid 6.10g, yield 40%.1H NMR (400MHz, CDCl3) δ (ppm): 7.25-7.36 (m,
10H), 4.45-4.50 (m, 2H), 4.37-4.40 (m, 1H), 3.70 (m, 4H), 3.63-3.68 (m, 1H), 1.80-1.87 (m,
1H), 0.94-0.96 (d, 3H), 0.86-0.88 (d, 2H).
Embodiment 4
The preparation of compound IV-4:
Compound II-4 (100.0g, 0.425mol, 1.0eq.) is dissolved in THF (2L), the NaHMDS of -78 DEG C of dropwise addition 1M
The THF solution of (850mL, 0.85mol, 2.0eq.) after being added dropwise, reacts 30min, compound III-4 is added dropwise at -78 DEG C
(97.05g, 0.85mol, 2.0eq.), adds and warms naturally to -5 DEG C, is stirred to react 2h, LC-MS detection display raw material reaction
It is complete, reaction solution is poured into saturated ammonium chloride solution (1L), liquid separation is layered, normal heptane is added in the dry concentration of organic phase
(100mL), stirring has solid precipitation under ice-water bath, filters, solid it is dry compound IV-4 white solid 87.34g, yield:
58.8%.
The preparation of compound V-4:
It is added dropwise compound IV-4 (80.0g, 0.23mol, 1.0eq.), is dissolved in 600mL glycol dimethyl ether, under ice bath,
NaBH is added portionwise4(25.98g, 0.687mol, 3.0eq.), ZnCl2(31.35g, 0.23mol, 1.0eq.), addition finish liter
To reaction 5h is stirred at room temperature, TLC prosecution raw material fully reacting is added dropwise MeOH quenching reaction, adds, by reaction solution down to down to ice
It in water, filters and removes residue, EA extraction merges organic phase, and after dry, normal heptane (100mL) mashing is added in concentration, is precipitated solid
Body, filter compound V-4 be white solid 41.85g, yield: 56.6%.
The preparation of compound VI-4:
Compound V-4 (40g, 0.124mol, 1.0eq.) is dissolved in toluene (500mL), triphenylphosphine is added
(48.79g, 0.186mol, 1.5eq.) is added dropwise DIAD (37.61g, 0.186mol, 1.5eq.), and drop finishes, and reacts at room temperature 10h, adds
Enter water (500mL), be layered liquid separation, water phase extracts (250mL × 1) with methyl tertiary butyl ether(MTBE), and organic phase is dry, concentration, column chromatography
(normal heptane: EA=20: 1), obtaining compound VI-4 is white solid 24.95g, yield: 66.3%.(ESI-TOF) m/z:[M+H
]+calcd for C20H33NO:303；Found:304.Purity: 98%.
Embodiment 5
The preparation of compound IV-5:
Diisopropylamine (56.0g, 0.55mol, 1.25eq.) is dissolved in THF, is cooled to -78 DEG C, n-BuLi is added dropwise
(212mL, 0.53mol, 1.2eq.) after being added dropwise, reacts 30min, the LDA solution for later use that will be prepared.
Compound II-5 (137.02g, 0.44mol, 1.0eq.) is dissolved in THF (2L), -78 DEG C of dropwise additions are above-mentioned homemade
LDA solution after being added dropwise, reacts 30min, is added dropwise compound III-5 (31.0g, 0.53mol, 1.2eq.), reacts 2h,
Enter in saturated ammonium chloride solution (1L), be layered liquid separation, the dry concentration of organic phase is added normal heptane (100mL), stirs under ice-water bath
There is solid precipitation, filter, solid is dry that compound IV-5 is white solid 105.3g, yield: 64.8%.
The preparation of compound V-5:
Compound IV-5 (81.28g, 0.22mol, 1.0eq.) is dissolved in 1L THF, under ice bath, AlCl is added3
(29.33g, 0.22mol, 1.0eq.), is added portionwise NaBH4(24.97g, 0.66mol, 3.0eq.), is stirred to react at room temperature
12h, TLC detection raw material have reacted, and concentration of reaction solution is added normal heptane (200mL) mashing, solid is precipitated, filters to obtain compound
V-5 is white solid 48.70g, yield: 67.6%.
The preparation of compound VI-5:
Compound V-5 (4.6g, 0.010mol, 1.00eq.) is dissolved in dimethyl carbonate (50mL), ice-water bath, is added
KOH (0.078g, 0.0014mol, 0.1eq.), reaction are heated at 180 DEG C, are stirred to react 30min, reaction solution sand column directly processed
Chromatographic purifying (normal heptane/EA elution), obtains white solid 1.25g, yield: 40.3%.(ESI-TOF) m/z:[M+H]+calcd
for C21H27NO:309；Found:310.Purity: 98%.
Embodiment 6 to 13
The method prepare compound VI of reference implementation example 1-5
Table one: the reaction route and Ms data of embodiment 6-13
Embodiment 14
The preparation of compound IV-6:
Diisopropylamine (4.46g, 0.044mol, 1.25eq.) is dissolved in THF (50mL), is cooled to -78 DEG C, is added dropwise just
Butyl lithium (17mL, 0.042mol, 1.2eq.), keeps the temperature 30min after being added dropwise, the LDA solution for later use that will be prepared.
