CN107879967B - Preparation method of 1-azaspiro [4.4] nonane-6-ketone - Google Patents

Preparation method of 1-azaspiro [4.4] nonane-6-ketone Download PDF

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CN107879967B
CN107879967B CN201710985131.3A CN201710985131A CN107879967B CN 107879967 B CN107879967 B CN 107879967B CN 201710985131 A CN201710985131 A CN 201710985131A CN 107879967 B CN107879967 B CN 107879967B
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azaspiro
nonane
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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 invention relates to a preparation method of 1-azaspiro [4.4] nonane-6-ketone, which takes high propargyl alcohol as a raw material, constructs a racemic aza [4.4] spiro compound by a semipinacol rearrangement method through hydroxyl protection, 1,2 addition and substitution reaction, and then obtains the product through manual resolution and separation. Compared with the prior art, the whole process is simple and efficient, and a large amount of two configurational compounds can be prepared and used for preparing various SPD chiral ligands and chiral catalysts.

Description

Preparation method of 1-azaspiro [4.4] nonane-6-ketone
Technical Field
The invention belongs to the technical field of organic chemical synthesis, and particularly relates to a preparation and chiral resolution method of 1-azaspiro [4.4] nonane-6-ketone.
Background
Asymmetric catalytic synthesis is a hot spot in the current research field of organic chemistry, and the key point of the synthesis lies in finding a chiral catalyst with high enantioselectivity and high activity. Chiral ligands derived from spiro backbone have been developed in recent years because of their properties. In 1992, Kumar group found that chiral diol of spiro [4.4] nonane skeleton had better effect on reduction of ketone compound in LAH system, and later, Chenozui, Zhongqilin, Diquinling and Sasai group developed a series of chiral ligands of spiro [4.4] nonane all-carbon skeleton based on this and achieved good performance in asymmetric catalytic methodology.
However, ligands and catalysts for the azaspiro [4.4] nonane skeleton have been rarely reported. 1-azaspiro [4.4] nonan-6-one compounds were synthesized by the Sha group as early as 1991 (C. -K.Sha et. J.org.Chem.1991,56, 2694-2696). Subsequently in 2015, we developed a chiral induction route to prepare (S) -9((S) -1-aza-1-tert-butoxycarbonyl-spiro [4.4] nonan-6-one) and convert it to SPD silyl ether catalyst that showed excellent enantioselectivity in asymmetric Michael addition reactions (j. -m.tianet. chem.commu., 2015,51, 9979-. However, the preparation route is long, the separation and purification are troublesome, and the most important trouble is that the preparation on a large scale cannot be realized, so that the development and the application of the azaspiro [4.4] nonane skeleton ligand and the chiral catalyst are limited.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a simple, convenient and efficient preparation method of 1-azaspiro [4.4] nonane-6-ketone.
The purpose of the invention can be realized by the following technical scheme:
the preparation method of 1-azaspiro [4.4] nonane-6-ketone comprises the steps of taking high propargyl alcohol as a raw material, carrying out hydroxyl protection, 1,2 addition and substitution reaction, constructing a racemic aza [4.4] spiro compound by a semipinacol rearrangement method, and obtaining a product by manual resolution and separation, wherein the reaction process is as follows:
Figure BDA0001440337640000021
the method comprises the following steps:
(1) taking high propargyl alcohol as a raw material, and carrying out tosyl (Ts) protection on hydroxyl under the condition of triethylamine to obtain a compound 3-butyne-1-tosyl ester 2;
(2) 1, 2-addition of cyclobutanone is carried out on the compound 3-butine-1-p-toluenesulfonyl ester 2 under the alkaline condition to obtain a compound 4- (1-hydroxycyclobutyl) -3-butine-1-p-toluenesulfonyl ester 3;
(3) carrying out substitution reaction on the compound 4- (1-hydroxycyclobutyl) -3-butyne-1-p-toluenesulfonyl ester 3 to obtain a compound 4-benzylamine-1-butyne cyclobutanol 4;
(4) the compound 4-benzylamine-1-butynylcyclobutanol 4 is subjected to a Semipinacol rearrangement reaction under the action of a catalyst to obtain a racemic aza [4.4] spiro compound 1-benzyl-1-aza [4.4] nonane-6-one 5;
(5) the compound 1-benzyl-1-aza [4.4] nonane-6-ketone 5 firstly removes a benzyl (Bn) protecting group under the action of palladium/carbon to obtain a compound 1-aza [4.4] nonane-6-ketone 6, carrying out primary crude separation under the action of a chiral resolving agent tartaric acid to obtain tartrate of (S) -1-azaspiro [4.4] nonane-6-ketone and tartrate of (R) -1-azaspiro [4.4] nonane-6-ketone, alkalifying by using sodium hydroxide, and carrying out secondary resolution by using a chiral resolving agent camphorsulfonic acid to obtain camphorsulfonate of (S) -1-azaspiro [4.4] nonane-6-ketone and camphorsulfonate of (R) -1-azaspiro [4.4] nonane-6-ketone;
(6) the camphor sulfonic acid salt of (S) -1-azaspiro [4.4] nonane-6-ketone and camphor sulfonic acid salt of (R) -1-azaspiro [4.4] nonane-6-ketone are alkalized and protected to obtain (S) -1-R group-1-azaspiro [4.4] nonane-6-ketone (S) -9 and (R) -1-R group-1-azaspiro [4.4] nonane-6-ketone (R) -9.
