CN107879967A - The preparation method of the ketone of 1 azaspiro [4.4] nonane 6 - Google Patents

The preparation method of the ketone of 1 azaspiro [4.4] nonane 6 Download PDF

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CN107879967A
CN107879967A CN201710985131.3A CN201710985131A CN107879967A CN 107879967 A CN107879967 A CN 107879967A CN 201710985131 A CN201710985131 A CN 201710985131A CN 107879967 A CN107879967 A CN 107879967A
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nonane
ketone
azaspiros
butine
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CN107879967B (en
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田金淼
涂永强
陈志华
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Shanghai Jiaotong University
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    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
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Abstract

The present invention relates to the preparation method of the ketone of 1 azaspiro [4.4] nonane 6, using high propargyl alcohol as raw material, by hydroxyl protection; 1,2 addition, substitution reaction; racemization azepine [4.4] spiro-compound is constructed by the semipinacol methods reset, then passes through the isolated product of chiral resolution.Compared with prior art, whole process of the present invention is simply efficient, can largely prepare two kinds of configuration of compound, as preparation all kinds SPD chiral ligands and chiral catalyst.

Description

The preparation method of 1- azaspiros [4.4] nonane -6- ketone
Technical field
The invention belongs to organic chemical synthesis technical field, more particularly, to a kind of 1- azaspiros [4.4] nonane -6- ketone Preparation and chiral separation method.
Background technology
Asymmetry catalysis synthesis is the focus of current organic chemistry research field, and its key synthesized is to find high mapping The chiral catalyst of selectivity and high activity.Speciality of the chiral ligand derived from spirocyclic ring scaffold because showing this respect in recent years And larger development is obtained.1992, Kumar groups found the chiral diol of spiral shell [4.4] nonane skeleton to ketone in LAH systems The also original preferable effect of compound, subsequent Chen Xin are grown, and Zhou Qilin, Ding Kuiling and Sasai groups have developed one on this basis The chiral ligand of the full carbon skeleton of serial spiral shell [4.4] nonane simultaneously achieves good achievement in asymmetry catalysis methodology.
However, the part and catalyst of azaspiro [4.4] nonane skeleton are but rarely reported.1- azaspiros [4.4] nonane -6- Assimilation compound was just synthesized (C.-K.Sha et.J.Org.Chem.1991,56,2694- early in 1991 by Sha groups 2696).Then in 2015, our groups have developed a chiral induction route to prepare (S) -9 ((S) -1- azepine -1- uncles Butoxy carbonyl-spiral shell [4.4] nonane -6- ketone), and SPD silicon ether catalyst is changed into asymmetric Michael addition reactions In show excellent enantioselectivity (J.-M.Tian et.Chem.Commun., 2015,51,9979-9982).But Its syntheti c route is longer, isolates and purifies cumbersome, and most important trouble is to prepare on a large scale, and which has limited azaspiro [4.4] exploitation and application of nonane framework counterpart and chiral catalyst.
The content of the invention
It is an object of the present invention to overcome the above-mentioned drawbacks of the prior art and provide a kind of easy, efficient 1- The preparation method of azaspiro [4.4] nonane -6- ketone.
The purpose of the present invention can be achieved through the following technical solutions：
The preparation method of 1- azaspiros [4.4] nonane -6- ketone, using high propargyl alcohol as raw material, add by hydroxyl protection, 1,2 Into, substitution reaction, racemization azepine [4.4] spiro-compound is constructed by the semipinacol methods reset, then tear open by chirality Point isolated product, its reaction process are as follows：
Specifically use following steps：
(1) p-toluenesulfonyl (Ts) protection is carried out to hydroxyl under conditions of triethylamine as raw material using high propargyl alcohol to obtain Compound 3- butine -1- tolysulfonyl fat 2；
(2) compound 3- butine -1- tolysulfonyl fat 2 carries out 1,2- additions to cyclobutanone in the basic conditions Compound 4- (1- hydroxycyclobutyls) -3- butine -1- tolysulfonyl fat 3；
(3) compound 4- (1- hydroxycyclobutyls) -3- butine -1- tolysulfonyl fat 3 carries out substitution reaction and obtains chemical combination Thing 4- benzylamine -1- butine cyclobutanol 4；
(4) Semipinacol rearrangement reactions occur in the presence of catalyst for compound 4- benzylamines -1- butine cyclobutanol 4 Obtain racemization azepine [4.4] spiro-compound 1- benzyl -1- azepines [4.4] nonane -6- ketone 5；
(5) compound 1- benzyls -1- azepines [4.4] nonane -6- ketone 5 first removes benzyl (Bn) protection under palladium/carbon effect Base obtains compound 1- azepines [4.4] nonane -6- ketone 6, and carrying out first time crude separation under the effect of chiral resolving agent tartaric acid obtains To the tartrate of tartrate and (R) -1- azaspiros [4.4] nonane -6- ketone of (S) -1- azaspiros [4.4] nonane -6- ketone, Alkalized using sodium hydroxide, then with chiral resolving agent camphorsulfonic acid carry out it is secondary fractionation obtain (S) -1- azaspiros [4.4] nonane - The camsilate of the camsilate of 6- ketone and (R) -1- azaspiros [4.4] nonane -6- ketone；
(6) to the camsilate and (R) -1- azaspiros [4.4] nonane -6- of (S) -1- azaspiros [4.4] nonane -6- ketone The camsilate of ketone is alkalized and protection be prepared (S) -1-R base -1- azaspiros [4.4] nonane -6- ketone (S) -9 with (R) -1-R bases -1- azaspiros [4.4] nonane -6- ketone (R) -9.
