CN107286031B - The preparation method of 2- lignocaine -1- Methylethyl -7- cyclohexyl -7- oxygen heptanoate - Google Patents
The preparation method of 2- lignocaine -1- Methylethyl -7- cyclohexyl -7- oxygen heptanoate Download PDFInfo
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Abstract
The present invention provides compound 2- lignocaine -1- Methylethyl -7- cyclohexyl -7- oxygen-heptanoates (1) and its synthetic method, the compound 1 to have following structure formula:
Description
Technical field
The invention belongs to chemicals to synthesize field, and in particular to the related substance of rociverine, 2- lignocaine -1- first
Base ethyl -7- cyclohexyl -7- oxygen-heptanoate preparation method.
Background technique
Rociverine (Rociverine), entitled 2- lignocaine -1- Methylethyl-cis- 1- hydroxyl [two hexamethylenes of chemistry
Base] -2- carboxylate, molecular formula C20H37NO3, trade name lira is logical.As spasmolysis and analgesia medicine, there is unique double action machine
On the one hand system has direct smooth muscle relaxation, on the other hand also has cholinolytic effect；Suitable for urogenital tract and
Spasmolysis, analgesia, dynamics difficult labour, puerperium uterine contraction pain and dysmenorrhea of biliary tract etc..Its structural formula is as follows:
Document mainly reports the synthetic route of two rociverines.
The synthetic route of patent GB1167386 report is: reacting using 2- methylol cyclohexanone as starting material by 5 steps
To rociverine.2- methylol cyclohexanone and the reaction of Grignard Reagent phenyl-magnesium-bromide first, obtain the cis- 1- phenyl -2- hydroxyl of intermediate
Methyl cyclohexanol；Cis- 1- phenyl -1- hydroxy-cyclohexyl -2- formic acid is aoxidized to obtain through alkalinity potassium permanganate；Through platinum oxide catalytic hydrogenation
Reduction phenyl ring obtains cis- 1- hydroxyl-[1,1 '-bis- (hexamethylenes)] -2- formic acid, then is condensed to yield 1- methyl-with 1,2- dibromopropane
Cis- 1- hydroxyl [the dicyclohexyl] -2- carboxylate of the bromo- ethyl-of 2-, last and diethylamine are condensed to yield target product rociverine.
Synthetic route 1
The synthetic route of patent US4336398 report is: reacting using 2- methylol cyclohexanone as starting material by 5 steps
To rociverine.2- methylol cyclohexanone and the reaction of Grignard Reagent phenyl-magnesium-bromide first, obtain the cis- 1- phenyl -2- hydroxyl of intermediate
Methyl cyclohexanol；Cis- 1- phenyl -1- hydroxy-cyclohexyl -2- formic acid is aoxidized to obtain through alkalinity potassium permanganate；Through aoxidizing platinum catalysis hydrogen
Change reduction phenyl ring and obtains cis- 1- hydroxyl-[1,1 '-bis- (hexamethylenes)] -2- formic acid；Obtained cis- 1- hydroxyl-[1,1 '-bis- (hexamethylenes
Alkane)] -2- formic acid is direct and the chloro- propylamine of N, N- diethyl -2- is condensed to yield rociverine.
Synthetic route 2
Present inventors have also extensively studied the route that existing two synthesize rociverine, two lines are had in common that finally
The operation of one step reaction requires heating operation, by the mixture of rociverine and the position isomer of rociverine at last
Hot-cast socket is walked at rociverine, other than the target product for preparing rociverine, it was found that unknown impurity.
The substance of any influence pharmaceutical purity is referred to as impurity, or is related substance, and miscellaneous Quality Research is drug research and development
An important content.Whether impurity can obtain rationally effective control, be directly related to the quality controllability and safety of drug
Property, state food and drug administration SFDA has formulated drug stringent quality standard for this.
