CN108218773A - A kind of method for preparing resisting allergic rhinitis drug loratadine intermedite - Google Patents
A kind of method for preparing resisting allergic rhinitis drug loratadine intermedite Download PDFInfo
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- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
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Abstract
The invention belongs to chemical drugs preparing technical fields, and in particular to a kind of method that solid acid prepares resisting allergic rhinitis drug loratadine intermedite.The present invention is using ammonium metatungstate as WO3Precursor, with ZrOCl2·8H2O is ZrO2Precursor carries out load WO on the silica gel of sulfamide groups graft modification3/ZrO2Solid super-strong acid forms silica gel load solid acid.8 chlorine, 5,6 dihydro 11 is prepared with novel silica gel loaded solid acid catalysisHBenzo [5,6] cycloheptane simultaneously [1,2b] 11 ketone of pyridine, it overcomes wastewater flow rate and alleviates environmental protection pressure greatly, improve reaction yield.
Description
Technical field
The invention belongs to chemical drugs preparing technical fields, and in particular to a kind of to prepare resisting allergic rhinitis drug Loratadine
The method of intermediate.
Background technology
Loratadine (loratadine) is developed by Schering Plough companies of the U.S., is second generation H1 receptors
Antagonist selects sex resistance peripheral H1-receptor, does not enter nervous centralis, the adverse reactions such as no calmness, drowsiness are one quick-acting, strong
Effect, long-acting antihistamine.Further, since cardiac toxic is low, has good treat to allergy such as rhinitis and chronic urticarias
Effect, prescription account for leading position in second generation antihistamine.U.S. FDA is ratified Loratadine and is sold as OTC medicines, and 2005
The antiallergic Clarityne of state food and drug administration's approval in year July Schering Plough enters OTC catalogues, before market
Scape is wide.
There are many preparation methods at present to obtain Loratadine, but one is all referred in its a variety of synthetic route and shares centre
Chloro- 5,6- dihydros -11H- benzos [5, the 6] cycloheptane of body 8- simultaneously-[1,2-b] pyridine -11- ketone, structural formula is as shown in (1) formula：
The method of synthesis formula (1) compound is mainly the following at present：
1) Grignard Reagent cyclisation method
Grignard Reagent property is extremely active, can be with compound (such as ROH, RC ≡ CH) aldehyde, ketone, ester, acyl with active hydrogen
The reactions such as halogen, nitrile, ethylene oxide, alkyl halide, carbon dioxide, phosphorus trichloride, boron chloride, silicon tetrachloride are unfavorable for workshop life
Produce amplifieroperation.
2) super acids cyclisation method
The route uses liquid super acids as cyclodehydration reagent, however super acids are high to equipment requirement, and generate
A large amount of spent acid bring huge environmental protection pressure；Sucking HF steams or contact skin can cause be difficult to cure to burn.
3) friedel-crafts acylation cyclisation method
Its starting carboxylic acid must be purified before Friedel-Crafts reaction in the route, and its yield of friedel-crafts acylation compared with
It is low, only 40% or so (Chinese Journal of Pharmaceuticals, 2013,44 (12)：Chloro- 5, the 6- dihydros -11H- benzos of 1215-1216,8-
[5,6] synthesis of cycloheptane simultaneously [1,2-b] pyridine -11- ketone).
4) dehydrating agent/super acids or dehydrating agent/lewis acid combination catalytic cyclization method
WO 00/30589 is disclosed a kind of to be cyclized using dehydrating agent/super acids or dehydrating agent/lewis acid combination
The method for preparing tricyclic compound, reaction equation are as follows：
The route is the research and development of Schering Plough company of the U.S., belongs to the improvement of super acids cyclisation method, and dehydrating agent may be used
P2O5、PCl5、POCl3, lewis acid is selected from AlCl3、FeCl3.Although the technique has larger improvement compared with super acids cyclisation method, receive
Rate is up between 50-70%；With PCl5/AlCl3System yield highest, up to 71% (see 00/30589 embodiments 6 of WO).But
It is still needed to after the technique using large excess of AlCl3(3.98eq) and PCl5(1.49eq) causes to generate a large amount of spent acid；After and
Handle it is cumbersome, due to AlCl3Addition is excessive, which to be caused to generate many jellies, causes subsequently to extract in liquid separation and should not be layered, and needs
It carries out at high temperature.