Control in step (1) temperature to arrive room temperature, according to high propargyl alcohol for 0 DEG C, mole of triethylamine and paratoluensulfonyl chloride Than for 1:1-1.5:1.5-2 hybrid reactions 10-12h.
Controlling reaction temperature is -78~0 DEG C in step (2), and addition reaction, 3- fourths are carried out in the presence of n-BuLi The mol ratio of alkynes -1- tolysulfonyl fat and cyclobutanone is 1:1~1.2.
The middle utilization benzylamine of step (3) is under conditions of 60-90 DEG C to 4- (1- hydroxycyclobutyls) -3- butine -1- to toluene Sulphonyl fat carries out substitution reaction, and the alkali of excessive addition removes to neutralize caused acidic materials in course of reaction, benzylamine with to 4- (1- hydroxyls Tetramethylcyclobutyl) -3- butine -1- tolysulfonyl fat mol ratio be 1:1.2~1.5.
Catalyst described in step (4) is triphenyl phosphorus chlorauride, and 4- benzylamines -1- butine cyclobutanol adds in catalyst Measure as under conditions of 0.1-1mol%, controlling reaction temperature is 40-60 DEG C of heating response 1-2h.
Crude separation is carried out using tartaric acid in step (5), at room temperature, by 1- azaspiros [4.4] nonane -6- ketone equimolars The tartaric acid of amount, which is added in acetone, reacts 6-10h.
Using the secondary fractionation of camphorsulfonic acid progress in step (5), at room temperature, will with (S) -1- azaspiros [4.4] nonane - It is added to after the tartrate alkalization of 6- ketone with (L)-camphorsulfonic acid of equimolar amounts in isopropanol and reacts 6-10h；Will with (R)- (D)-camphorsulfonic acid after the tartrate alkalization of 1- azaspiros [4.4] nonane -6- ketone with equimolar amounts is added in isopropanol React 6-10h.
Step (6) in the basic conditions, adds acid anhydrides or acyl chlorides etc., reacts 2-24h.1- azaspiros [4.4] nonane -6- Ketone, the mol ratio of the protection reagent such as alkali and acid anhydrides or acyl chlorides is 1:1.5~3:1.2~1.5, the R bases in the product being prepared For Boc, Bn, Ts, PhCO, alkyl, aryl, sulfonyl or acyl group etc..
Compared with prior art, the present invention obtains (S) -9 using the method for Semipinacol rearrangement reactions/chiral resolution (R) -9, route is shorter, without column chromatographic isolation and purification, and can prepare on a large scale, and repeatability preferably, has good Researching value and prospects for commercial application.
Embodiment
With reference to specific embodiment, the present invention is described in detail.Following examples will be helpful to the technology of this area Personnel further understand the present invention, but the invention is not limited in any way.It should be pointed out that the ordinary skill to this area For personnel, without departing from the inventive concept of the premise, various modifications and improvements can be made.These belong to the present invention Protection domain.
