CN1535967A - Preparation of spirocyclic template compound - Google Patents
Preparation of spirocyclic template compound Download PDFInfo
- Publication number
- CN1535967A CN1535967A CNA031163122A CN03116312A CN1535967A CN 1535967 A CN1535967 A CN 1535967A CN A031163122 A CNA031163122 A CN A031163122A CN 03116312 A CN03116312 A CN 03116312A CN 1535967 A CN1535967 A CN 1535967A
- Authority
- CN
- China
- Prior art keywords
- compound
- reaction
- benzyl
- preparation
- piperidines
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Abstract
The present invention relates to a preparation method of spiro-compound, specially relates to a preparation method of spirans template compound. Said invention is aimed at resolving the defects of existent preparation method which is high in reagent cost and difficult in product separation, and provides its chemical structure formula and chemical reaction formula for preparing said invented spirans template compound. Said invention is mainly used for small molecule medicine precursor research, development and production in the development of new medicine.
Description
Technical field: the present invention relates to a kind of preparation method of spirocyclic compound, particularly a kind of preparation of volution class template compound.
Background technology: at present, expensive, low output that Chinese pharmaceutical enterprises adopts mostly, inefficient traditional synthetic technology, the new drug development cycle is long, scientific and technological content is low, makes Chinese pharmaceutical technology far lag behind western developed country.Middle nineteen nineties in 1500 kinds of new drug products of domestic research and development, only has 70 kinds to meet international standard, only has 2 kinds and have the unique chemical constructed products.Because the new drug development cycle is long, cost is high, so most of developed country adopts " many, fast, high, province " method---combinatorial chemistry technique platform more, accelerate research and development of small-molecule drug precursor and production, can make the new drug development cycle shorten 5～7 years.So-called " template compound " is meant and can makes the researchist can synthesize a kind of " template " compound of hundreds thousand of kinds of micromolecular compounds with main structure rapidly for " template " in conjunction with " combinatorial chemistry " technology.These hundreds thousand of kinds of micromolecular compounds are by efficient screening, just can search out to have similar active even specificity is stronger, toxicity is littler prodrug.If this prodrug not within existing scope of patent protection, so just has an opportunity to develop " transformation formula initiative new drug "-" me-too-plus " that a class has independent intellectual property rights.Early than the seventies in 20th century, volution compound is found biologically active, develop through 30 years of researches, its multiple volution analog derivative has been proved has the therapeutic action that has a extensive future, as antidepressant, the generation (antitumor) that suppresses new vessel, antiplatelet cohesion (antithrombotic), anti-Alzheimer thatch disease (very early dementia) etc.At present, in the spiro drug that has gone on the market, the most noticeable thymoleptic---the buspirone that surely belongs to, this medicine is succeeded in developing by Bristol-Myers Squibb Co..Through clinical verification for many years, this medical instrument has superior curative effect and security, so worldwide always as the depression medication of a line.
Related to the present invention is a kind of preparation of spirocyclic medicament template compound, is to be the volution compound of core, spirocyclic medicament template compound chemistry with " 1,2,3,4-tetrahydrochysene-spiral shell [isoquinoline 99.9-4,4 '-piperidines] " ring
Structural formula is as follows:
(Compound I)
Wherein, R in the formula
1For replacing functional group, as H, C
1～C
6Alkyl, C
1～C
6Alkoxyl group, halogen (F, Cl, I etc.) etc.; R in the formula
2, R
3Be amino substituted radical, as H, C
1～C
3Alkyloyl, formic acid ring butyl ester, t-butyl formate, formic acid ring pentyl ester, benzyl formate, chloroformic acid benzyl ester (CBZCl), two carbonic acid tert-butyl ester (BOC)
2O etc.Wherein, R
1The position of substitution can be ortho position (on the phenyl ring 5,8), a position (on the phenyl ring 6,7).
Wherein main spirocyclic compound is:
In the past few years, spirocyclic compound shown in the Compound I a normally carries out according to following formula (formula 1) reaction (U.S. Pat Patent 5,536,716), wherein mentioned two kinds of reaction process routes (A and B), but only be mentioned to a spirocyclic compound (Compound I synthesis technique a):
(formula 1).Start material all is:
(formula 2), relevant (formula
The synthesis technique of start material 2) please refer to above-mentioned document (US Patent 5,536,716).