Related object Quality Research is most important, finds in the gas-chromatography GC analysis of rociverine crude product, when retaining
Between the position 44.976min have a unknown impuritie, content is less, passes through the equal nothing of the methods of conventional lock out operation and HPLC preparative separation
Method obtains.By gas chromatography mass spectrometry GC-MS atlas analysis, know that the molecular weight of the unknown impuritie only has 339, without other molecular weight
Peak, and the molecular weight of rociverine is also 339, it is inferred that the molecular weight of the impurity is consistent with the molecular weight of rociverine.
Inventor has extensively studied the reaction mechanism of correlation step, it is found that last step operation requires heating behaviour
Make, infers in finally preparing the operating procedure in rociverine, the hydroxyl being heated at high temperature in the rociverine that may cause
The carbon atom open loop in position adjacent thereto of base position carbon atom, and then forming compound 1 is 2- lignocaine -1- Methylethyl -7- hexamethylene
Base -7- oxygen-heptanoate (1), structural formula:
Whether impurity can obtain rationally effective control, be directly related to the quality controllability and safety of drug, related
Object Quality Research is most important.In order to develop the rociverine bulk pharmaceutical chemicals of high-quality, it is necessary to further study this in relation to object
Matter.For this purpose, inventor's designed, designed synthetic route and controlled syntheses this in relation to substance, compared by gas phase, out peak position one
It causes, and mass spectrum MS comparison peak is consistent；Additionally by NMR nuclear magnetic data, confirm that the related substance is what inventor inferred before this
Structural formula 1.The compound 1 is reported without any pertinent literature, is novel compounds.
Summary of the invention
On the one hand, the present invention provides compounds 1, such as following structural formula:
Chemical structure is that the compound of formula 1 can be named as 2- lignocaine -1- Methylethyl -7- cyclohexyl -7- oxygen-enanthic acid
Ester.
On the other hand, the present invention provides the synthetic methods of compound 1, comprising the following steps:
1) it is starting material with cycloheptanone 2, obtains cyclic ester 4 with the oxidation of oxidant 3；2) cyclic ester 4 successively with compound 5, change
It closes the reaction of object 6 and generates alcohol 7；3) alcohol 7 obtains carboxylic acid 8 through oxidation reaction；4) carboxylic acid 8 and compound 9 are condensed to yield compound 1,
With reference to following synthetic route.
Synthetic route 3
The preferred embodiment and implementation condition of above steps in the present invention are provided further below.
In the route of above-mentioned synthesis compound 1, the oxidant 3 in the step 1) is peroxide, such as peroxide second
Acid, peroxy trifluoroacetic acid, benzoyl hydroperoxide, metachloroperbenzoic acid；It is preferred that metachloroperbenzoic acid.When with chloroperoxybenzoic acid
For oxidant, it is to insert the carbonyl site of cyclic ketone that the oxidation reaction of step 1), which is also referred to as Baeyer-Villiger oxidation,
Enter the oxidation reaction of oxygen atom, reaction obtains corresponding ester compounds.
In the step 2), the cyclic ester 4 and the reaction of compound 5 obtain Weinreb amide intermediate 10, described
Weinreb amide intermediate 10 is reacted with compound 6 again generates alcohol 7.Above-mentioned steps 2) operation preferably " one kettle way " operation, i.e.,
It is not necessary that the cyclic ester 4 and the reaction of compound 5 are obtained Weinreb amide and isolated and purified, directly in resulting reaction solution
Compound 6 is added, reaction further obtains the alcohol 7.
In the step 3), the end position hydroxyl in 7 structure of alcohol obtains corresponding carboxylic acid through oxidation operation appropriate
Compound；Preferred oxidation operation are as follows: alcohol 7 aoxidizes to obtain intermediate aldehydes by TEMPO, then aoxidizes to obtain carboxylic acid through Pinnick
8, preferred to operate: TEMPO oxidation and Pinnick oxidation can be operated by one kettle way.