Compound II-1 (10.00g, 0.035mol, 1.0eq.) is dissolved in THF (80mL), -78 DEG C are added dropwise above-mentioned self-control
LDA solution, after being added dropwise, react 30min, be added dropwise compound III-6 (8.43g, 0.042mol, 1.2eq.), drip
Insulation reaction 30min after finishing rises to 16 DEG C of reactions 2h, TLC naturally and monitors end of reaction, is added saturated ammonium chloride (100mL), point
Layer liquid separation, the dry concentration of organic phase, (normal heptane: EA=10: 1~4: 1), it is colorless and transparent for obtaining compound IV-6 to sand column chromatography processed
Grease 15.00g, yield: 88.23%.
The preparation of compound V-6:
Compound IV-6 (15.00g, 0.031mol, 1.0eq.) is dissolved in THF (80mL), controls temperature under ice-water bath
Less than 5 DEG C, Lithium Aluminium Hydride (1.20g, 0.031mol, 1.0eq.) is added portionwise, insulation reaction 30min after addition, TLC prison
End of reaction is controlled, is added dropwise water (1.2g), 15% sodium hydroxide (1.2g) and water (1.2g) filter, and filter cake is washed with THF (20mL)
It washs, organic phase concentration, (normal heptane: ethyl acetate=8: 1~4: 1~1: 1), it is white for being concentrated to give compound V-6 to sand column chromatography processed
Color solid 7.0g, yield: 51.4%.1H-NMR (400MHz, CDCl3) δ (ppm) 7.20-7.32 (m, 10H), 4.62-4.65 (m,
1H), 4.36 (m, 1H), 3.90-4.05 (m, 3H), 3.63-3.66 (d, 2H), 3.35-3.42 (m, 1H), 3.25-3.30 (m,
1H), 2.95 (s, 2H), 2.44-2.46 (m, 1H), 1.65-1.68 (m, 1H), 1.24-1.26 (m, 13H).
The preparation of compound VI-6:
Compound V-6 (7.00g, 0.016mol, 1.0eq.) is dissolved in THF (100mL), potassium tert-butoxide is added
Under (3.56g, 0.032mol, 2.0eq.) ice-water bath, TsCl (3.03g, 0.016mol, 1.0eq.) heat release, 22 DEG C of reactions are added
30min, TLC monitor end of reaction, are added water (50mL), are layered liquid separation, organic phase concentration, and sand column processed chromatographs (normal heptane: EA=
5: 1), obtaining compound VI-6 is white solid 4.30g, yield: 64.17%.1H-NMR(400MHz,CDCl3)δ(ppm)7.26-
7.36 (m, 10H), 4.23-4.32 (m, 2H), 3.84-4.14 (m, 2H), 3.56-3.59 (d, 2H), 3.49-3.53 (m, 1H),
3.29-3.32 (d, 2H), 2.94-3.04 (m, 2H), 2.46-2.49 (m, 1H), 1.82-1.91 (m, 1H), 1.60-1.80 (m,
2H), 1.45 (s, 9H).
Embodiment 15
The preparation of compound IV-7:
Compound II-6 (100.0g, 0.321mol, 1.0eq.) is dissolved in tetrahydrofuran (2L), -78 DEG C are added dropwise 1M's
The THF solution of NaHMDS (337mL, 0.337mol, 1.05eq.) after being added dropwise, reacts 30min, chemical combination is added dropwise at -78 DEG C
Object III-7 (33.74g, 0.337mol, 1.05eq.), adds and warms naturally to -5 DEG C, is stirred to react 2h, LC-MS detection display
Raw material has reacted, and reaction solution is poured into saturated ammonium chloride solution (1L), is layered liquid separation, and positive heptan is added in the dry concentration of organic phase
Alkane (100mL), stirring has solid precipitation under ice-water bath, filters, solid it is dry compound IV-7 white solid 72.39g, receive
Rate: 54.8%.
The preparation of compound V-7:
Compound IV-7 (15.00g, 0.036mol, 1.0eq.) is dissolved in tetrahydrofuran (100mL), is controlled under ice-water bath
Temperature processed is added dropwise to the toluene solution (36mL, 0.036mol, 1.0eq.) of 2.5M DIBAL-H, protects after addition less than 5 DEG C
Temperature reaction 5h, TLC monitor end of reaction, after methanol quenching reaction is added dropwise, tartaric acid solution are added, stirring to system is clarified, EA
Extraction merges organic phase, is concentrated after dry, and sand column chromatography (normal heptane/ethyl acetate elution) processed, being concentrated to give compound V-7 is
White solid 7.10g, yield: 53.4%.