(US 5 at United States Patent (USP), 536,716) in the A operational path described in, compound shown in the employing formula 2 is a reactant, obtain the midbody compound of carbonylation after oxidation, this compound carries out rearrangement reaction under the hydrazoic acid effect, after will resetting mix products and using silica gel column chromatography to separate to purify, after the rearrangement mix products employing reductive agent Lithium Aluminium Hydride reduction after purifying, just obtain target compound.
In the B operational path described in the United States Patent (USP) (US 5,536,716), also adopting compound shown in the formula 2 is reactant, under very low temperature (78 ℃) condition, with ozone (O
3) oxidation obtains the intermediate superoxide, logical then ammonia displacement back reduction hydroxyl obtains target compound, but need be further purified.
In the described two kinds of technologies of United States Patent (USP) (US 5,536,716) (A and B) route, the start material that is adopted (shown in the formula 2) has used expensive reagent n-Butyl Lithium in preparation process, and needs cold condition.Explosive reagent---hydrazoic acid has been used in Schmidt rearrangement reaction in A technology, and has two kinds of products to produce, and has increased the difficulty on the product separation.In the B route, adopt very low temperature (78 ℃) condition to carry out technologies such as ozone oxidation, ammonification reduction, this is in industrial very difficult realization, and final product need be further purified, and purge process is also very difficult.
Summary of the invention: the technical issues that need to address of the present invention are: problem, solution prior art that too high problem, the solution prior art of solution prior art reagent cost needs very low temperature to react have two products generations, the problem of product separation difficulty solves prior art is carried out chromatography, purifying to product problem.
Technical solution of the present invention is: the preparation of volution class template compound relates to template compound I
Synthetic, its synthetic operational path is:
The intermediate compound that forms in building-up process: 4,5,6,7,8 also is a kind of among the template compound I, and its final product Ia, Ib also are a kind of among the template compound I certainly.
It is basic raw material that the present invention adopts benzyl cyanide, under the alkaline matter effect, with the reaction of nitrogen benzyl two (2-halogen ethane) amine, obtains compound 1 described in the above-mentioned operational path.
Wherein, alkaline matter is potassium hydroxide, lithium hydroxide, sodium hydroxide, hydrolith, di-isopropyl amination lithium, methyl two silicon amination lithiums.Reaction solvent is selected water, tetrahydrofuran (THF) or normal hexane, ether for use; Temperature of reaction is 0～120 ℃; The alkaline matter consumption is 3～5 equivalent moles.
The catalyzer that adopt low price, is easy to get carries out shortening to compound 1, gets compound 2 after the hydrogenation.Wherein, in this step reaction, adopt catalytic hydrogenation and chemical hydrogenation method.Catalyzer adopts Raney's nickel, and consumption is 5～10% mole numbers of reaction substrate.Reaction solvent is methyl alcohol, ethanol, water, and adds alkaline matter, as, ammonia, ammoniacal liquor, triethylamine, dimethylamine etc.; Reaction pressure is 2～5 normal atmosphere, and temperature of reaction is 25～40 ℃.
Adopt different acylations groups (COR) to protect amido in the compound 2, obtain compound 3.Wherein, R is the aliphatic group or the aromatic substituents of 0～5 carbon atom, or the halogenated aliphatic compound of 0～5 carbon atom.
Solvent and reaction reagent according to the present invention selects make compound 3 carry out intramolecular ring-closing reaction, obtain compound 4.Wherein, reaction reagent adopts formalin, methylal, Paraformaldehyde 96; Reaction solvent choose hydrochloric acid, hydrochloric acid-ethanol, acetic acid, acetic acid-vitriol oil; Temperature of reaction is 25～120 ℃.
After removing the acylations blocking group of compound 4, obtain compound 5; This step reaction adopts alkaline matter as sodium hydroxide, potassium hydroxide, ammonia soln etc.; Temperature of reaction is 80～120 ℃.
Use suitable acylating reagent to handle compound 5, obtain compound 6; Wherein acylating reagent has carboxylamine ring butyl ester, t-butyl carbamate, carboxylamine ring pentyl ester, benzyl carbamate, chloroformic acid benzyl ester (CBZCl), two carbonic acid tert-butyl ester (BOC)
2O etc.
Re-use the catalytic hydrogenation method and remove benzyl, obtain final compounds ib.Catalyzer is 5-20% Pd/C etc., and reaction solvent is methyl alcohol, ethanol etc.Hydrogenation pressure is 2～4 normal atmosphere; Temperature of reaction is 25～40 ℃.
After compound 4 is removed benzyl earlier, obtain compound 7; Wherein, removal benzyl method is the same.