In the step (1), the temperature is controlled to be 0 ℃ to room temperature, and the mixture is reacted for 10 to 12 hours according to the molar ratio of the high propargyl alcohol to the triethylamine to the p-toluenesulfonyl chloride of 1:1 to 1.5:1.5 to 2.
And (3) controlling the reaction temperature to be-78-0 ℃, and carrying out addition reaction under the action of n-butyllithium, wherein the molar ratio of the 3-butyne-1-p-toluenesulfonyl ester to the cyclobutanone is 1: 1-1.2.
In the step (3), benzylamine is used for carrying out substitution reaction on 4- (1-hydroxycyclobutyl) -3-butyne-1-p-toluenesulfonyl ester at the temperature of 60-90 ℃, excessive alkali is added in the reaction process to neutralize generated acidic substances, and the molar ratio of benzylamine to p-4- (1-hydroxycyclobutyl) -3-butyne-1-p-toluenesulfonyl ester is 1: 1.2-1.5.
The catalyst in the step (4) is triphenylphosphine gold chloride, and the 4-benzylamine-1-butyne cyclobutanol is heated and reacted for 1-2h under the condition that the adding amount of the catalyst is 0.1-1 mol%, and the reaction temperature is controlled to be 40-60 ℃.
In the step (5), tartaric acid is used for crude separation, and tartaric acid with the same molar amount as 1-azaspiro [4.4] nonane-6-ketone is added into acetone at room temperature for reaction for 6-10 h.
In the step (5), camphor sulfonic acid is used for secondary resolution, and tartrate of (S) -1-azaspiro [4.4] nonane-6-ketone is alkalized and added into isopropanol with equal molar quantity to react for 6-10h at room temperature; basified with (R) -1-azaspiro [4.4] nonan-6-one tartrate and reacted with an equimolar amount of (D) -camphorsulfonic acid in isopropanol for 6-10 h.
And (6) adding acid anhydride or acid chloride and the like under the alkaline condition, and reacting for 2-24 h. The molar ratio of the 1-azaspiro [4.4] nonane-6-one to the alkali to the protective reagents such as acid anhydride or acyl chloride is 1: 1.5-3: 1.2-1.5, and the R group in the prepared product is Boc, Bn, Ts, PhCO, alkyl, aryl, sulfonyl or acyl.
Compared with the prior art, the invention adopts a Semipinacol rearrangement reaction/chiral resolution method to obtain (S) -9 and (R) -9, has shorter route, does not need column chromatography separation and purification, can be prepared in large scale, has better repeatability, and has good research value and industrial application prospect.
Detailed Description
The present invention will be described in detail with reference to specific examples. The following examples will assist those skilled in the art in further understanding the invention, but are not intended to limit the invention in any way. It should be noted that variations and modifications can be made by persons skilled in the art without departing from the spirit of the invention. All falling within the scope of the present invention.