So a kind of acid catalyzed method of green solid is provided to substitute stoichiometric acid catalysed cyclisation in the prior art
Method prepare chloro- 5,6- dihydros -11H- benzos [5,6] cycloheptane of 8- simultaneously-[1,2-b] pyridine -11- ketone have important meaning
Justice.
Invention content
The purpose of the present invention is overcoming deficiency of the prior art, a kind of solid acid is provided and prepares resisting allergic rhinitis drug
The method of loratadine intermedite, the present invention is using ammonium metatungstate as WO3Precursor, with ZrOCl2·8H2O is ZrO2Precursor, in amino
Load WO is carried out on the silica gel of sulfonic group graft modification3/ZrO2Solid super-strong acid forms silica gel load solid acid.With novel silica gel
Supported solid acid catalysis prepares chloro- 5,6- dihydros -11H- benzos [5, the 6] cycloheptane of 8- simultaneously-[1,2-b] pyridine -11- ketone, overcomes
Wastewater flow rate alleviates greatly environmental protection pressure, improves reaction yield.
According to the first aspect of the invention, the present invention provides a kind of solid acids to prepare resisting allergic rhinitis drug chlorine thunder
He determines the method for intermediate, and amide SM cyclizations generation imines IND, is then hydrolyzed under the action of nonaqueous solvents and catalyst
Obtain chloro- 5,6- dihydros -11H- benzos [5, the 6] cycloheptane of 8- simultaneously-[1,2-b] pyridine -11- ketone, reaction equation Scheme 1；
The catalyst is prepared by following preparation method：
1) preparation of modified silica gel carrier：10.0g high-purity silica gels are placed in 100ml dry toluenes, are warming up to 40-60
DEG C, 5ml 3- (2- aminoethylaminos) propyl trimethoxy silicanes and 10ml 3- mercaptopropyl trimethoxysilanes is then added dropwise,
Back flow reaction 8-10h under nitrogen atmosphere；It is cooled to room temperature filtering, acetone elution and then dry amino mercapto modified silica-gel；It will
Amino mercapto modified silica-gel is placed in the aqueous solution of nitric acid of 68%wt ultrasonic immersing 1-2h at 40-50 DEG C, and filtering is washed to filtrate
Into neutrality, filter cake is dried under vacuum to the silica gel that constant weight obtains sulfamide groups graft modification；The present invention is with 3- (2- amino-ethyl ammonia
Base) propyl trimethoxy silicane and 3- mercaptopropyl trimethoxysilanes as silane coupling agent, introduce long chain amino and sulfydryl, so
It carries out oxidation to sulfydryl using nitric acid afterwards and is converted into the final silica-gel carrier for obtaining amino and sulfonic group grafting of sulfonic group；
2) co-precipitation prepares solid acid：By 13-15g ammonium metatungstates, 3-4g ZrOCl28H2O reflux 1- soluble in water
2h, ammonium hydroxide regulation system pH to 8.0-8.2 generate sediment, be cooled to 50-60 DEG C of aging for 24 hours, filtering, washing go dechlorination from
Son, calcining 1-2h obtains solid super-strong acid under the atmosphere of air；
3) modified silica-gel supported solid acid：Silica gel, the 1.0g PEG-800 of 100g sulfamide groups graft modifications are placed in
Ultrasonic disperse 30min in 500ml ethyl alcohol, then filtering, acetone wash, at 80 DEG C after addition solid super-strong acid 5-20g reflux 12h
Drying to constant weight obtains catalyst.
The present invention is using ammonium metatungstate as WO3Precursor, with ZrOCl2·8H2O is ZrO2Precursor changes in sulfamide groups grafting
Load WO is carried out on the silica gel of property3/ZrO2Solid super-strong acid forms silica gel load solid acid.The present invention uses amino and sulfonic group
The silica gel of graft modification improves the adsorption capacity of solid acid and silica-gel carrier, avoids solid acid and reacted in catalysis as carrier
In the shortcomings that being easy to run off；In addition it can follow the catalyst prepared as carrier using amino and the silica gel of sulfonic group graft modification
Ring set is used.
Preferably, the temperature of the step 2) calcining is 600-700 DEG C.Calcination temperature influence is urged in solid acid preparation process
The pattern and activity of agent, the present invention obtain catalyst activity highest to be calcined at 600-700 DEG C.