TEMPO oxidation refers to that using sodium hypochlorite as oxidant, TEMPO is catalyst, and sodium bromide is co-catalyst, -10
DEG C~10 DEG C at, alcohol is oxidized to the oxidation reaction of aldehyde in methylene chloride and water two-phase solvent.
Pinnick oxidation refers to that using sodium chlorite as oxidant, 30% hydrogen peroxide is hypochlorous acid remover, and the tert-butyl alcohol is equal
Phase reaction solvent, saturation biphosphate sodium water solution provide suitable system pH, at room temperature, the oxidation of formoxy- chemical conversion acid is anti-
It answers.
In the step 4), the carboxylic acid 8 and compound 9 are condensed to yield target product 1.
Therefore, a kind of preferred embodiment, the synthetic method of compound 1 provided by the invention, comprising the following steps:
It 1) is that starting material is aoxidized by oxidant 3 of metachloroperbenzoic acid through Baeyer-Villiger with cycloheptanone 2
To compound 4；2) compound 4 is through one kettle way, and first and the reaction of compound 5 generates Weinreb amide intermediate 10, then with compound
6 reactions generate alcohol 7；3) alcohol 7 first passes through TEMPO and aoxidizes to obtain intermediate aldehydes also through one kettle way, then aoxidizes to obtain through Pinnick
Carboxylic acid 8；4) target product 1 is condensed to yield finally by carboxylic acid 8 and compound 9.
The preferred embodiment of the synthetic method for the compound 1 that aforementioned present invention provides, this field those having ordinary skill in the art can
To select the specific operating conditions such as reaction temperature according to reaction type, and the reaction time can be by chromatography method for example
The tracking reaction of the conventional technical means such as thin-layer chromatography or gas-chromatography is known.
Further, it in the synthetic method that aforementioned present invention provides compound 1, additionally provides and is not disclosed or reports
The novel compounds crossed, alcohol 7, it may be assumed that 1- cyclohexyl -7- hydroxyl -1- heptanone.
The third aspect, 1 (2- lignocaine -1- Methylethyl -7- cyclohexyl -7- oxygen-enanthic acid of compound provided by the invention
Ester) as the purposes for monitoring the impurity reference substance that rociverine bulk pharmaceutical chemicals synthesize.
Present invention has an advantage that cycloheptanone is used to synthesize compound 1 through four-step reaction for starting material, products therefrom is each
Step post-processing is simple, and product is conveniently easy to get, and is suitble to a large amount of synthesis, and the quality research for the synthesis of rociverine bulk pharmaceutical chemicals is provided with
Close substance or impurity reference substance.
Specific embodiment
The specific embodiment and embodiment of a kind of specific detailed operating process presented below, to further elucidate this hair
It is bright.It should be pointed out that without departing from the inventive concept of the premise, can also be done for those skilled in the art
Several improvements and modifications out, it is interior that these modifications and embellishments should also be considered as the scope of protection of the present invention.
Specific embodiment
The preparation of step 1), cyclic ester 4:
Metachloroperbenzoic acid is added in reaction flask first, adds methylene chloride, ice bath stirring cooling, drop
To -5 DEG C~5 DEG C, cycloheptanone is added dropwise, after dripping, is warming up to 25 DEG C~40 DEG C, continues stirring 5~10 days, after having reacted, add
Saturated aqueous sodium thiosulfate is quenched, and is washed for several times after being quenched with saturated sodium bicarbonate aqueous solution, then uses saturated salt solution
Washing, anhydrous magnesium sulfate is dry, is concentrated to get 4 crude product of compound, obtains compound 4 by column.In step 1), reaction temperature is excellent
It selects 25 DEG C (room temperatures), the reaction time is preferably 7 days.