The preparation of compound VI-7:
Compound V-7 (7.00g, 0.0189mol, 1.0eq.) is dissolved in tetrahydrofuran (100mL), is cooled to -30 DEG C,
It is added dropwise to 2.5M n-BuLi (15.1mL, 0.0379mol, 2.0eq.), is dripped under ice-water bath, addition TsCl (7.21g,
0.0378mol, 2.0eq.), heat release, 22 DEG C of reactions 30min, TLC monitor end of reaction, and water is added, is layered liquid separation, organic phase is dense
Contracting, sand column chromatography (normal heptane/EA elution) processed, obtaining compound VI-7 is white solid 3.87g, yield: 58.2%.(ESI-
TOF) m/z:[M+H]+calcd for C23H29NO2: 351；Found:352.Purity: 98%.
Embodiment 16
The preparation of compound IV-8:
Compound II-7 (100.0g, 0.303mol, 1.0eq.) is dissolved in toluene (2L), the KHMDS of -78 DEG C of dropwise addition 1M
The THF solution of (303mL, 0.303mol, 1.0eq.) after being added dropwise, reacts 30min, compound III-8 is added dropwise at -78 DEG C
(21.23g, 0.303mol, 1.0eq.), adds and warms naturally to -5 DEG C, is stirred to react 2h, LC-MS detection display raw material reaction
It is complete, reaction solution is poured into saturated ammonium chloride solution (1L), liquid separation is layered, normal heptane is added in the dry concentration of organic phase
(100mL), stirring has solid precipitation under ice-water bath, filters, solid it is dry compound IV-8 white solid 70.53g, yield:
56.3%.
The preparation of compound V-8:
In 500mL four-hole bottle, under nitrogen atmosphere, 70% toluene solution of red aluminum (20.97g, 0.0726mol, 2.0e.q.) is molten
The 100mL tetrahydro furan of compound IV-8 (15.00g, 0.0363mol, 1.0eq.) is added dropwise at THF (300mL) solution, 0 DEG C
It mutters solution, drips off 0 DEG C of reaction 2.0h.TLC detects fully reacting, and 20mL water quenching reaction, stirring is added dropwise, and pad diatomite filters,
Dry, evaporating solvent under reduced pressure, sand column chromatographic purifying (normal heptane/EA elution) processed, obtaining compound V-8 is white solid 7.47g, is received
Rate: 55.4%.
The preparation of compound VI-8:
Compound V-8 (7.00g, 0.0188mol, 1.0eq.) is dissolved in THF (100mL), is cooled to -30 DEG C, is added dropwise
Enter 2.5M n-BuLi (11.3mL, 0.0282mol, 1.5eq.), drips under ice-water bath, addition MsCl (3.23g,
0.0282mol, 1.5eq.), heat release, 22 DEG C of reactions 30min, TLC monitor end of reaction, and water is added, is layered liquid separation, organic phase is dense
Contracting, sand column chromatography (normal heptane/ethyl acetate elution) processed, obtaining compound VI-8 is white solid 4.53g, yield: 68.2%.
(ESI-TOF) m/z:[M+H]+calcd for C22H27NO3: 353；Found:354.Purity: 98%.
Embodiment 17 to 21
The method prepare compound VI of reference implementation example 1-5 and embodiment 14-16
Table two: the reaction route and Ms data of embodiment 17-21
Embodiment 22
The preparation of compound IV-9:
Diisopropylamine (57.7g, 0.57mol, 1.25eq.) is dissolved in tetrahydrofuran, is cooled to -78 DEG C, positive fourth is added dropwise
Base lithium (212mL, 0.53mol, 1.2eq.) after being added dropwise, reacts 30min, the LDA solution for later use that will be prepared.
Compound II-8 (100.0g, 0.456mol, 1.0eq.) is dissolved in tetrahydrofuran (2L), -78 DEG C of dropwise additions are above-mentioned
Homemade LDA solution after being added dropwise, reacts 30min, is added dropwise acetone (32.0g, 0.547mol, 1.2eq.), reacts 2h,
Enter in saturated ammonium chloride solution (1L), be layered liquid separation, the dry concentration of organic phase is added normal heptane (100mL), stirs under ice-water bath
Have solid precipitation, filter, solid it is dry compound IV-9 white solid 71.81g, yield: 56.8%.
The preparation of compound V-9:
Lithium Aluminium Hydride (8.4g, 0.22mol, 1.0eq.) is dissolved in tetrahydrofuran (600mL), control temperature is lower than 10
DEG C, it is added dropwise compound IV-9 (61.01g, 0.22mol, 1.0eq.), 20min is reacted after addition, TLC monitors raw material reaction
Completely, water (8.4g) is added dropwise, 15% sodium hydroxide (8.4g) and water (8.4g) filter, and filter cake washs (100mL with tetrahydrofuran
× 2), be concentrated, be added normal heptane (200mL) mashing, be precipitated solid, filter compound V-9 be white solid 29.94g, receive
Rate: 54.6%.