Preferably, amide SM cyclizations generate imines IND under the action of nonaqueous solvents and catalyst, are then hydrolyzed
Chloro- 5,6- dihydros -11H- benzos [5,6] cycloheptane of 8- simultaneously-[1,2-b] pyridine -11- ketone the specific steps are：
A) raw material amide SM, catalyst are placed in nonaqueous solvents, are warming up to back flow reaction 4-12h；
B) it after HPLC detects raw material amide SM conversions completely, is cooled to room temperature filtering removal catalyst and obtains filtrate；
C) sodium hydrate aqueous solution that 2mol/L is added in into filtrate adjusts pH to 10-11；
D) it is warming up to 80-90 DEG C of stirring to be hydrolyzed for 2-3 hours, the aqueous hydrochloric acid solution regulation system pH of 2mol/L is added dropwise extremely
Purified water or normal heptane crystallization, filtering, dry chloro- 5,6- dihydros -11H- benzos [5, the 6] rings of off-white powder 8- is added dropwise in 6-7
Heptane simultaneously-[1,2-b] pyridine -11- ketone.
Preferably, the nonaqueous solvents for tetrahydrofuran, dichloromethane, chloroform, isopropyl acetate, butanone, more preferably
Tetrahydrofuran；
Preferably, the catalyst amount is the 5%wt-40%wt, more preferably 10%wt-20%wt of amide SM；It closes
Generate a molecular water in ring reaction process, the carrier of catalyst contains a large amount of amino and sulfonic group in the present invention, can play
Absorb the water of generation.
Preferably, the nonaqueous solvents is tetrahydrofuran, and normal heptane crystallization is added dropwise in step d).Compared to tetrahydrofuran/
For the binary mixture of water, impurity more enough can be effectively removed, and can obtain using tetrahydrofuran/water/normal heptane ternary system
Obtain higher yields.
Compared with prior art, the invention has the advantages that：
1) present invention carries out amino and sulfonated modification to silica gel, then carries out supported solid acid and obtains a kind of novel solid
Acid catalyst；
2) novel solid acid catalyst prepared by the present invention can prepare the chloro- 5,6- dihydros -11H- of 8- with catalytic cyclization reaction
Benzo [5,6] cycloheptane simultaneously-[1,2-b] pyridine -11- ketone；
3) novel solid acid catalyst prepared by the present invention can solve the generation of acid waste water in the prior art, alleviate ring
Packing pressure；
4) novel solid acid catalyst prepared by the present invention can prepare the chloro- 5,6- dihydros -11H- of 8- with catalytic cyclization reaction
Simultaneously-[1,2-b] pyridine -11- ketone can realize recycled to benzo [5,6] cycloheptane, and activity is basically unchanged after applying mechanically five times；
5) Catalytic processes are optimized in the present invention, and tetrahydrofuran is selected normal heptane to be used to match for anti-solvent for solvent
It closes and uses, do not only reached more than 90% yield, and product purity is up to 99.9%.
Specific embodiment
Understand to make the object, technical solutions and advantages of the present invention clearer, With reference to embodiment, to this
Invention is further described.It should be understood that these descriptions are merely illustrative, and it is not intended to limit the scope of the present invention.
The raw material amide SM that the present invention uses is to make sample by oneself with reference to introduction (WO00/30589) of the prior art, is used
Column chromatography purifying is carried out after isopropanol crystallization, HPLC purity is 99.95%, and fusing point is 80.5 DEG C；Remaining reagent is commercially available sample
Product.
Chloro- 5,6- dihydros -11H- benzos [5,6] cycloheptane of 8- simultaneously-[1,2-b] pyridine -11- ketone HPLC detection methods：Peace
Prompt 1260 liquid chromatograph of human relations, C18 chromatographic columns, mobile phase (volume ratio A phases：B phase=20:80, A phases are the phosphate of pH=6.0
Aqueous solution, B phases are methanol), flow velocity 1ml/min；Detection wavelength 247nm.