The preparation method of 1-azaspiro [4.4] nonane-6-ketone comprises the following steps of taking high propargyl alcohol as a raw material, carrying out hydroxyl protection, 1,2 addition and substitution reaction, constructing a racemic aza [4.4] spiro compound by a semipinacol rearrangement method, and carrying out manual resolution and separation to obtain the product, wherein the method comprises the following steps:
(1) taking high propargyl alcohol as a raw material, controlling the temperature to be 0 ℃ to room temperature, and carrying out mixed reaction for 10-12h according to the molar ratio of the high propargyl alcohol to triethylamine to p-toluenesulfonyl chloride of 1:1-1.5:1.5-2, so as to carry out p-toluenesulfonyl (Ts) protection on hydroxyl of the high propargyl alcohol under the condition of triethylamine to obtain a compound 3-butine-1-p-toluenesulfonyl ester;
(2) controlling the reaction temperature to be-78-0 ℃, and carrying out addition reaction under the action of n-butyllithium, wherein the molar ratio of 3-butyne-1-p-toluenesulfonyl ester to cyclobutanone is 1: 1-1.2, so as to prepare 4- (1-hydroxycyclobutyl) -3-butyne-1-p-toluenesulfonyl ester;
(3) performing substitution reaction on 4- (1-hydroxycyclobutyl) -3-butyne-1-p-toluenesulfonyl ester by benzylamine at the temperature of 60-90 ℃, adding excessive alkali to neutralize generated acid substances in the reaction process, wherein the molar ratio of benzylamine to p-4- (1-hydroxycyclobutyl) -3-butyne-1-p-toluenesulfonyl ester is 1: 1.2-1.5, and obtaining a compound, namely 4-benzylamine-1-butyne cyclobutanol, through the substitution reaction;
(4) heating the compound 4-benzylamine-1-butynylcyclobutanol at 40-60 ℃ for 1-2h under the condition of 0.1-1 mol% of catalyst triphenylphosphine gold chloride and 0.1-1 mol% of catalyst addition to perform a Semipinacol rearrangement reaction to obtain a racemic aza [4.4] spiro compound 1-benzyl-1-aza [4.4] nonane-6-one;
(5) 1-benzyl-1-aza [4.4] nonane-6-one is subjected to primary crude separation under the action of palladium/carbon to obtain a compound 1-aza [4.4] nonane-6-one 6, tartaric acid in an equal molar amount of 1-azaspiro [4.4] nonane-6-one is added into acetone to react for 6-10h at room temperature under the action of a chiral resolving agent tartaric acid to obtain a tartrate of (S) -1-azaspiro [4.4] nonane-6-one and a tartrate of (R) -1-azaspiro [4.4] nonane-6-one, the tartrate is alkalized by sodium hydroxide and secondarily resolved by a chiral resolving agent camphorsulfonic acid, and the tartrate of (S) -1-azaspiro [4.4] nonane-6-one is alkalized and then in an equal molar amount (L) at room temperature -camphorsulfonic acid is added into isopropanol to react for 6-10 h; alkalizing tartrate of (R) -1-azaspiro [4.4] nonane-6-one, adding equimolar amount of (D) -camphorsulfonic acid into isopropanol, and reacting for 6-10h to obtain camphorsulfonate of (S) -1-azaspiro [4.4] nonane-6-one and camphorsulfonate of (R) -1-azaspiro [4.4] nonane-6-one;
(6) under the alkaline condition, adding acid anhydride or acyl chloride and the like, reacting for 2-24h to obtain 1-azaspiro [4.4] nonane-6-one, wherein the molar ratio of alkali to protective reagents such as the acid anhydride or the acyl chloride is 1: 1.5-3: 1.2-1.5, preparing to obtain (S) -1-R group-1-azaspiro [4.4] nonane-6-one and (R) -1-R group-1-azaspiro [4.4] nonane-6-one, and the R group in the prepared product is Boc, Bn, Ts, PhCO, alkyl, aryl, sulfonyl or acyl and the like.
The invention is further illustrated by the following (S) -1-aza-1-tert-butoxycarbonyl-spiro [4.4] nonan-6-one (S) -9 example, which is intended only for a better understanding of the contents of the invention. Therefore, the scope of protection of the patent is not limited to these embodiments.
In the present embodiment, the hydrogen nuclear magnetic resonance spectrum of the compound (b) ((b))1H NMR) by Bruker AVANCE III HD 400; the ee value is determined by Agilent 6120; all reagents used were commercially available reagents.