The preparation of compound VI-9:
Compound V-9 (20g, 0.0802mol, 1.0eq.) is dissolved in dioxane (200mL), triphenylphosphine is added
(42.09g, 0.16mol, 2.0eq.) is added dropwise DEAD (27.86g, 0.16mol, 2.0eq.), and drop finishes, and reacts at room temperature 10h, is added
Water (500mL) is layered liquid separation, and water phase extracts (250mL × 1) with MTBE, and organic phase is dry, and concentration, column chromatographs (normal heptane/EA
Elution), obtaining compound VI-9 is white solid 12.48g, yield: 67.3%.(ESI-TOF) m/z:[M+H]+calcd for
C13H13NO3: 231；Found:232.Purity: 98%.
Embodiment 23
The preparation of compound IV-10:
Compound II-8 (100.0g, 0.456mol, 1.0eq.) is dissolved in n-hexane (2L), -78 DEG C are added dropwise 1M's
The THF solution of LiHMDS (684mL, 0.684mol, 1.5eq.) after being added dropwise, reacts 30min, compound is added dropwise at -78 DEG C
III-9 (117.15g, 0.684mol, 1.5eq.), adds and warms naturally to -5 DEG C, is stirred to react 2h, and LC-MS detection display is former
Material has reacted, and reaction solution is poured into saturated ammonium chloride solution (1L), is layered liquid separation, and normal heptane is added in the dry concentration of organic phase
(100mL), stirring has solid precipitation under ice-water bath, filters, solid it is dry compound IV-10 white solid 103.78g, receive
Rate: 58.3%.
The preparation of compound V-10:
Under ice bath, aluminum hydride (13.2g, 0.44mol, 2.0eq.) is suspended in 500mL THF, compound is added dropwise to
The 500mL THF solution of IV-10 (85.88g, 0.22mol, 1.0eq.) adds and is stirred to react 12h, TLC prosecution at room temperature after finishing
Raw material fully reacting, is added dropwise water quenching reaction, and concentration of reaction solution is added normal heptane (200mL) mashing, solid is precipitated, filters
Compound V-10 is white solid 45.92g, yield: 57.6%.
The preparation of compound VI-10:
Compound V-10 (20.00g, 0.0912mol, 1.0eq.) is dissolved in THF (100mL), is cooled to -30 DEG C, drop
It is added 2.5M n-BuLi (54.7mL, 0.137mol, 1.5eq.), drips under ice-water bath, addition TsCl (26.08g,
0.137mol, 1.5eq.), heat release, 22 DEG C of reactions 30min, TLC monitor end of reaction, and water is added, is layered liquid separation, organic phase is dense
Contracting, sand column chromatography (normal heptane/EA elution) processed, obtaining compound VI-10 is white solid 18.28g, yield: 58.2%.(ESI-
TOF) m/z:[M+H]+calcd for C18H20N2O5: 344；Found:345.Purity: 98%.
Embodiment 24
The method prepare compound VI of reference implementation example 22-23
Table three: the reaction route and Ms data of embodiment 24
Embodiment 25
The method prepare compound VI of reference implementation example 22-23
Table four: the reaction route and Ms data of embodiment 25
Embodiment 26
The preparation of compound IV-11:
Diisopropylamine (56.0g, 0.55mol, 1.25eq.) is dissolved in THF, is cooled to -78 DEG C, n-BuLi is added dropwise
(212mL, 0.53mol, 1.2eq.) after being added dropwise, reacts 30min, the LDA solution for later use that will be prepared.
Compound II-9 (92.97g, 0.44mol, 1.0eq.) is dissolved in THF (2L), -78 DEG C of dropwise additions are above-mentioned homemade
LDA solution after being added dropwise, reacts 30min, is added dropwise acetone (31.0g, 0.53mol, 1.2eq.), reacts 2h, pour into saturation chlorine
Change in ammonium salt solution (1L), be layered liquid separation, the dry concentration of organic phase is added normal heptane (100mL), stirring has solid analysis under ice-water bath
Out, it filters, solid is dry that compound IV-11 is white solid 67.32g, yield: 56.8%.
The preparation of compound V-11:
Lithium Aluminium Hydride (8.51g, 0.22mol, 1.0eq.) is dissolved in THF (600mL), control temperature is lower than 10 DEG C, drop
Adding compound IV-11 (60.0g, 0.223mol, 1.0eq.), 20min is reacted after addition, TLC monitors raw material fully reacting,
Be added dropwise water (8.51g), 15% sodium hydroxide (8.51g) and water (8.51g), filter, filter cake washed with tetrahydrofuran (100mL ×
2) it, is concentrated, normal heptane (200mL) mashing is added, solid is precipitated, filters to obtain compound V-11 white solid 34.27g, yield:
67.6%.
The preparation of compound VI-11:
Compound V-11 (20g, 0.0880mol, 1.0eq.) is dissolved in dioxane (200mL), triphenylphosphine is added
(23.07g, 0.0880mol, 1.0eq.) is added dropwise DEAD (15.32g, 0.088mol, 1.0eq.), and drop finishes, and reacts at room temperature 10h,
It is added water (500mL), is layered liquid separation, water phase extracts (250mL × 1) with methyl tertiary butyl ether(MTBE), and organic phase is dry, concentration, column layer
Analysis (normal heptane/ethyl acetate elution), obtaining compound VI-11 is white solid 10.55g, yield: 57.3%.(ESI-TOF)m/
Z:[M+H]+calcd for C13H23NO:209；Found:210.Purity: 98%.