The preparation method of 1- azaspiros [4.4] nonane -6- ketone, using high propargyl alcohol as raw material, add by hydroxyl protection, 1,2 Into, substitution reaction, racemization azepine [4.4] spiro-compound is constructed by the semipinacol methods reset, then tear open by chirality Divide isolated product, specifically using following steps：
(1) using high propargyl alcohol as raw material, temperature is controlled to arrive room temperature, according to high propargyl alcohol, triethylamine and to toluene sulphur for 0 DEG C The mol ratio of acyl chlorides is 1:1-1.5:1.5-2 hybrid reaction 10-12h, so as to the hydroxyl of high propargyl alcohol under conditions of triethylamine Base carries out p-toluenesulfonyl (Ts) protection and obtains compound 3- butine -1- tolysulfonyl fat；
(2) controlling reaction temperature is -78~0 DEG C, carries out addition reaction in the presence of n-BuLi, wherein 3- butine - The mol ratio of 1- tolysulfonyl fat and cyclobutanone is 1:1~1.2,4- (1- hydroxycyclobutyls) -1- pairs of -3- butine is prepared Tosyl fat；
(3) utilize benzylamine under conditions of 60-90 DEG C to 4- (1- hydroxycyclobutyls) -3- butine -1- tolysulfonyl fat Carry out substitution reaction, the alkali of excessive addition removes to neutralize caused acidic materials in course of reaction, benzylamine with to 4- (1- hydroxyl ring fourths Base) -3- butine -1- tolysulfonyl fat mol ratio be 1:1.2~1.5, compound 4- benzylamines -1- is obtained by substitution reaction Butine cyclobutanol；
(4) compound 4- benzylamines -1- butine cyclobutanol is in catalyst triphenyl phosphorus chlorauride, catalyst charge 0.1- Under conditions of 1mol%, controlling reaction temperature is that 40-60 DEG C of heating 1-2h generation Semipinacol rearrangement reaction obtains racemization nitrogen Miscellaneous [4.4] spiro-compound 1- benzyl -1- azepines [4.4] nonane -6- ketone；
(5) 1- benzyls -1- azepines [4.4] nonane -6- ketone first removes benzyl (Bn) protection group under palladium/carbon effect Compound 1- azepines [4.4] nonane -6- ketone 6, first time crude separation is carried out at room temperature under the effect of chiral resolving agent tartaric acid, will The tartaric acid of 1- azaspiros [4.4] nonane -6- ketone equimolar amounts, which is added in acetone, reacts 6-10h, obtains (S) -1- azaspiros [4.4] tartrate of the tartrate of nonane -6- ketone and (R) -1- azaspiros [4.4] nonane -6- ketone, utilizes sodium hydroxide alkali Change, then secondary fractionation is carried out with chiral resolving agent camphorsulfonic acid, at room temperature, will be with (S) -1- azaspiros [4.4] nonane -6- ketone Tartrate alkalization after be added to (L)-camphorsulfonic acid of equimolar amounts in isopropanol and react 6-10h；Will be with (R) -1- nitrogen It is added in isopropanol and reacts with (D)-camphorsulfonic acid of equimolar amounts after the tartrate alkalization of miscellaneous spiral shell [4.4] nonane -6- ketone 6-10h, obtain the camsilate and (R) -1- azaspiros [4.4] nonane -6- ketone of (S) -1- azaspiros [4.4] nonane -6- ketone Camsilate；
(6) in the basic conditions, acid anhydrides or acyl chlorides etc. are added, reacts 2-24h, 1- azaspiros [4.4] nonane -6- ketone, alkali Mol ratio with the protection reagent such as acid anhydrides or acyl chlorides is 1:1.5~3:1.2~1.5, (S) -1-R base -1- azaspiros are prepared [4.4] nonane -6- ketone and (R) -1-R base -1- azaspiros [4.4] nonane -6- ketone, the R bases in the product being prepared are Boc, Bn, Ts, PhCO, alkyl, aryl, sulfonyl or acyl group etc..
The present invention is done followed by (S) -1- azepines -1- tertbutyloxycarbonyls-spiral shell [4.4] nonane -6- ketone (S) -9 example It is expanded on further, its purpose, which is only that, is best understood from present disclosure.Therefore, the protection domain of this patent is not limited to these Embodiment.
In present embodiment, the hydrogen nuclear magnetic resonance spectrum of compound (1H NMR) surveyed by Bruker AVANCE III HD 400 It is fixed；Ee values are determined by Agilent agilent 6120；Agents useful for same is commercial reagent.
Embodiment 1
The synthesis of compound 4
1 (1400g, 19.97mol) and 7L DCM is added in 20L four-hole bottles；At 10 DEG C add TEA (11038ml, 27.6mol), TsCl (7254g, 38.04mol) is added portionwise, heating naturally is stirred overnight；Nuclear-magnetism adds when showing no raw material 2.33L water, aqueous phase are stripped 1 time (1.17L) with DCM, merge organic phase, wash 2 times (2*2.73L), and anhydrous magnesium sulfate is dried 10min, filtering, 50 DEG C are spin-dried for obtaining 2 common 4081g of brown yellow oil liquid, yield 91%.