Embodiment 1
Prepare catalyst：
1) preparation of modified silica gel carrier：By 10.0g high-purity silica gels, (aperture isGrain size is 300-400 mesh) it puts
In 100ml dry toluenes, 40-60 DEG C is warming up to, 5ml 3- (2- aminoethylaminos) propyl trimethoxy silicon is then added dropwise
Alkane and 10ml 3- mercaptopropyl trimethoxysilanes, back flow reaction 8-10h under nitrogen atmosphere；It is cooled to room temperature filtering, 20ml acetone
Elution, dry amino mercapto modified silica-gel at 80 DEG C；Amino mercapto modified silica-gel is placed in the aqueous solution of nitric acid of 68%wt
Ultrasonic immersing 1-2h at 40-50 DEG C, filtering, is washed to filtrate into neutrality, filter cake is dried under vacuum to constant weight at 65 DEG C and obtains amino
The silica gel of sulfonic group graft modification；
2) co-precipitation prepares solid acid：By 14g ammonium metatungstates, 3.2g ZrOCl2〃8H2O reflux 1-2h soluble in water, ammonium hydroxide
Regulation system pH to 8.0-8.2 generates sediment, is cooled to 50-60 DEG C of aging for 24 hours, and removing chloride is removed in filtering, washing, in air
Atmosphere under at 650 DEG C calcine 1-2h obtain solid super-strong acid；
3) modified silica-gel supported solid acid：Silica gel, the 1.0g PEG-800 of 100g sulfamide groups graft modifications are placed in
Ultrasonic disperse 30min in 500ml ethyl alcohol, then filtering, acetone are washed, are done at 80 DEG C after addition solid super-strong acid 10g reflux 12h
Dry to obtain catalyst to constant weight, catalyst sample is defined as Cat-SA/MSol-650.
Comparative example 1
Compared with Example 1, sulfamide groups graft modification is not carried out to silica gel, remaining is completely the same with embodiment 1, system
It is Cat-SA/Sol-650 for sample identity is gone out.
Comparative example 2
Compared with Example 1, the calcination temperature in changing the step 2), respectively 100 DEG C, 200 DEG C, 300 DEG C, 400 DEG C,
500 DEG C, 600 DEG C, 700 DEG C, 800 DEG C, 900 DEG C, the sample prepared is respectively defined as Cat-SA/MSol-100, Cat-SA/
MSol-200、Cat-SA/MSol-300、Cat-SA/MSol-400、Cat-SA/MSol-500、Cat-SA/MSol-600、Cat-
SA/MSol-700、Cat-SA/MSol-800、Cat-SA/MSol-900。
Catalytic performance detects：
The chloro- 5,6- dihydros -11H- of 8- are prepared using embodiment 1 and its comparative example 1-2 the catalyst amide SM prepared
Simultaneously-[1,2-b] pyridine -11- ketone, influence of the investigation different solvents to reaction, preparation process are as follows for benzo [5,6] cycloheptane：
A) 3.4g raw material amide SM, 0.5g catalyst is placed in 20ml dichloromethane, is warming up to back flow reaction；
B) it when HPLC detections raw material amide SM is no longer reduced, is cooled to room temperature filtering removal catalyst and obtains filtrate；
C) sodium hydrate aqueous solution that 10ml 2mol/L are added in into filtrate adjusts pH to 10-11；
D) it is warming up to 80-90 DEG C of stirring to be hydrolyzed for 2-3 hours, the aqueous hydrochloric acid solution regulation system pH of 2mol/L is added dropwise extremely
6-7, be added dropwise purified water crystallization, filtering, dry chloro- 5,6- dihydros -11H- benzos [5, the 6] cycloheptane of off-white powder 8- simultaneously -
[1,2-b] pyridine -11- ketone.
Count the chloro- 5,6- dihydros -11H- of conversion ratio, product 8- of substrate amide SM in above-mentioned different catalysts catalysis reaction
Simultaneously-[1,2-b] pyridine -11- ketone separation HPLC purity, statistical result are shown in Table 1 to benzo [5,6] cycloheptane.
1 different catalysts catalytic performance result of table
Note："-" expression is not detected product.
The above result shows that the calcination temperature of solid acid has significant impact to the catalytic performance of catalyst, it is necessary to pass through
It crosses high temperature to be activated, temperature is advisable with 600-700 DEG C；But temperature is decreased higher than 800 DEG C or more activity, so calcining
Temperature should not be higher than 800 DEG C；In addition, the more simple silica gel of silica gel catalyst activity using sulfamide groups graft modification is carried
It is high.
Embodiment 2
The influence of differential responses solvent is investigated using catalyst prepared by embodiment 1, preparation process is as follows：
A) 3.4g raw material amide SM, 0.5g catalyst is placed in 20ml solvents, is warming up to back flow reaction；
B) it when HPLC detections raw material amide SM is no longer reduced, is cooled to room temperature filtering removal catalyst and obtains filtrate；
C) sodium hydrate aqueous solution that 10ml 2mol/L are added in into filtrate adjusts pH to 10-11；
D) it is warming up to 80-90 DEG C of stirring to be hydrolyzed for 2-3 hours, the aqueous hydrochloric acid solution regulation system pH of 2mol/L is added dropwise extremely
6-7, be added dropwise purified water crystallization, filtering, dry chloro- 5,6- dihydros -11H- benzos [5, the 6] cycloheptane of off-white powder 8- simultaneously -
[1,2-b] pyridine -11- ketone, HPLC detection product purities and maximum list are miscellaneous, as a result such as table 2.