Embodiment 27
The preparation of compound IV-12:
Diisopropylamine (93.5g, 0.924mol, 2.1eq.) is dissolved in THF, is cooled to -78 DEG C, n-BuLi is added dropwise
(352mL, 0.88mol, 2.0eq.) after being added dropwise, reacts 30min, the LDA solution for later use that will be prepared.
Compound II-10 (118.54g, 0.44mol, 1.0eq.) is dissolved in THF (2L), -78 DEG C are added dropwise above-mentioned self-control
LDA solution, after being added dropwise, react 30min, be added dropwise acetone (31.0g, 0.53mol, 1.2eq.), react 2h, pour into saturation
In ammonium chloride solution (1L), it is layered liquid separation, the dry concentration of organic phase is added normal heptane (100mL), stirring has solid under ice-water bath
It is precipitated, filtering, solid is dry that compound IV-12 is white solid 74.64g, yield: 51.8%.
The preparation of compound V-12:
Compound IV-12 (70.01g, 0.214mol, 1.0eq.) is dissolved in 1L glycol dimethyl ether, under ice bath, in batches
NaBH is added4(28.33g, 0.749mol, 3.5eq.), addition, which finishes to be warmed to room temperature, is stirred to react 3h, and TLC monitors raw material reaction
Completely, MeOH quenching reaction is added dropwise, adds, by reaction solution down to down in ice water, EA extraction merges organic phase, dense after dry
Contracting reaction solution, be added normal heptane (200mL) mashing, be precipitated solid, filter compound V-12 be white solid 41.30g, receive
Rate: 67.6%.
The preparation of compound VI-12:
Compound V-12 (20.00g, 0.07mol, 1.0eq.) is dissolved in 200mL methylene chloride, under ice bath, is added dropwise to
The concentrated sulfuric acid (6.79g, 0.07mol, 1.0eq.) adds 30 DEG C and is stirred to react 15h, and LC-MS shows that raw material has reacted, by reaction solution
Down in ice water, saturated sodium carbonate washs organic phase, and after dry, sand processed is concentrated, (normal heptane/EA is washed column chromatographic purifying in liquid separation
It is de-), obtaining compound VI-12 is colourless transparent liquid 7.88g, yield 42.1%.(ESI-TOF) m/z:[M+H]+calcd for
C17H33NO:267；Found:270.Purity: 98%.
Embodiment 28
The preparation of compound IV-13:
Compound II-11 (100.0g, 0.636mol, 1.0eq.) is dissolved in n-hexane (2L), -78 DEG C are added dropwise 1M's
The THF solution of LiHMDS (763mL, 0.763mol, 1.2eq.) after being added dropwise, reacts 30min, compound is added dropwise at -78 DEG C
III-1 (55.41g, 0.954mol, 1.5eq.), adds and warms naturally to -5 DEG C, is stirred to react 2h, LC-MS detection display raw material
It has been reacted that, reaction solution has been poured into saturated ammonium chloride solution (1L), be layered liquid separation, normal heptane is added in the dry concentration of organic phase
(100mL), stirring has solid precipitation under ice-water bath, filters, solid it is dry compound IV-13 white solid 74.35g, yield:
54.3%.
The preparation of compound V-13:
It is added dropwise compound IV-13 (70.0g, 0.325mol, 1.0eq.), is dissolved in 600mL 1, in 2- dichloroethanes, ice bath
Under, LiBH is added portionwise4(28.33g, 1.30mol, 4.0eq.), addition, which finishes to be warmed to room temperature, is stirred to react 5h, and TLC monitoring is former
Expect fully reacting, MeOH quenching reaction is added dropwise, adds, by reaction solution down to removing residue down to filtering in ice water, EA extraction,
Merge organic phase, after dry, concentration is added normal heptane (100mL) mashing, solid is precipitated, filter compound V-13 is white
Solid 30.74g, yield: 54.6%.
The preparation of compound VI-13:
Compound V-13 (5.01g, 0.0289mol, 1.0eq.) is dissolved in dimethyl carbonate (20mL), ice-water bath adds
Enter KOH (0.078g, 0.0014mol, 0.05eq.), ethyl alcohol (0.67g, 0.0145mol, 0.5eq.) reaction is heated to 200 DEG C
Under, it is stirred to react 30min, reaction solution sand column chromatographic purifying (normal heptane/ethyl acetate elution) directly processed obtains compound VI-13
For colourless liquid 1.85g, yield: 41.3%.(ESI-TOF) m/z:[M+H]+calcd for C9H17NO:155；Found:
156.Purity: 98%.