2 (4081g, 18.2mol) and 8L THF are added in 50L bilayer reactors；- 80 DEG C are cooled to, normal-butyl is added dropwise Lithium (8L, 20mol), after stirring 30min, -80 DEG C of temperature control, cyclobutanone (140g, 20mol) is added dropwise for 2 hours, heated up naturally To room temperature；Nuclear-magnetism adds 8L water when showing no raw material, adds 24L MTBE, liquid separation, and aqueous phase is stripped once with 12L MTBE, is merged Organic phase, anhydrous magnesium sulfate are dried, and 50 DEG C are concentrated to give 3 common 5682g of yellow oily liquid, quantitative yield.
3 (5682g, 18.2mol) and toluene (28L) are added in 50L bilayer reactors；Addition benzylamine (2340g, 25.4mol) and potassium carbonate (7546g, 21.4)；(about 80 DEG C) reaction 16h of temperature rising reflux, gradually have a large amount of white solids to produce； Nuclear-magnetism is cooled to 30 DEG C or so when showing no raw material, adding 16L water makes solid dissolving, liquid separation, and aqueous phase is stripped once with 8L EA, Merge organic phase, 50 DEG C are concentrated to dryness；24L EA and 24L saturated ammonium chlorides, liquid separation are added, organic phase uses 24L saturation chlorinations again Ammonium is washed, liquid separation, merges aqueous phase, and 16L EA are stripped once, merges organic phase, and anhydrous magnesium sulfate is dried, and 50 DEG C are spin-dried for obtaining Huang Color oily liquids 4370g, 4.4L MTBE are added, dry ice ethanol is cooled to 0 DEG C or so, adds 4.4L normal heptanes, is stirred overnight (16h) separates out a large amount of solids, filtering, obtains solid 42730g, yield 65%.
Embodiment 2
The synthesis of compound 5
4 (1023g, 4.46mol) are added in 10L four-hole bottles, add ethyl acetate 5L；Add triphenyl phosphorus chlorauride (3.786g, 4.46mmol)；(60 DEG C) reaction 1h of temperature rising reflux；Nuclear-magnetism shows no raw material, 50 DEG C of reaction solution be spin-dried for yellow is consolidated 5 common 920g of body, yield 90%.
1H NMR (400MHZ, CDCl3) δ (ppm) 7.18~7.35 (m, 5H), 3.71 (d, 1H), 3.58 (d, 1H), 2.90 ~2.96 (m, 1H), 2.79~2.83 (m, 1H), 2.27~2.29 (m, 1H), 1.76~2.10 (m, 9H).
Embodiment 3
The synthesis of compound (S) -9
5 (3000g, 13.08mol) are added in 10L four-hole bottles, add methanol dissolving；Add Pd/C；Normal pressure leads to hydrogen； After 5h, nuclear-magnetism shows no raw material, by system filtering and concentrating to doing, obtains unhindered amina 6 and throws in next step.
Unhindered amina 6 is added in 20L four-hole bottles, adds acetone, dry ice ethanol is cooled to 20 DEG C or so, disposably three kinds Tartaric acid adds after mixing, and is stirred overnight；A large amount of solids are separated out, are filtered, solid (S) -7 and mother liquor (R) -7 are handled respectively；Solid For preparing (S) -9, liquid is used to prepare (R) -9.
Solid (S) -7 is added into 13L DCM, white suspension, it is 11 (about 3L), aqueous phase DCM then to adjust pH with ammoniacal liquor It is stripped (3 × 3L), merges organic phase, anhydrous magnesium sulfate is dried, and is spin-dried for obtaining -6 common 746g of brownish red oily liquids (S).
Then 7.4L isopropanols are added thereto, are added the L- camphorsulfonic acids 1243g of equimolar amounts into salt, are stirred overnight, A large amount of solids are separated out, are filtered, solid triplication recrystallisation from isopropanol 3 times, obtain (the L- camphor trees of S anomeric products of white solid (S) -8 Brain sulfonate) common 1271g.