Example 1
Synthesis of Compound 4
Figure BDA0001440337640000051
1(1400g, 19.97mol) and 7L DCM were added to a 20L four-necked flask; TEA (11038ml, 27.6mol) was added at 10 ℃ and TsCl (7254g, 38.04mol) was added in portions, and stirred overnight at natural temperature; when no material was detected by nuclear magnetic resonance, 2.33L of water was added, the aqueous phase was back-extracted 1 time with DCM (1.17L), the organic phases were combined, washed 2 times with water (2X 2.73L), dried over anhydrous magnesium sulfate for 10min, filtered and spin-dried at 50 ℃ to give a total of 4081g of brown-yellow oily liquid 2, 91% yield.
2(4081g, 18.2mol) and 8L THF were added to a 50L double layer reactor; cooling to-80 ℃, dropwise adding n-butyllithium (8L, 20mol), stirring for 30min, controlling the temperature to-80 ℃, dropwise adding cyclobutanone (140g, 20mol) for 2 hours, and naturally heating to room temperature; when no material was detected by nuclear magnetism, 8L of water was added, 24L of MTBE was added, the mixture was separated, the aqueous phase was back-extracted with 12L of MTBE, the organic phases were combined, dried over anhydrous magnesium sulfate, and concentrated at 50 ℃ to give 5682g in total of yellow oily liquid 3, and the yield was quantitative.
3(5682g,18.2mol) and toluene (28L) were added to a 50L double layer reactor; benzylamine (2340g,25.4mol) and potassium carbonate (7546g, 21.4 mol) were added; heating and refluxing (about 80 ℃) to react for 16 hours, and gradually generating a large amount of white solid; cooling to about 30 deg.C when no raw material is available due to nuclear magnetism, adding 16L water to dissolve solid, separating liquid, back-extracting water phase with 8L EA, mixing organic phases, and concentrating at 50 deg.C to dry; adding 24L of EA and 24L of saturated ammonium chloride, separating, washing an organic phase with 24L of saturated ammonium chloride again, separating, combining aqueous phases, carrying out back extraction on 16L of EA once, combining organic phases, drying by anhydrous magnesium sulfate, carrying out spin drying at 50 ℃ to obtain 4370g of yellow oily liquid, adding 4.4L of MTBE, cooling to about 0 ℃ by dry ice ethanol, adding 4.4L of n-heptane, stirring overnight (16h) to precipitate a large amount of solid, and filtering to obtain 42730g of solid with the yield of 65%.
Example 2
Synthesis of Compound 5
Figure BDA0001440337640000061
4(1023g, 4.46mol) was added to a 10L four-necked flask, and 5L of ethyl acetate was added; triphenylphosphoryl gold chloride (3.786g, 4.46mmol) was added; heating and refluxing (60 ℃) to react for 1 hour; nuclear magnetism shows that no raw material exists, reaction liquid is dried in a spinning mode at 50 ℃ to obtain 5g of yellow solid totally, and the yield is 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)。
Example 3
Synthesis of Compound (S) -9
Figure BDA0001440337640000062
Adding 5(3000g,13.08mol) into a 10L four-mouth bottle, and adding methanol to dissolve; adding Pd/C; introducing hydrogen at normal pressure; after 5h, nuclear magnetic showed no material, the system was filtered and concentrated to dryness to give the free amine 6 for the next step.
Adding free amine 6 into a 20L four-mouth bottle, adding acetone, cooling to about 20 ℃ with dry ice ethanol, uniformly mixing three kinds of tartaric acid at one time, adding, and stirring overnight; separating out a large amount of solid, filtering, and treating the solid (S) -7 and the mother liquor (R) -7 respectively; the solid was used for the preparation of (S) -9 and the liquid was used for the preparation of (R) -9.
The solid (S) -7 was added to 13L DCM and the suspension was white, then adjusted to pH 11 (ca. 3L) with aqueous ammonia, the aqueous phase was back-extracted with DCM (3X 3L), the organic phases were combined, dried over anhydrous magnesium sulfate and spin-dried to give 746g total of (S) -6 as a brownish red oily liquid.
Then adding 7.4L of isopropanol, adding 1243g of L-camphorsulfonic acid with equal molar amount into the mixture to form salt, stirring the mixture overnight, precipitating a large amount of solid, filtering the solid, and recrystallizing the solid for 3 times by using three times of isopropanol to obtain 1271g of white solid (S) -8 (L-camphorsulfonate of S configuration product).