Embodiment 29 to 33
The method prepare compound VI of reference implementation example 1-5 and embodiment 14-16 and embodiment 26-28
Table five: the reaction route and Ms data of embodiment 29-33
Embodiment 34
The preparation of compound I-1:
Compound VI-1 (30.0g, 0.10mol, 1.0eq.) is dissolved in methanol (150mL), is added palladium carbon (7.5g), is led to
Enter hydrogen, detects raw material fully reacting in 26 DEG C of reactions 8h, GC, filter, concentration, water pump is evaporated under reduced pressure evaporating for 50~60 DEG C of collection
Point, colourless transparent liquid 6.20g is obtained, yield: 73.8%.1H-NMR (400MHz, CDCl3) δ (ppm) 4.38-4.41 (m, 1H),
3.91-3.94 (m, 1H), 3.48-3.51 (m, 1H), 1.83 (s, 2H), 1.24 (s, 3H), 1.20 (s, 3H).
Embodiment 35
The preparation of compound I-2:
Compound VI-2 (4.30g, 0.01mol, 1.0eq.) is dissolved in methanol (50mL), hydroxide palladium carbon is added
(1.00g) is passed through hydrogen, and 30 DEG C of reactions 6h, LC-MS detect raw material fully reacting, and filtering is concentrated to give off-white powder, with just
Heptane (20mL) foam washing, filter compound I-2 be off-white powder 2.03g, yield: 82.5%.1H-NMR (400MHz,
CDCl3) δ (ppm) 4.69-4.73 (m, 1H), 4.12-4.1 5 (m, 1H), 3.68-3.84 (m, 3H), 3.15-3.23 (m, 2H),
1.67-1.91 (m, 4H), 1.42 (s, 9H).
Embodiment 36
The preparation of compound I-3:
Compound VI-2 (5.01g, 0.0154mol, 1.0eq.) is dissolved in 1,2- dichloroethanes (50mL), is added
CF3COOH(1mL).60 DEG C of reactions 2h, LC-MS detect raw material fully reacting, and concentration sand column chromatographic purifying processed obtains compound I-3 and is
Off-white powder 2.07g, yield: 85.5%.
(ESI-TOF) m/z:[M+H]+calcd for C9H19NO:157；Found:158.Purity: 98%.
Embodiment 37
The preparation of compound I-4:
Compound VI-4 (5.01g, 0.0165mol, 1.0eq.) is dissolved in methanol (50mL), and hydroxide palladium carbon is added
(1.00g) is added ammonium formate (2.08,0.0330,2.0eq.), and 50 DEG C of reactions 16h, LC-MS detect raw material fully reacting, mistake
Filter, by reaction solution down in water after concentration, EA extraction merges organic phase, is concentrated to give off-white powder, steeped with normal heptane (20mL)
Wash, filter compound I-4 be off-white powder 2.66g, yield: 75.5%.(ESI-TOF) m/z:[M+H]+calcd for
C13H27NO:213；Found:214.Purity: 98%.
Embodiment 38
The preparation of compound I-1:
Compound VI-1 (10.0g, 0.0323mol, 1.0eq.) is dissolved in methanol (150mL), is added palladium carbon (2g), adds
Enter 5mL formic acid, be heated to 50 DEG C and be stirred to react, GC detects raw material fully reacting, filters, concentration, and oil pump vacuum distillation collects 60
~70 DEG C of fraction obtains colourless transparent liquid 2.48g, yield: 75.8%.(ESI-TOF) m/z:[M+H]+calcd for
C5H11NO:101；Found:102.Purity: 98%.
Embodiment 39
The preparation of compound I-6:
Compound VI-9 (10.0g, 0.0432mol, 1.0eq.) is dissolved in ethyl alcohol (150mL), hydrazine hydrate is added
(10.82g, 0.216mol, 5.0eq.) is heated to return stirring reaction 2h, sand column chromatography processed is concentrated, obtaining compound I-6 is nothing
Color transparency liquid 3.31g, yield: 75.8%.(ESI-TOF) m/z:[M+H]+calcd for C5H11NO:101；Found:
102.Purity: 98%.
Embodiment 40
The preparation of compound I-7:
Compound VI-10 (10.0g, 0.029mol, 1.0eq.) is dissolved in ethyl alcohol (150mL), 1.5M methylamine is added
Ethanol solution (87mL, 0.087mol, 3.0eq.) is heated to 110 DEG C and is stirred to react 12h, by reaction solution down to 300mL ice water
In, EA extraction merges organic phase, after dry, sand column chromatography processed is concentrated, obtaining compound I-6 is colourless transparent liquid 4.46g, is received
Rate: 71.8%.(ESI-TOF) m/z:[M+H]+calcd for C10H18N2O3: 214；Found:215.Purity: 98%.
Embodiment 41
The preparation of compound I-8:
Compound VI-14 (5.01g, 0.0116mol, 1.0eq.) is dissolved in toluene (50mL), addition DDQ (26.4g,
0.116mol, 10.0eq.), 80 DEG C of reactions 3h, LC-MS detect raw material fully reacting, and sand column chromatographic purifying processed is concentrated and obtains compound
I-8 is off-white powder 1.13g, yield: 75.5%.(ESI-TOF) m/z:[M+H]+calcd for C7H15NO:129；
Found:130.Purity: 98%.