(S) -8 (635.5g, 1.713mol) and 3.2L DCM are added in 5L four-hole bottles；Add (Boc)2O(448.4g 2.055mol), temperature does not rise；TEA is slowly dropped into, temperature slowly rises, 32 DEG C of highest, effervescent；Nuclear-magnetism shows no original after 2h Material, system are concentrated to dryness to obtain (S) -9 common 1103g,
1H NMR (400MHZ, CDCl3) δ (ppm) 3.57~3.52 (m, 1H), 3.48~3.44 (m, 1H), 2.65~2.53 (m, 1H), 2.34~2.29 (m, 2H), 2.14~2.07 (m, 1H), 1.99~1.75 (m, 5H), 1.72~1.58 (m, 1H), 1.43~1.38 (d, 9H).GC purity:98.4%, ee value 99.88%.
Embodiment 4
The preparation method of 1- azaspiros [4.4] nonane -6- ketone, using high propargyl alcohol as raw material, add by hydroxyl protection, 1,2 Into, substitution reaction, racemization azepine [4.4] spiro-compound is constructed by the semipinacol methods reset, then tear open by chirality Divide isolated product, specifically using following steps：
(1) using high propargyl alcohol as raw material, control temperature for 0 DEG C, according to high propargyl alcohol, triethylamine and paratoluensulfonyl chloride Mol ratio is 1:1:1.5 hybrid reaction 12h, so as to carry out tolysulfonyl to the hydroxyl of high propargyl alcohol under conditions of triethylamine Base (Ts) protection obtains compound 3- butine -1- tolysulfonyl fat；
(2) controlling reaction temperature is -78 DEG C, and addition reaction, wherein -1- pairs of 3- butine are carried out in the presence of n-BuLi The mol ratio of tosyl fat and cyclobutanone is 1:1,4- (1- hydroxycyclobutyls) -3- butine -1- tolysulfonyl is prepared Fat；
(3) 4- (1- hydroxycyclobutyls) -3- butine -1- tolysulfonyl fat is carried out under conditions of 60 DEG C using benzylamine Substitution reaction, the alkali of excessive addition removes to neutralize caused acidic materials in course of reaction, benzylamine with to 4- (1- hydroxycyclobutyls)- The mol ratio of 3- butine -1- tolysulfonyl fat is 1:1.2, compound 4- benzylamine -1- butine ring fourths are obtained by substitution reaction Alcohol；
(4) compound 4- benzylamines -1- butine cyclobutanol is in catalyst triphenyl phosphorus chlorauride, catalyst charge Under conditions of 0.1mol%, controlling reaction temperature is that 40 DEG C of heating 2h generation Semipinacol rearrangement reactions obtain racemization azepine [4.4] spiro-compound 1- benzyls -1- azepines [4.4] nonane -6- ketone；
(5) 1- benzyls -1- azepines [4.4] nonane -6- ketone first removes benzyl (Bn) protection group under palladium/carbon effect Compound 1- azepines [4.4] nonane -6- ketone 6, first time crude separation is carried out at room temperature under the effect of chiral resolving agent tartaric acid, will The tartaric acid of 1- azaspiros [4.4] nonane -6- ketone equimolar amounts, which is added in acetone, reacts 6-10h, obtains (S) -1- azaspiros [4.4] tartrate of the tartrate of nonane -6- ketone and (R) -1- azaspiros [4.4] nonane -6- ketone, utilizes sodium hydroxide alkali Change, then secondary fractionation is carried out with chiral resolving agent camphorsulfonic acid, at room temperature, will be with (S) -1- azaspiros [4.4] nonane -6- ketone Tartrate alkalization after be added to (L)-camphorsulfonic acid of equimolar amounts in isopropanol and react 6h；Will be with (R) -1- azaspiros [4.4] it is added to after the tartrate alkalization of nonane -6- ketone with (D)-camphorsulfonic acid of equimolar amounts in isopropanol and reacts 6- 10h, obtain the camsilate and (R) -1- azaspiros [4.4] nonane -6- ketone of (S) -1- azaspiros [4.4] nonane -6- ketone Camsilate；
(6) in the basic conditions, acid anhydrides etc. is added, reacts 2h, 1- azaspiros [4.4] nonane -6- ketone, alkali is protected with acid anhydrides The mol ratio of reagent is 1:1.5:1.2, be prepared (S) -1-R base -1- azaspiros [4.4] nonane -6- ketone and (R) -1-R bases - 1- azaspiros [4.4] nonane -6- ketone, the R bases in the product being prepared are Boc.