The preparation of step 2), alcohol 7:
By compound 4, N, O- dimethyl hydroxylamine hydrochloride, methylene chloride sequentially add reaction flask, and ice salt bath cools down,
It is down to -10 DEG C~0 DEG C, the tetrahydrofuran solution of 2M isopropylmagnesium chloride is added dropwise, continues low temperature and stirs 1~3h, after fully reacting,
The tetrahydrofuran solution of 1M cyclohexyl magnesium bromide is slowly added dropwise, after being all added dropwise, is warmed to room temperature 3~5h of stirring, has reacted
Quan Hou is quenched with 2M aqueous hydrochloric acid solution, then obtains yellow oil i.e. 7 crude product of alcohol through conventional post-processing, chromatographs to obtain alcohol through column
7.In step 2), reaction mass molar ratio is preferably compound 4:N, O- dimethyl hydroxylamine hydrochloride: isopropylmagnesium chloride:
Cyclohexyl magnesium bromide=1:1:2:8.
The preparation of step 3), carboxylic acid 8:
Alcohol 7, methylene chloride, water, sodium bromide, TEMPO are sequentially added in reaction flask, stirring is cooled to -5 DEG C, then drips
Add commercially available 5.2% aqueous sodium hypochlorite solution for mixing up pH with saturated sodium bicarbonate aqueous solution, continues stirring 0.5 after being added dropwise
~1.5h, then with 2M aqueous hydrochloric acid solution tune reaction system pH to 6~7, sequentially adds the tert-butyl alcohol, 30% hydrogen peroxide, then with saturation
Sodium chlorite is finally added dropwise in biphosphate sodium water solution tune reaction system pH to 4.3 or so, reacts 2~4h, is added a small amount of anhydrous
Sodium sulfite is quenched, concentration, obtains concentrate and is extracted with ethyl acetate for several times, dry, is concentrated up to 8 crude product of carboxylic acid, then with just
Hexane washing, obtains carboxylic acid 8.In step 3), reaction mass molar ratio is alcohol 7:TEMPO:NaBr:NaClO:30%H2O2: NaClO2=1:(1~2%): (0.1~0.5): (1.1~1.4): (1.5~2): (1.1~1.4)；Saturated sodium bicarbonate water is molten
The pH of liquid tune aqueous sodium hypochlorite solution is preferably 8.5~9.5；Being saturated biphosphate sodium water solution tune reaction system pH is preferably
4.3。
Step 4), the preparation of 2- lignocaine -1- Methylethyl -7- cyclohexyl -7- oxygen-heptanoate (1):
The carboxylic acid 8 being prepared is dissolved in isopropanol, catalyst potassium carbonate is added, is heated to reflux, by N, N- diethyl-
The chloro- propylamin hydrochloride of 2- is dissolved in isopropanol and is slowly added dropwise into the reaction solution of above-mentioned reflux, after dripping off, continues stirring 1
~5h, has reacted, and filters, and concentration obtains crude product, obtains target product 1 through column separation.In step 4), the reaction time is preferred
For 3h.
Further provide for embodiment below.
In the following examples, the experimental methods for specific conditions are not specified, according to conventional methods and conditions, or says according to commodity
Bright book selection.The commercially available acquisition of agents useful for same and raw material of the present invention is prepared according to known references method.