(S) -8(635.5g, 1.713mol) and 3.2L DCM were charged into a 5L four-necked flask; addition (Boc)2O (448.4g 2.055mol), temperature does not rise; slowSlowly dripping TEA, slowly raising the temperature to 32 ℃ at the maximum, and bubbling; after 2h, nuclear magnetism shows no raw material, the system is concentrated to be dry to obtain 1103g of (S) -9 in total,
1H NMR(400MHZ，CDCl3) Delta (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% and ee value 99.88%.
Example 4
The preparation method of 1-azaspiro [4.4] nonane-6-ketone comprises the following steps of taking high propargyl alcohol as a raw material, carrying out hydroxyl protection, 1,2 addition and substitution reaction, constructing a racemic aza [4.4] spiro compound by a semipinacol rearrangement method, and carrying out manual resolution and separation to obtain the product, wherein the method comprises the following steps:
(1) taking high propargyl alcohol as a raw material, controlling the temperature to be 0 ℃, and carrying out mixed reaction for 12 hours according to the molar ratio of the high propargyl alcohol to triethylamine to p-toluenesulfonyl chloride of 1:1:1.5, so as to carry out p-toluenesulfonyl (Ts) protection on hydroxyl of the high propargyl alcohol under the condition of triethylamine, thereby obtaining a compound 3-butyne-1-p-toluenesulfonyl ester;
(2) controlling the reaction temperature to be-78 ℃, and carrying out addition reaction under the action of n-butyllithium, wherein the molar ratio of 3-butyne-1-p-toluenesulfonyl ester to cyclobutanone is 1:1, so as to prepare 4- (1-hydroxycyclobutyl) -3-butyne-1-p-toluenesulfonyl ester;
(3) performing substitution reaction on 4- (1-hydroxycyclobutyl) -3-butyne-1-p-toluenesulfonyl ester by benzylamine at 60 ℃, adding excessive alkali to neutralize generated acid substances in the reaction process, wherein the molar ratio of benzylamine to p-4- (1-hydroxycyclobutyl) -3-butyne-1-p-toluenesulfonyl ester is 1:1.2, and obtaining a compound of 4-benzylamine-1-butyne cyclobutanol through substitution reaction;
(4) heating the compound 4-benzylamine-1-butynylcyclobutanol at 40 ℃ for 2h under the condition of a catalyst of triphenylphosphine gold chloride and the addition of 0.1 mol% of the catalyst to perform a Semipinacol rearrangement reaction to obtain a racemic aza [4.4] spiro compound 1-benzyl-1-aza [4.4] nonane-6-one;
(5) 1-benzyl-1-aza [4.4] nonane-6-one is subjected to primary crude separation under the action of palladium/carbon to obtain a compound 1-aza [4.4] nonane-6-one 6, tartaric acid in an equal molar amount of 1-azaspiro [4.4] nonane-6-one is added into acetone to react for 6-10h at room temperature under the action of a chiral resolving agent tartaric acid to obtain a tartrate of (S) -1-azaspiro [4.4] nonane-6-one and a tartrate of (R) -1-azaspiro [4.4] nonane-6-one, the tartrate is alkalized by sodium hydroxide and secondarily resolved by a chiral resolving agent camphorsulfonic acid, and the tartrate of (S) -1-azaspiro [4.4] nonane-6-one is alkalized and then in an equal molar amount (L) at room temperature -camphorsulfonic acid is added to isopropanol to react for 6 h; alkalizing tartrate of (R) -1-azaspiro [4.4] nonane-6-one, adding equimolar amount of (D) -camphorsulfonic acid into isopropanol, and reacting for 6-10h to obtain camphorsulfonate of (S) -1-azaspiro [4.4] nonane-6-one and camphorsulfonate of (R) -1-azaspiro [4.4] nonane-6-one;
(6) under the alkaline condition, adding acid anhydride and the like to react for 2h, 1-azaspiro [4.4] nonane-6-ketone, wherein the molar ratio of alkali to acid anhydride protecting reagent is 1:1.5:1.2, thus obtaining (S) -1-R group-1-azaspiro [4.4] nonane-6-ketone and (R) -1-R group-1-azaspiro [4.4] nonane-6-ketone, and the R group in the prepared product is Boc.