Embodiment 5
The preparation method of 1- azaspiros [4.4] nonane -6- ketone, using high propargyl alcohol as raw material, add by hydroxyl protection, 1,2 Into, substitution reaction, racemization azepine [4.4] spiro-compound is constructed by the semipinacol methods reset, then tear open by chirality Divide isolated product, specifically using following steps：
(1) using high propargyl alcohol as raw material, it is room temperature, according to high propargyl alcohol, triethylamine and paratoluensulfonyl chloride to control temperature Mol ratio be 1:1.4:1.9 hybrid reaction 11h, so as to carry out the hydroxyl of high propargyl alcohol to toluene under conditions of triethylamine Sulfonyl (Ts) protection obtains compound 3- butine -1- tolysulfonyl fat；
(2) controlling reaction temperature is -50 DEG C, and addition reaction, wherein -1- pairs of 3- butine are carried out in the presence of n-BuLi The mol ratio of tosyl fat and cyclobutanone is 1:1.1,4- (1- hydroxycyclobutyls) -3- butine -1- are prepared to toluene sulphur Acyl fat；
(3) 4- (1- hydroxycyclobutyls) -3- butine -1- tolysulfonyl fat is carried out under conditions of 70 DEG C using benzylamine Substitution reaction, the alkali of excessive addition removes to neutralize caused acidic materials in course of reaction, benzylamine with to 4- (1- hydroxycyclobutyls)- The mol ratio of 3- butine -1- tolysulfonyl fat is 1:1.4, compound 4- benzylamine -1- butine ring fourths are obtained by substitution reaction Alcohol；
(4) compound 4- benzylamines -1- butine cyclobutanol is in catalyst triphenyl phosphorus chlorauride, catalyst charge Under conditions of 0.5mol%, controlling reaction temperature is that 50 DEG C of heating 2h generation Semipinacol rearrangement reactions obtain racemization azepine [4.4] spiro-compound 1- benzyls -1- azepines [4.4] nonane -6- ketone；
(5) 1- benzyls -1- azepines [4.4] nonane -6- ketone first removes benzyl (Bn) protection group under palladium/carbon effect Compound 1- azepines [4.4] nonane -6- ketone, first time crude separation is carried out at room temperature under the effect of chiral resolving agent tartaric acid, will The tartaric acid of 1- azaspiros [4.4] nonane -6- ketone equimolar amounts, which is added in acetone, reacts 8h, obtains (S) -1- azaspiros [4.4] tartrate of the tartrate of nonane -6- ketone and (R) -1- azaspiros [4.4] nonane -6- ketone, utilizes sodium hydroxide alkali Change, then secondary fractionation is carried out with chiral resolving agent camphorsulfonic acid, at room temperature, will be with (S) -1- azaspiros [4.4] nonane -6- ketone Tartrate alkalization after be added to (L)-camphorsulfonic acid of equimolar amounts in isopropanol and react 6-10h；Will be with (R) -1- nitrogen It is added in isopropanol and reacts with (D)-camphorsulfonic acid of equimolar amounts after the tartrate alkalization of miscellaneous spiral shell [4.4] nonane -6- ketone 8h, obtain the camsilate of (S) -1- azaspiros [4.4] nonane -6- ketone and the camphor tree of (R) -1- azaspiros [4.4] nonane -6- ketone Brain sulfonate；
(6) in the basic conditions, acid anhydrides is added, reacts 12h, 1- azaspiros [4.4] nonane -6- ketone, alkali and acid anhydrides or acyl The mol ratio of the protection reagent such as chlorine is 1:2:1.4, be prepared (S) -1-R base -1- azaspiros [4.4] nonane -6- ketone and (R) - 1-R base -1- azaspiros [4.4] nonane -6- ketone, the R bases in the product being prepared are 4 sulfonyls.