Embodiment 42
The preparation of compound I-3:
Compound VI-2 (5.01g, 0.0154mol, 1.0eq.) is dissolved in glycol dimethyl ether (50mL), and Pd/C is added
(1g), under atmosphere of hydrogen, 60 DEG C of reactions 12h, LC-MS detect raw material fully reactings, and sand column chromatographic purifying processed is concentrated and obtains compound
I-3 is off-white powder 1.537g, yield: 63.2%.(ESI-TOF) m/z:[M+H]+calcd for C9H19NO:157；
Found:158.Purity: 98%.
Embodiment 43
The preparation of compound I-8:
Compound VI-14 (5.01g, 0.0116mol, 1.0eq.) is dissolved in acetonitrile (200mL) and water (20mL), and nitre is added
Sour cerium ammonium (31.80g, 0.058mol, 5.0eq.) is stirred to react 3h at room temperature, and LC-MS detects raw material fully reacting, is added
10% sodium bicarbonate aqueous solution, after stirring, EA is extracted, dry after salt water washing, and sand column chromatographic purifying processed is concentrated and obtains compound I-
8 be off-white powder 0.98g, yield: 65.5%.(ESI-TOF) m/z:[M+H]+calcd for C7H15NO:129；Found:
130.Purity: 98%.
Claims (10)
1. 3- amino-oxetane derivative of structural formula VI:
Wherein: R and R1Separately selected from C1~C6 linear or branched alkyl group, C3~C6 naphthenic base or Heterocyclylalkyl, benzyl,
α-methylbenzyl, to methoxy-benzyl, 2,4- dimethoxy-benzyl, benzhydryl or R and R1Collectively constitute phthalyl
Base；
R3And R4Separately it is selected from H, C1~C6 linear or branched alkyl group, phenyl, substituted-phenyl or R3And R4It collectively constitutes
The cycloalkanes and heterocycle alkane of C4~C6, the atom adjacent with spiro-atom is C in heterocycle alkane therein；
Wherein, R3And R4It is not simultaneously selected from H.
2. derivative according to claim 1, the derivative is selected from:
3. 3- amino-oxetane derivative preparation method of structural formula VI a kind of:
Using compound V as raw material
Under the action of sulfuric acid or alkali/cyclization reagent, reaction generates compound VI
Wherein: R and R1Separately selected from C1~C6 linear or branched alkyl group, C3~C6 naphthenic base or Heterocyclylalkyl, benzyl,
α-methylbenzyl, to methoxy-benzyl, 2,4- dimethoxy-benzyl, benzhydryl or R and R1Collectively constitute phthalyl
Base；
R3And R4Separately it is selected from H, C1~C6 linear or branched alkyl group, phenyl, substituted-phenyl or R3And R4It collectively constitutes
The cycloalkanes and heterocycle alkane of C4~C6, the atom adjacent with spiro-atom is C in heterocycle alkane therein；
Wherein, R3And R4It is not simultaneously selected from H；
The cyclization reagent is selected from triphenylphosphine, diethyl carbonate, paratoluensulfonyl chloride or mesyl chloride.
4. preparation method according to claim 3, it is characterised in that:
(1) when using 30%~98% sulfuric acid, solvent is methylene chloride, 1,2- dichloroethanes, chloroform or carbon tetrachloride；Reaction
Temperature is 0~60 DEG C；Compound V: the molar ratio of sulfuric acid is 1: 0.01~1: 1.
(2) when cyclization reagent is triphenylphosphine, alkali is selected from diisopropyl azodiformate or diethyl azodiformate；Solvent
For tetrahydrofuran, benzene,toluene,xylene, ether, dioxane, glycol dimethyl ether, diethylene glycol dimethyl ether, normal heptane, just
Hexane, hexamethylene, pentane or pentamethylene；Reaction temperature is -20~50 DEG C；Compound V: triphenylphosphine: the molar ratio of alkali
It is 1: 1~2: 1~2.
(3) when cyclization reagent is diethyl carbonate, alkali is potassium hydroxide；Reaction temperature is 100~200 DEG C；In reaction system also
Ethyl alcohol can be added, compound V: potassium hydroxide: the molar ratio of ethyl alcohol is 1: 0.01~0.1: 0~0.5；Diethyl carbonate is molten
Dosage.
(4) when cyclization reagent is paratoluensulfonyl chloride or mesyl chloride, alkali is selected from potassium tert-butoxide or n-BuLi；Solvent is selected from
Tetrahydrofuran, benzene,toluene,xylene, ether, dioxane, glycol dimethyl ether, diethylene glycol dimethyl ether, normal heptane, just oneself
Alkane, hexamethylene, pentane or pentamethylene；Temperature is selected from -80~50 DEG C；Compound V: cyclization reagent: the molar ratio of alkali is 1: 1
~1.5: 2~5.