Example 5
The preparation method of 1-azaspiro [4.4] nonane-6-ketone comprises the following steps of taking high propargyl alcohol as a raw material, carrying out hydroxyl protection, 1,2 addition and substitution reaction, constructing a racemic aza [4.4] spiro compound by a semipinacol rearrangement method, and carrying out manual resolution and separation to obtain the product, wherein the method comprises the following steps:
(1) taking high propargyl alcohol as a raw material, controlling the temperature to be room temperature, and carrying out mixed reaction for 11 hours according to the molar ratio of the high propargyl alcohol to triethylamine to p-toluenesulfonyl chloride of 1:1.4:1.9, so as to carry out p-toluenesulfonyl (Ts) protection on hydroxyl of the high propargyl alcohol under the condition of triethylamine, thereby obtaining a compound 3-butyne-1-p-toluenesulfonyl ester;
(2) controlling the reaction temperature to be-50 ℃, and carrying out addition reaction under the action of n-butyllithium, wherein the molar ratio of 3-butyne-1-p-toluenesulfonyl ester to cyclobutanone is 1:1.1, so as to prepare 4- (1-hydroxycyclobutyl) -3-butyne-1-p-toluenesulfonyl ester;
(3) performing substitution reaction on 4- (1-hydroxycyclobutyl) -3-butyne-1-p-toluenesulfonyl ester by benzylamine at 70 ℃, adding excessive alkali to neutralize generated acid substances in the reaction process, wherein the molar ratio of benzylamine to p-4- (1-hydroxycyclobutyl) -3-butyne-1-p-toluenesulfonyl ester is 1:1.4, and obtaining a compound of 4-benzylamine-1-butyne cyclobutanol through substitution reaction;
(4) heating the compound 4-benzylamine-1-butynylcyclobutanol at 50 ℃ for 2h under the condition of a catalyst of triphenylphosphine gold chloride and the addition of 0.5 mol% of the catalyst to perform a Semipinacol rearrangement reaction to obtain a racemic aza [4.4] spiro compound 1-benzyl-1-aza [4.4] nonane-6-one;
(5) 1-benzyl-1-aza [4.4] nonane-6-one is subjected to primary crude separation under the action of palladium/carbon to obtain a compound 1-aza [4.4] nonane-6-one, tartaric acid in an equal molar amount of 1-azaspiro [4.4] nonane-6-one is added into acetone to react for 8 hours at room temperature under the action of a chiral resolving agent tartaric acid to obtain tartrate of (S) -1-azaspiro [4.4] nonane-6-one and tartrate of (R) -1-azaspiro [4.4] nonane-6-one, sodium hydroxide is utilized, chiral resolving agent camphorsulfonic acid is used for secondary resolution, the tartrate of (S) -1-azaspiro [4.4] nonane-6-one is alkalized at room temperature and then is mixed with (L) -camphor in an equal molar amount Adding sulfonic acid into isopropanol to react for 6-10 h; basified with tartrate of (R) -1-azaspiro [4.4] nonan-6-one and reacted with equimolar amount of (D) -camphorsulfonic acid in isopropanol for 8h to give camphorsulfonate of (S) -1-azaspiro [4.4] nonan-6-one and camphorsulfonate of (R) -1-azaspiro [4.4] nonan-6-one;
(6) under the alkaline condition, adding acid anhydride to react for 12h, wherein the molar ratio of alkali to protective reagents such as acid anhydride or acyl chloride is 1:2:1.4, 1-azaspiro [4.4] nonane-6-ketone and (R) -1-R group-1-azaspiro [4.4] nonane-6-ketone are obtained, and the R group in the prepared product is 4 sulfonyl.