Embodiment 6
The preparation method of 1- azaspiros [4.4] nonane -6- ketone, using high propargyl alcohol as raw material, add by hydroxyl protection, 1,2 Into, substitution reaction, racemization azepine [4.4] spiro-compound is constructed by the semipinacol methods reset, then tear open by chirality Divide isolated product, specifically using following steps：
(1) using high propargyl alcohol as raw material, control temperature for 0 DEG C, according to high propargyl alcohol, triethylamine and paratoluensulfonyl chloride Mol ratio is 1:1.5:2 hybrid reaction 12h, so as to carry out tolysulfonyl to the hydroxyl of high propargyl alcohol under conditions of triethylamine Base (Ts) protection obtains compound 3- butine -1- tolysulfonyl fat；
(2) controlling reaction temperature is 0 DEG C, addition reaction is carried out in the presence of n-BuLi, wherein 3- butine -1- are to first The mol ratio of benzene sulfonyl fat and cyclobutanone is 1:1.2,4- (1- hydroxycyclobutyls) -3- butine -1- tolysulfonyl is prepared Fat；
(3) 4- (1- hydroxycyclobutyls) -3- butine -1- tolysulfonyl fat is carried out under conditions of 90 DEG C using benzylamine Substitution reaction, the alkali of excessive addition removes to neutralize caused acidic materials in course of reaction, benzylamine with to 4- (1- hydroxycyclobutyls)- The mol ratio of 3- butine -1- tolysulfonyl fat is 1:1.5, compound 4- benzylamine -1- butine ring fourths are obtained by substitution reaction Alcohol；
(4) compound 4- benzylamines -1- butine cyclobutanol is in catalyst triphenyl phosphorus chlorauride, catalyst charge Under conditions of 1mol%, controlling reaction temperature is that 60 DEG C of heating 1h generation Semipinacol rearrangement reactions obtain racemization azepine [4.4] spiro-compound 1- benzyls -1- azepines [4.4] nonane -6- ketone；
(5) 1- benzyls -1- azepines [4.4] nonane -6- ketone first removes benzyl (Bn) protection group under palladium/carbon effect Compound 1- azepines [4.4] nonane -6- ketone, first time crude separation is carried out at room temperature under the effect of chiral resolving agent tartaric acid, will The tartaric acid of 1- azaspiros [4.4] nonane -6- ketone equimolar amounts, which is added in acetone, reacts 10h, obtains (S) -1- azaspiros [4.4] tartrate of the tartrate of nonane -6- ketone and (R) -1- azaspiros [4.4] nonane -6- ketone, utilizes sodium hydroxide alkali Change, then secondary fractionation is carried out with chiral resolving agent camphorsulfonic acid, at room temperature, will be with (S) -1- azaspiros [4.4] nonane -6- ketone Tartrate alkalization after be added to (L)-camphorsulfonic acid of equimolar amounts in isopropanol and react 6-10h；Will be with (R) -1- nitrogen It is added in isopropanol and reacts with (D)-camphorsulfonic acid of equimolar amounts after the tartrate alkalization of miscellaneous spiral shell [4.4] nonane -6- ketone 10h, obtain the camsilate and (R) -1- azaspiros [4.4] nonane -6- ketone of (S) -1- azaspiros [4.4] nonane -6- ketone Camsilate；
(6) in the basic conditions, add acyl chlorides etc., react 24h, 1- azaspiros [4.4] nonane -6- ketone, alkali and acid anhydrides or The mol ratio of the protection reagent such as acyl chlorides is 1:3:1.5, be prepared (S) -1-R base -1- azaspiros [4.4] nonane -6- ketone with (R) -1-R bases -1- azaspiros [4.4] nonane -6- ketone, the R bases in the product being prepared are acyl group.
The specific embodiment of the present invention is described above.It is to be appreciated that the invention is not limited in above-mentioned Particular implementation, those skilled in the art can make various deformations or amendments within the scope of the claims, this not shadow Ring the substantive content of the present invention.

Claims (10)

  1. The preparation method of 1.1- azaspiros [4.4] nonane -6- ketone, it is characterised in that this method is passed through using high propargyl alcohol as raw material Hydroxyl protection, 1,2 addition, substitution reaction, racemization azepine [4.4] spiro compounds are constructed by the semipinacol methods reset Thing, then pass through the isolated product of chiral resolution.