Embodiment
Embodiment one: the preparation of cyclic ester 4
First by 85% m-CPBA (95g, 0.55mol, 1.8eq), methylene chloride (1000ml) sequentially adds the reaction of 2L
In bottle, ice bath cooling stirring starts that cycloheptanone (34g, 0.31mol) is added dropwise, the phase is added dropwise when temperature of reaction system reaches 0 DEG C
Between system temperature be basically unchanged, recession is added dropwise and removes ice bath, room temperature (25 DEG C) continues to stir, react 7 days, present invention liquid by
It is transparent to become white opacity.Add saturated sodium thiosulfate solution to be quenched, be quenched plus 10% sodium bicarbonate aqueous solution washs for several times,
Saturated common salt water washing, organic layer dry, filter, and are concentrated to give 4 crude product of compound, then chromatograph to obtain compound 4 through column
(19.5g), yield 50.2%.[M+H]+=129
1H-NMR (400MHz, CDCl3) δ 4.34 (t, 2H), 2.53 (t, 2H), 1.90~1.77 (m, 4H), 1.64~1.53
(m, 4H)
Embodiment two: the preparation of alcohol 7
Successively by compound 4 (0.64g, 5mmol), N, O- dimethyl hydroxylamine hydrochloride (0.4875g, 5mmol, 1eq), two
Chloromethanes (20ml) is added in reaction flask, and it is different to start dropwise addition 2M when system temperature reaches -3~-4 DEG C for ice salt bath stirring cooling
The THF solution (5.5ml, 11mmol, 2.2eq) of propyl magnesium chloride obtains golden yellow liquid after being added dropwise, continue low temperature stirring
1h.After contact plate monitors fully reacting, start the THF solution (15ml, 15mmol, 3eq) that the hexamethylene magnesium bromide of 1M is slowly added dropwise,
System temperature is maintained at -3.5 DEG C, reacts at room temperature 4h after being added dropwise, and is quenched with 2M aqueous hydrochloric acid solution (10ml), with saturation
Sodium bicarbonate aqueous solution washs 2 times, washes 2 times, organic layer dries, filters, and is concentrated to give 1.72g yellow oil, chromatographs through column
Obtain 0.2g alcohol 7, yield 18.9%.[M+H]+=213
1H-NMR (400MHz, CDCl3) δ 3.64 (t, 2H), 2.43 (t, 2H), 2.40-2.25 (m, 1H), 1.84-1.54
(m, 9H), 1.41-1.18 (m, 10H)
Embodiment three: the preparation of alcohol 7
Successively by compound 4 (1.92g, 15mmol), N, O- dimethyl hydroxylamine hydrochloride (1.46g, 15mmol, 1eq), two
Chloromethanes (60ml) is added in reaction flask, and it is different to start dropwise addition 2M when system temperature reaches -3~-4 DEG C for ice salt bath stirring cooling
The THF solution (15ml, 30mmol, 2eq) of propyl magnesium chloride obtains golden yellow liquid after being added dropwise, continue low temperature and stir 1h.Point
After plate monitoring has been reacted, start the THF solution (120ml, 120mmol, 8eq) that the hexamethylene magnesium bromide of 1M is slowly added dropwise, system
Temperature is maintained at 0 DEG C hereinafter, react at room temperature 2h after being added dropwise, and is quenched with 2M aqueous hydrochloric acid solution (90ml), uses saturated carbon
Sour hydrogen sodium water solution washs 2 times, washes 2 times, organic layer dries, filters, and is concentrated to give yellow oil, chromatographs to obtain 1.35g through column
Alcohol 7, yield 42.5%.[M+H]+=213
Example IV: the preparation of carboxylic acid 8
By alcohol 7 (1.06g, 5mmol), methylene chloride (20ml), TEMPO (0.0156g, 0.1mmol, 0.02eq), NaBr
(0.05g, 0.5mmol, 0.1eq), water (5ml) sequentially add in reaction flask, low temperature stirring, when system temperature is down to -5 DEG C, drop
Add sodium hypochlorite (7.15ml, 5.5mmol, 1.1eq) aqueous solution with saturated sodium bicarbonate aqueous solution tune pH to 9.2, drips