Influence of 2 solvent of table to reaction
Note：Maximum list is miscellaneous to be referred to calculate by area percentage in HPLC detections, the impurity of other maximums in addition to product, in table
Miscellaneous maximum list is the complete substrate of unreacted.
The above result shows that the solvent of low pole such as normal heptane, toluene can not almost be reacted, esters solvent have compared with
Improvement rate such as isopropyl acetate；Alcohols solvent is also unfavorable for the progress of reaction；The solvent of middle polarity such as dichloromethane, chlorine
Imitative, tetrahydrofuran has good conversion ratio, especially using tetrahydrofuran as reaction dissolvent.
Embodiment 3
The catalyst that is prepared using embodiment 1, tetrahydrofuran for solvent investigation catalyst dosage and solvents tetrahydrofurane
Influence of the dosage to reaction, preparation process are as follows：
A) be placed in 3.4g raw material amides SM, catalyst in tetrahydrofuran (on the basis of the addition of amide SM) (ml/g,
I.e. every gram of substrate raw material SM adds in the milliliter number of solvent), it is warming up to back flow reaction；
B) it when HPLC detections raw material amide SM is no longer reduced, is cooled to room temperature filtering removal catalyst and obtains filtrate；
C) sodium hydrate aqueous solution that 10ml 2mol/L are added in into filtrate adjusts pH to 10-11；
D) it is warming up to 80-90 DEG C of stirring to be hydrolyzed for 2-3 hours, the aqueous hydrochloric acid solution regulation system pH of 2mol/L is added dropwise extremely
6-7, be added dropwise purified water crystallization, filtering, dry chloro- 5,6- dihydros -11H- benzos [5, the 6] cycloheptane of off-white powder 8- simultaneously -
[1,2-b] pyridine -11- ketone, HPLC detection product purities and maximum list are miscellaneous, as a result such as table 3：
Influence of the 3 catalysts and solvents dosage of table to reaction
With the increase of catalyst amount, the conversion ratio of substrate gradually rises, and catalyst charge must reach substrate weight
More than 10% amount；Solvents tetrahydrofurane dosage influences the progress of reaction, and illustrating substrate, there are certain concentration effects.
Embodiment 4
Amplification research：Catalyst amount is the 15%wt of substrate amide SM, and tetrahydrofuran dosage is 4.5ml/g, prepares work
Skill is as follows：
A) 340g raw material amide SM, 46.5g catalyst, 1.1L anhydrous tetrahydro furans are placed in 5L double-layer glass reaction kettles
In, it is warming up to back flow reaction；
B) it is 0.5% that HPLC detection raw material amide SM contents are detected after 12h, and being cooled to room temperature filtering removal catalyst must filter
Liquid；
C) sodium hydrate aqueous solution (230ml) that 2mol/L is added in into filtrate adjusts pH to 10-11；
D) it is warming up to 80-90 DEG C of stirring to be hydrolyzed for 2-3 hours, the aqueous hydrochloric acid solution regulation system pH of 2mol/L is added dropwise extremely
6-7, is warming up to 70 DEG C, and normal heptane crystallization, filtering, dry chloro- 5, the 6- dihydros -11H- benzene of 221.3g off-white powders 8- is added dropwise
And simultaneously-[1,2-b] pyridine -11- ketone, HPLC detection product purities are 99.92% to [5,6] cycloheptane, yield 91%wt.
If finding that then purity is only 99.6% come crystallization using purified water is added dropwise in step d) post processings in R＆D process,
Reason is that the binary system of water/tetrahydrofuran composition can not remove unreacted partial amides SM, using dropwise addition normal heptane group
Unreacted amide SM can be then effectively removed into tetrahydrofuran/water/normal heptane ternary system, purity is up to after purifying products
99.92%.
Embodiment 5
The catalyst that embodiment 4 separates and recovers carries out supersound washing at 40 DEG C of tetrahydrofuran and for 24 hours, filters, carried out at 80 DEG C
It is dry to carry out repeat performance test, test result such as 4 institute of table according to the technique in embodiment 4 to constant weight progress catalyst
Show：
4 catalyst repeat performance of table is tested
Although embodiments of the present invention are described in detail, it should be understood that, without departing from the present invention's
In the case of spirit and scope, can embodiments of the present invention be made with various changes, replacement and change.