  2. 2. the preparation method of 1- azaspiros [4.4] nonane -6- ketone according to claim 1, it is characterised in that this method is adopted Use following steps：
    (1) p-toluenesulfonyl (Ts) protection is carried out to hydroxyl under conditions of triethylamine as raw material using high propargyl alcohol and obtains 3- fourths Alkynes -1- tolysulfonyl fat；
    (2) 3- butine -1- tolysulfonyl fat carries out 1,2- additions to cyclobutanone in the basic conditions and obtains 4- (1- hydroxyl ring fourths Base) -3- butine -1- tolysulfonyl fat；
    (3) 4- (1- hydroxycyclobutyls) -3- butine -1- tolysulfonyl fat carries out substitution reaction and obtains 4- benzylamine -1- butine rings Butanol；
    (4) Semipinacol rearrangements occur in the presence of catalyst triphenylphosphine chlorauride for 4- benzylamines -1- butine cyclobutanol anti- Racemization azepine [4.4] spiro-compound 1- benzyl -1- azepines [4.4] nonane -6- ketone should be obtained；
    (5) 1- benzyls -1- azaspiros [4.4] nonane -6- ketone first removes benzyl (Bn) protection group under palladium/carbon effect and obtains 1- nitrogen Miscellaneous spiral shell [4.4] nonane -6- ketone, chiral resolving agent tartaric acid effect under carry out first time crude separation obtain (S) -1- azaspiros [4.4] tartrate of the tartrate of nonane -6- ketone and (R) -1- azaspiros [4.4] nonane -6- ketone, utilizes sodium hydroxide alkali Change, then carry out secondary fractionation with chiral resolving agent camphorsulfonic acid and obtain the camphorsulfonic acid of (S) -1- azaspiros [4.4] nonane -6- ketone The camsilate of salt and (R) -1- azaspiros [4.4] nonane -6- ketone；
    (6) to the camsilate and (R) -1- azaspiros [4.4] nonane -6- ketone of (S) -1- azaspiros [4.4] nonane -6- ketone Camsilate is alkalized and protection be prepared (S) -1-R base -1- azaspiros [4.4] nonane -6- ketone and (R) -1-R bases - 1- azaspiros [4.4] nonane -6- ketone.
  3. 3. the preparation method of 1- azaspiros [4.4] nonane -6- ketone according to claim 2, it is characterised in that step (1) It is middle control temperature for 0 DEG C to room temperature, according to high propargyl alcohol, the mol ratio of triethylamine and paratoluensulfonyl chloride is 1:1-1.5:1.5- 2 ratio hybrid reaction 10-12h.
  4. 4. the preparation method of 1- azaspiros [4.4] nonane -6- ketone according to claim 2, it is characterised in that step (2) Middle controlling reaction temperature is -78~0 DEG C, and addition reaction, 3- butine -1- tolysulfonyl fat are carried out in the presence of n-BuLi Mol ratio with cyclobutanone is 1:1~1.2.
  5. 5. the preparation method of 1- azaspiros [4.4] nonane -6- ketone according to claim 2, it is characterised in that step (3) It is middle that 4- (1- hydroxycyclobutyls) -3- butine -1- tolysulfonyl fat substitute instead under conditions of 60-90 DEG C using benzylamine Should, the alkali of excessive addition removes to neutralize caused acidic materials in course of reaction, benzylamine with to 4- (1- hydroxycyclobutyls) -3- fourths The mol ratio of alkynes -1- tolysulfonyl fat is 1:1~1.5.
  6. 6. the preparation method of 1- azaspiros [4.4] nonane -6- ketone according to claim 2, it is characterised in that step (4) Described in catalyst be triphenyl phosphorus chlorauride, 4- benzylamines -1- butine cyclobutanol is 0.1-1mol% in catalyst charge Under conditions of, controlling reaction temperature is 40-60 DEG C of heating response 1-2h.
  7. 7. the preparation method of 1- azaspiros [4.4] nonane -6- ketone according to claim 2, it is characterised in that step (5) It is middle to carry out crude separation using tartaric acid, at room temperature, the tartaric acid of 1- azaspiros [4.4] nonane -6- ketone and equimolar amounts is added Enter and 6-10h is reacted into acetone.
  8. 8. the preparation method of 1- azaspiros [4.4] nonane -6- ketone according to claim 2, it is characterised in that step (5) It is middle to carry out secondary fractionation using camphorsulfonic acid, at room temperature, will be with the tartrate of (S) -1- azaspiros [4.4] nonane -6- ketone It is added to after alkalization with (L)-camphorsulfonic acid of equimolar amounts in isopropanol and reacts 6-10h；Will be with (R) -1- azaspiros [4.4] nonyl It is added to after the tartrate alkalization of alkane -6- ketone with (D)-camphorsulfonic acid of equimolar amounts in isopropanol and reacts 6-10h.
  9. 9. the preparation method of 1- azaspiros [4.4] nonane -6- ketone according to claim 2, it is characterised in that step (6) In the basic conditions, addition acid anhydrides or acyl chlorides, reaction 2-24h, 1- azaspiros [4.4] nonane -6- ketone, alkali and acid anhydrides or acyl chlorides Mol ratio is 1:1.5~3:1.2~1.5.
  10. 10. the preparation method of 1- azaspiros [4.4] nonane -6- ketone according to claim 2, it is characterised in that step (6) In R bases include Boc, Bn, Ts, PhCO, alkyl, aryl, sulfonyl or acyl group.
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