Bi Hou, TLC monitor fully reacting, continue to stir 1h, then use 2M aqueous hydrochloric acid solution tune system pH to 6~7, sequentially add tertiary fourth
Alcohol (15ml), 30% hydrogen peroxide (1ml, 10mmol, 2eq), then with biphosphate sodium water solution tune system pH to 4.3 is saturated, most
The 20ml aqueous solution of sodium chlorite (0.79g, 7mmol, 1.4eq) is added dropwise afterwards, after being added dropwise, the reaction was continued 2.5h, TLC monitoring
Fully reacting is added a small amount of sodium sulfite and is quenched, and concentration is extracted with ethyl acetate 3 times, and each 100ml is dried, filtered, concentration
Yellow oil is obtained, n-hexane is added to be beaten to obtain white solid, 0.9g, yield 80% are obtained after drying.[M+H]+=227, [M+K]+
=265
1H-NMR (400MHz, CDCl3) δ 2.42 (t, 2H), 2.35-2.27 (m, 3H), 1.81-1.12 (m, 16H)
Embodiment five: the synthesis of compound 1
Carboxylic acid 8 (0.7g, 3.1mmol) is dissolved in isopropanol (15ml) and is added in reaction flask, potassium carbonate is added
(0.68g, 4.9mmol, 1.5eq), heating stirring is to flowing back, by the isopropanol of compound 9 (0.56g, 3mmol, 0.97eq)
(15ml) solution is slowly added dropwise into reaction solution, after being added dropwise, continues to be heated at reflux, and reacts 3h, and TLC is monitored, fully reacting,
Cooling, filtering is concentrated to get 1 crude product of 1g target product, chromatographs to obtain 0.25g target product 1,24.6% [M+ of yield by column
H]+=340
Embodiment six: the synthesis of compound 1
Carboxylic acid 8 (1.4g, 6.2mmol) is dissolved in isopropanol (30ml) and is added in reaction flask, potassium carbonate is added
(1.36g, 9.8mmol, 1.5eq), heating stirring is to flowing back, by the isopropanol of compound 9 (1.12g, 6mmol, 0.97eq)
(30ml) solution is slowly added dropwise into reaction solution, after being added dropwise, continues to be heated at reflux, and reacts 3h, and TLC is monitored, fully reacting,
Cooling, filtering is concentrated to get 1 crude product of 2.1g target product, chromatographs to obtain 0.6g target product 1,29.5% [M+ of yield by column
H]+=340
1H-NMR (400MHz, CDCl3) δ 4.98 (m, 1H), 2.54-2.49 (m, 5H), 2.43-2.24 (m, 6H), 1.81-
1.52 (m, 9H), 1.35-1.15 (m, 10H), 0.98 (t, 6H)
The vapor detection condition of rociverine bulk pharmaceutical chemicals product:
Chromatographic column: -95% dimethyl polysiloxane of 5%- diphenyl be fixer capillary column (30m × 0.32mm ×
0.25um, DB-5MS UI), 180 DEG C of column temperature, detector is flame ionization ditector, and detection temperature is 280 DEG C；Injection port
Temperature is 240 DEG C；Split ratio is 5:1；Flow rate of carrier gas is 2.0ml/min.
Rociverine crude product is synthesized according to the corresponding conditions of patent route, when last step synthesizes rociverine, oil bath
Temperature reacts 6 hours at 180 DEG C~200 DEG C, rociverine is prepared.Inventor by rociverine carry out GC analysis,
There is peak area to be greater than the impurity of 0.1% (0.36%) when retention time is 44.976min, is compound 1 according to reaction and judgement.
Designed, designed route, for the first time controlled syntheses compound 1.It is confirmed through GC, the compound 1 synthesized is in aforementioned gas phase
Under the conditions of detect, retention time 45.777min.In error range, having in rociverine crude product is prepared with above-mentioned
It is identical to close substance retention time.For this purpose, the controlled syntheses of the present invention related substance of rociverine bulk pharmaceutical chemicals, synthesis side used
Method yield is higher, can prepare enough impurity for the quality controling research in rociverine bulk pharmaceutical chemicals synthesis technology.