5. preparation method according to claim 3 or claim 4, it is characterised in that:
Using compound IV as raw material
Under reducing agent effect, compound V is prepared,
6. preparation method according to claim 5, it is characterised in that: the reducing agent be selected from Lithium Aluminium Hydride, sodium borohydride,
Lithium borohydride, potassium borohydride/lithium chloride, red aluminum, sodium borohydride/aluminium chloride, sodium borohydride/zinc chloride, aluminum hydride, aluminum hydride
Lithium/boron trifluoride ether, tri-tert lithium aluminium hydride reduction or diisobutyl aluminium hydride；Solvent be selected from tetrahydrofuran, benzene, toluene,
Dimethylbenzene, ether, dioxane, glycol dimethyl ether, diethylene glycol dimethyl ether, methylene chloride, 1,2- dichloroethanes, positive heptan
Alkane, n-hexane, hexamethylene, pentane or pentamethylene；Reaction temperature is -80~60 DEG C；Compound IV: the molar ratio of reducing agent
It is 1: 0.5~1: 5.
7. according to claim 5 or preparation method as claimed in claim 6, it is characterised in that:
Using compound II and compound III as raw material
Under the conditions of existing for the alkali 1, compound IV is prepared.
8. preparation method according to claim 7, it is characterised in that: the alkali 1 is selected from lithium diisopropylamine, hexamethyl
Two silicon substrate amido sodium, hexamethyldisilazide lithium, potassium hexamethyldisilazide or 2,2,6,6- tetramethyl piperidine lithium salts；
Solvent is selected from tetrahydrofuran, benzene,toluene,xylene, ether, dioxane, glycol dimethyl ether, diethylene glycol dimethyl ether, just
Heptane, n-hexane, hexamethylene, pentane or pentamethylene；Reaction temperature is -80~10 DEG C；Compound II: compound III: alkali
1 molar ratio is 1: 1~3: 1~3.
9. a kind of preparation method of compound I:
Using compound VI as raw material
Reduction reaction occurs under the conditions of existing for hydrogen source, hydrogen source/catalyst or hydrogen source/deprotection reagent, obtains compound
I-1 or I-2,
Wherein: R is selected from C1~C6 linear or branched alkyl group, C3~C6 naphthenic base or Heterocyclylalkyl, benzyl, α-methylbenzyl, right
Methoxy-benzyl, 2,4- dimethoxy-benzyl or benzhydryl；
R1Selected from benzyl, α-methylbenzyl, to methoxy-benzyl, 2,4- dimethoxy-benzyl, benzhydryl or R and R1Jointly
Form phthalyl；
R3And R4Separately it is selected from H, C1~C6 linear or branched alkyl group, phenyl, substituted-phenyl or R3And R4It collectively constitutes
The cycloalkanes and Heterocyclylalkyl of C4~C6, wherein atom adjacent with spiro-atom in Heterocyclylalkyl is C；Wherein, R3And R4It does not select simultaneously
From H.
10. preparation method according to claim 9, it is characterised in that:
(1) work as R1Selected from benzyl, α-methylbenzyl, benzhydryl, to methoxy-benzyl or 2, when 4- dimethoxy-benzyl, institute
Stating hydrogen source is hydrogen, hydrazine, formic acid or ammonium formate；The catalyst is palladium carbon, hydroxide palladium carbon or palladium chloride；Temperature is 0
~60 DEG C；Compound VI: the mass ratio of catalyst is 1: 0.01~1: 1；
(2) as R and R1When collectively constituting phthalyl, the hydrogen source is hydrazine hydrate or methylamine solution；Temperature be -10~
50℃；
(3) work as R1Selected to methoxy-benzyl or 2, when 4- dimethoxy-benzyl,
Deprotection reagent is p-methyl benzenesulfonic acid, hydrochloric acid, sulfuric acid, nitric acid, trifluoroacetic acid, formic acid, acetic acid or phosphoric acid；Hydrogen source is molten
The water being added during agent or post-reaction treatment；Solvent be methanol, ethyl alcohol, isopropanol, methylene chloride, 1,2- dichloroethanes,
Chloroform, carbon tetrachloride, benzene, toluene, tetrahydrofuran, ether, dioxane, dimethylbenzene, glycol dimethyl ether, diethylene glycol diformazan
Ether or acetonitrile；
Deprotecting reagent is the chloro- 5,6- dicyanoquinone of 2,3- bis-, ammonium ceric nitrate or means of samarium iodide；Hydrogen source is solvent or reaction
The water being added in last handling process；Solvent is methylene chloride, 1,2- dichloroethanes, chloroform, carbon tetrachloride, benzene, toluene, tetrahydro furan
It mutters, ether, dioxane, dimethylbenzene, glycol dimethyl ether, diethylene glycol dimethyl ether, acetonitrile or water；
Temperature is -10~60 DEG C；Compound VI: the molar ratio for deprotecting reagent is 1: 1~1: 10.
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| CN116120152A (en) * | 2021-11-12 | 2023-05-16 | 上海医药工业研究院 | Synthesis method of (E) -2-butene-1, 4-diol |
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