Claims (8)
1. a kind of method that solid acid prepares resisting allergic rhinitis drug loratadine intermedite, in nonaqueous solvents and catalyst
The lower amide SM cyclizations generation imines IND of effect, is then hydrolyzed to obtain 8- chloro- 5,6- dihydro -11H- benzos [5,6] cycloheptane
And-[1,2-b] pyridine -11- ketone, reaction equation Scheme 1；
It is characterized in that：The catalyst is prepared by following preparation method：
1) preparation of modified silica gel carrier：10.0g high-purity silica gels are placed in 100ml dry toluenes, are warming up to 40-60 DEG C,
Then 5ml 3- (2- aminoethylaminos) propyl trimethoxy silicanes and 10ml 3- mercaptopropyl trimethoxysilanes, nitrogen is added dropwise
Atmosphere encloses lower back flow reaction 8-10h；It is cooled to room temperature filtering, acetone elution and then dry amino mercapto modified silica-gel；By ammonia
The sulfhydryl modified silica gel of base is placed in the aqueous solution of nitric acid of 68%wt ultrasonic immersing 1-2h at 40-50 DEG C, filtering, be washed to filtrate into
Neutrality, filter cake are dried under vacuum to the silica gel that constant weight obtains sulfamide groups graft modification；
2) co-precipitation prepares solid acid：By 13-15g ammonium metatungstates, 3-4g ZrOCl28H2O reflux 1-2h soluble in water, ammonia
Water regulation system pH to 8.0-8.2 generates sediment, is cooled to 50-60 DEG C of aging for 24 hours, and removing chloride is removed in filtering, washing, in sky
1-2h is calcined at 500-800 DEG C obtain solid super-strong acid under the atmosphere of gas；
3) modified silica-gel supported solid acid：Silica gel, the 1.0g PEG-800 of 100g sulfamide groups graft modifications are placed in 500ml second
Ultrasonic disperse 30min in alcohol, then add in filtering after solid super-strong acid 5-20g reflux 12h, acetone washing, at 80 DEG C it is dry extremely
Constant weight obtains catalyst.
2. preparation method according to claim 1, it is characterised in that：The temperature of the step 2) calcining is 600-700 DEG C.
3. preparation method according to claim 1, it is characterised in that：The amide SM under the action of nonaqueous solvents and catalyst
Cyclization generates imines IND, and chloro- 5,6- dihydros -11H- benzos [5, the 6] cycloheptane of 8- simultaneously-[1,2-b] pyrrole is then hydrolyzed to obtain
Pyridine -11- ketone the specific steps are：
A) raw material amide SM, catalyst are placed in nonaqueous solvents, are warming up to back flow reaction 4-12h；
B) it after HPLC detects raw material amide SM conversions completely, is cooled to room temperature filtering removal catalyst and obtains filtrate；
C) sodium hydrate aqueous solution that 2mol/L is added in into filtrate adjusts pH to 10-11；
D) it is warming up to 80-90 DEG C of stirring to be hydrolyzed for 2-3 hours, the aqueous hydrochloric acid solution regulation system pH to 6-7 of 2mol/L is added dropwise,
Purified water or normal heptane crystallization, filtering, dry chloro- 5,6- dihydros -11H- benzos [5,6] cycloheptane of off-white powder 8- is added dropwise
And-[1,2-b] pyridine -11- ketone.
4. according to claim 1-3 any one of them preparation methods, it is characterised in that：The nonaqueous solvents for tetrahydrofuran,
Dichloromethane, chloroform, isopropyl acetate or butanone.
5. according to claim 1-3 any one of them preparation methods, it is characterised in that：The catalyst amount is amide SM's
5%wt-40%wt.
6. preparation method according to claim 4, it is characterised in that：The nonaqueous solvents is tetrahydrofuran.
7. preparation method according to claim 5, it is characterised in that：The catalyst amount is the 10%wt- of amide SM
20%wt.
8. preparation method according to claim 6, it is characterised in that：Normal heptane crystallization is added dropwise in step d).
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| CN1326444A (en) * | 1998-11-20 | 2001-12-12 | 先灵公司 | Synthesis of intermediates useful in preparing tricyclic compounds |
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