Example 6
The preparation method of 1-azaspiro [4.4] nonane-6-ketone comprises the following steps of taking high propargyl alcohol as a raw material, carrying out hydroxyl protection, 1,2 addition and substitution reaction, constructing a racemic aza [4.4] spiro compound by a semipinacol rearrangement method, and carrying out manual resolution and separation to obtain the product, wherein the method comprises the following steps:
(1) taking high propargyl alcohol as a raw material, controlling the temperature to be 0 ℃, and carrying out mixed reaction for 12 hours according to the molar ratio of the high propargyl alcohol to triethylamine to p-toluenesulfonyl chloride of 1:1.5:2, so as to carry out p-toluenesulfonyl (Ts) protection on hydroxyl of the high propargyl alcohol under the condition of triethylamine, thereby obtaining a compound 3-butyne-1-p-toluenesulfonyl ester;
(2) controlling the reaction temperature to be 0 ℃, and carrying out addition reaction under the action of n-butyllithium, wherein the molar ratio of the 3-butyne-1-p-toluenesulfonyl ester to the cyclobutanone is 1:1.2, so as to prepare 4- (1-hydroxycyclobutyl) -3-butyne-1-p-toluenesulfonyl ester;
(3) performing substitution reaction on 4- (1-hydroxycyclobutyl) -3-butyne-1-p-toluenesulfonyl ester by benzylamine at 90 ℃, adding excessive alkali to neutralize generated acid substances in the reaction process, wherein the molar ratio of benzylamine to p-4- (1-hydroxycyclobutyl) -3-butyne-1-p-toluenesulfonyl ester is 1:1.5, and obtaining a compound of 4-benzylamine-1-butyne cyclobutanol through substitution reaction;
(4) heating the compound 4-benzylamine-1-butynylcyclobutanol at 60 ℃ for 1h under the condition of 1 mol% of catalyst triphenylphosphine gold chloride, and heating for 1h to perform a Semipinacol rearrangement reaction to obtain a racemic aza [4.4] spiro compound 1-benzyl-1-aza [4.4] nonane-6-one;
(5) 1-benzyl-1-aza [4.4] nonane-6-one is subjected to primary crude separation under the action of palladium/carbon to obtain a compound 1-aza [4.4] nonane-6-one, tartaric acid in an equimolar amount of 1-azaspiro [4.4] nonane-6-one is added into acetone to react for 10 hours at room temperature under the action of a chiral resolving agent tartaric acid to obtain tartrate of (S) -1-azaspiro [4.4] nonane-6-one and tartrate of (R) -1-azaspiro [4.4] nonane-6-one, sodium hydroxide is utilized, chiral resolving agent camphorsulfonic acid is used for secondary resolution, the tartrate of (S) -1-azaspiro [4.4] nonane-6-one is alkalized at room temperature and then is mixed with (L) -camphor in an equimolar amount Adding sulfonic acid into isopropanol to react for 6-10 h; basified with tartrate of (R) -1-azaspiro [4.4] nonan-6-one and reacted with equimolar amount of (D) -camphorsulfonic acid in isopropanol for 10h to give camphorsulfonate of (S) -1-azaspiro [4.4] nonan-6-one and camphorsulfonate of (R) -1-azaspiro [4.4] nonan-6-one;
(6) under the alkaline condition, adding acyl chloride and the like to react for 24h, wherein the molar ratio of alkali to protective reagents such as acid anhydride or acyl chloride is 1:3:1.5, so as to obtain (S) -1-R group-1-azaspiro [4.4] nonane-6-ketone and (R) -1-R group-1-azaspiro [4.4] nonane-6-ketone, and the R group in the prepared product is acyl.
The foregoing description of specific embodiments of the present invention has been presented. It is to be understood that the present invention is not limited to the specific embodiments described above, and that various changes and modifications may be made by one skilled in the art within the scope of the appended claims without departing from the spirit of the invention.