Claims (11)
1. such as 1 compound represented 1 of following formula:
2. the synthetic method of compound 1 as described in claim 1, comprising the following steps:
1) it is starting material with cycloheptanone 2, obtains cyclic ester 4 through the oxidation of oxidant 3；2) cyclic ester 4 successively with compound 5, compound 6
Reaction generates alcohol 7；3) alcohol 7 obtains carboxylic acid 8 through oxidation reaction；4) carboxylic acid 8 and compound 9 are condensed to yield compound 1, synthesize road
Line are as follows:
3. the synthetic method of compound 1 as claimed in claim 2, which is characterized in that the oxidant 3 in the step 1) is choosing
From Peracetic acid, peroxy trifluoroacetic acid, benzoyl hydroperoxide, metachloroperbenzoic acid peroxide.
4. the synthetic method of compound 1 as claimed in claim 3, which is characterized in that between the oxidant 3 in the step 1) is
Chloroperoxybenzoic acid.
5. the synthetic method of compound 1 as claimed in claim 2, which is characterized in that in the step 2), cyclic ester 4 successively and
Compound 5, the reaction of compound 6 generate alcohol 7；The operation of step 2) is " one kettle way " operation.
6. the synthetic method of compound 1 as claimed in claim 2, which is characterized in that the oxidation reaction of the step 3) are as follows: alcohol
7 obtain intermediate aldehydes by tetramethyl piperidine nitrogen oxides, then obtain carboxylic acid 8 through Jouko Lindgren's oxidation reaction.
7. the synthetic method of compound 1 as claimed in claim 6, which is characterized in that the oxidation reaction of the step 3) is four
Methyl piperidine nitrogen oxides and Jouko Lindgren's oxidation reaction, two step are operated by " one kettle way ".
8. the synthetic method of compound 1 as claimed in claims 6 or 7, which is characterized in that in the step 3), tetramethyl piperazine
The reaction condition of pyridine nitrogen oxides are as follows: using sodium hypochlorite as oxidant, tetramethyl piperidine nitrogen oxides is catalyst, bromination
Sodium is co-catalyst, and at -10 DEG C~10 DEG C, as reaction dissolvent, alcohol is oxidized to aldehyde for methylene chloride and water two-phase solvent.
9. the synthetic method of compound 1 as claimed in claims 6 or 7, which is characterized in that in the step 3), Jouko Lindgren
The reaction condition of oxidation reaction are as follows: using sodium chlorite as oxidant, 30% hydrogen peroxide is hypochlorous acid remover, and the tert-butyl alcohol is homogeneous
Reaction dissolvent, saturation biphosphate sodium water solution provide suitable system pH, at room temperature, formoxy- chemical conversion acid.
10. the synthetic method of compound 1 as claimed in claim 2, which comprises the following steps:
It 1) is that starting material obtains compound 4 through oxidation by oxidant 3 of metachloroperbenzoic acid with cycloheptanone 2；2) compound 4
Through one kettle way, is successively reacted with compound 5, compound 6 and generate alcohol 7；3) alcohol 7 first passes through tetramethyl piperidine nitrogen oxygen through one kettle way
Compound aoxidizes to obtain intermediate aldehydes, then obtains carboxylic acid 8 through Jouko Lindgren's oxidation reaction；4) finally by the contracting of carboxylic acid 8 and compound 9
Conjunction obtains target product 1.
11. its use as the impurity reference substance of monitoring rociverine bulk pharmaceutical chemicals synthesis of compound 1 according to claim 1
On the way.
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| WO2009018169A1 (en) * | 2007-07-27 | 2009-02-05 | Auspex Pharmaceuticals, Inc. | Substituted cyclohexanols |
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| WO2009018169A1 (en) * | 2007-07-27 | 2009-02-05 | Auspex Pharmaceuticals, Inc. | Substituted cyclohexanols |
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| L-Threonine-catalysed asymmetric a-hydroxymethylation of cyclohexanone:application to the synthesis of pharmaceutical compounds and natural products;Anqi Chen等;《Tetrahedron》;20091202;第66卷;第1489-1495页 * |
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