Claims (5)

  1. A preparation method of (S) -1-R group-1-azaspiro [4.4] nonane-6-ketone and (R) -1-R group-1-azaspiro [4.4] nonane-6-ketone is characterized in that 3-butyn-1-ol is used as a raw material, a racemic aza [4.4] spiro compound is constructed by a semipinacol rearrangement method through hydroxyl protection, 1,2 addition and substitution reaction, and then a product is obtained by manual resolution and separation;
    the method comprises the following steps:
    (1) 3-butyne-1-alcohol is used as a raw material to react with p-toluenesulfonyl chloride under the condition of triethylamine to carry out p-toluenesulfonyl (Ts) protection on hydroxyl to obtain 3-butyne-1-p-toluenesulfonyl ester;
    (2) 1, 2-addition of cyclobutanone is carried out on 3-butine-1-p-toluenesulfonyl ester under alkaline condition to obtain 4- (1-hydroxycyclobutyl) -3-butine-1-p-toluenesulfonyl ester; controlling the reaction temperature to be-78-0 ℃ in the step (2), and carrying out addition reaction under the action of n-butyllithium, wherein the molar ratio of 3-butyne-1-p-toluenesulfonyl ester to cyclobutanone is 1: 1-1.2;
    (3) 4- (1-hydroxy cyclobutyl) -3-butyne-1-p-toluenesulfonyl ester is subjected to substitution reaction to obtain 4-benzylamine-1-butyne cyclobutanol; in the step (3), benzylamine is used for carrying out substitution reaction on 4- (1-hydroxycyclobutyl) -3-butyne-1-p-toluenesulfonyl ester at the temperature of 60-90 ℃, excessive alkali is added in the reaction process to neutralize generated acid substances, and the molar ratio of benzylamine to p-4- (1-hydroxycyclobutyl) -3-butyne-1-p-toluenesulfonyl ester is 1: 1-1.5;
    (4) 4-benzylamine-1-butynylcyclobutanol is subjected to a Semipinacol rearrangement reaction under the action of a catalyst triphenylphosphine gold chloride to obtain a racemic aza [4.4] spiro compound 1-benzyl-1-aza [4.4] nonane-6-one; the catalyst in the step (4) is triphenylphosphine gold chloride, and the 4-benzylamine-1-butyne cyclobutanol is heated and reacted for 1-2h at the reaction temperature of 40-60 ℃ under the condition that the addition amount of the catalyst is 0.1-1 mol%;
    (5) 1-benzyl-1-azaspiro [4.4] nonane-6-ketone is subjected to primary crude separation under the action of palladium/carbon to obtain tartrate of (S) -1-azaspiro [4.4] nonane-6-ketone and tartrate of (R) -1-azaspiro [4.4] nonane-6-ketone, the tartrate is alkalized by sodium hydroxide, and the tartrate is subjected to secondary separation by chiral resolving agent camphorsulfonic acid to obtain camphorsulfonate of (S) -1-azaspiro [4.4] nonane-6-ketone and camphorsulfonate of (R) -1-azaspiro [4.4] nonane-6-ketone;
    (6) alkalifying and protecting camphor sulfonate of (S) -1-azaspiro [4.4] nonane-6-one and camphor sulfonate of (R) -1-azaspiro [4.4] nonane-6-one to obtain (S) -1-R group-1-azaspiro [4.4] nonane-6-one and (R) -1-R group-1-azaspiro [4.4] nonane-6-one; the R group is selected from Boc, Bn, Ts and PhCO.
  2. 2. The process for producing (S) -1-Ryl-1-azaspiro [4.4] nonan-6-one and (R) -1-Ryl-1-azaspiro [4.4] nonan-6-one according to claim 1, wherein the reaction mixture of step (1) is reacted at a temperature of 0 ℃ to room temperature in a molar ratio of 1:1 to 1.5:1.5 to 2 of 3-butyn-1-ol, triethylamine and p-toluenesulfonyl chloride for 10 to 12 hours.
  3. 3. The process for producing (S) -1-Ryl-1-azaspiro [4.4] nonan-6-one and (R) -1-Ryl-1-azaspiro [4.4] nonan-6-one according to claim 1, wherein the crude separation is carried out in step (5) using tartaric acid, and 1-azaspiro [4.4] nonan-6-one and an equimolar amount of tartaric acid are added to acetone and reacted for 6 to 10 hours at room temperature.
  4. 4. The process for producing (S) -1-Ryl-1-azaspiro [4.4] nonan-6-one and (R) -1-Ryl-1-azaspiro [4.4] nonan-6-one according to claim 1, wherein in step (5), the secondary resolution is carried out using camphorsulfonic acid, and the tartrate salt of (S) -1-azaspiro [4.4] nonan-6-one is alkalinized at room temperature and reacted with an equimolar amount of (L) -camphorsulfonic acid in isopropanol for 6 to 10 hours; basified with (R) -1-azaspiro [4.4] nonan-6-one tartrate and reacted with an equimolar amount of (D) -camphorsulfonic acid in isopropanol for 6-10 h.
  5. 5. The method for producing (S) -1-Ryl-1-azaspiro [4.4] nonane-6-one and (R) -1-Ryl-1-azaspiro [4.4] nonane-6-one according to claim 1, wherein in the step (6), an acid anhydride or acid chloride is added under an alkaline condition to react for 2 to 24 hours, and the molar ratio of the base to the acid anhydride or acid chloride is 1:1.5 to 3:1.2 to 1.5.
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