Use suitable acylting agent to handle compound 7, just obtain compound 8; Treatment process is with preparation compound 6 methods.
After removing the acylations blocking group again, treatedly just can get Compound I a.Wherein, treatment process with alkaline matter as Na
2CO
3, K
2CO
3Alcoholic solution remove blocking group, then with hydrochloric acid neutralization and salify.
The invention has the beneficial effects as follows: " a kind of spiro drug template compound " involved in the present invention can synthesize the small molecules volution compound storehouse of a large amount of biologically actives at short notice in conjunction with the combinatorial chemistry technique platform.The utilisation technology technology of this " spiro drug template compound " is as follows: with reference to accompanying drawing, PT and MG are fixed on template compound on the resin after the reaction of resin stationary phase link small molecules, obtain template resin 1 (product 1) after adding the micromolecular compound reaction, obtain template resin 2 (product 2) by derivatization reaction again, can obtain micromolecular compound storehouse (product 3) by continuous reaction, small molecules can be obtained a lot of small molecules spirocyclic compounds after resin cuts off.
A kind of " volution class template compound " main body itself involved in the present invention is exactly a primary structure unit in the medicament production; Modify wherein two active groups by different methods, can obtain having the medicine of different activities, and by combinatorial chemistry technique shown in the drawings, and this " template compound " can derive the hundreds of thousands of kind and have similar active small molecules spirocyclic compound.By this derivatization reaction technology, it is the spirocyclic compound of the biologically active of main structure with " volution class template compound " that the researchist can cut off many.By high-throughput, triage techniques efficiently, the researchist will search out faster, more accurately have similar biological activity, prodrug that specificity is stronger.
In the technology of the present invention, adopt the raw material of large-scale production---benzyl cyanide, adopted conventional reagent to carry out the mannich ring-closure reaction of aromatic hydrocarbons, the scalable scale of reaction is carried out, be easy to industrial operation.Reaction process of the present invention is selected rationally, and no coupling product produces, and need not to carry out chromatography, purifying, is easy to obtain pure product.In ring-closure reaction, adopt different blocking groups, and the differential responses solvent, reaction is carried out smoothly.
Description of drawings:
Accompanying drawing is an application art FB(flow block) of the present invention
Embodiment:
Embodiment 1
1, compound 4:1 '-benzyl-2-ethanoyl-1,2,3, the closing of 4-tetrahydrochysene-spiral shell [isoquinoline 99.9-4,4 '-piperidines]
Become:
The first step: compound 1:(1-benzyl-4-phenyl) the piperidyl formonitrile HCN is synthetic
In the 10L reaction flask, add 6L NaOH (3kg) solution, under agitation add two (2-chloroethyl) amine (1.933kg) of benzyl then, Bn
4NHSO
4(70g), drip benzyl cyanide (860g) under the room temperature, after dropwising, be heated to 120 ℃, the cooling after 1.5 hours that refluxes, reaction solution ethyl acetate extraction, concentrate the back with 12NHCl (1000mL) salify, get white solid, water (1000mL) successively, sherwood oil (1000mL), ethyl acetate (1000mL) is washed, and then it is dissolved in the saturated solution of NaOH (260g), uses ethyl acetate extraction again, organic phase is extremely neutral with the saturated brine washing, anhydrous Na
2SO
4After the drying, (do) after the filtering and concentrating as far as possible, add anhydrous methanol (1000mL) and leave standstill crystallization in concentrated solution, mother liquor obtains colourless acicular crystal 1200g, productive rate 60% after concentrating once more.
Second step: (1-benzyl-4-phenyl) piperidinylmethylamine (compound 2) synthetic
To go up methyl alcohol (1400mL) solution of step gained compound (222g), Raney's nickel 50g, the ammoniacal liquor 150ml hydrogenation 48 hours of in the hydrogenation bottle, pressurizeing under the 3-4 normal atmosphere, the mother liquor filtration catalizer, rotation concentrates methyl alcohol, resistates is dissolved in ethyl acetate, extremely neutral with the saturated brine washing, the organic phase anhydrous Na
2SO
4After the drying, concentrate white solid 205g, productive rate 91%.
The 3rd step: compound 3:N-ethanoyl-(1-benzyl-4-phenyl) piperidinylmethylamine and compound 4:1 '-benzyl-2-ethanoyl-1,2,3,4-tetrahydrochysene-spiral shell [isoquinoline 99.9-4,4 '-piperidines] synthetic
To go up step gained compound (240g) and be dissolved in the acetic acid (250mL), and drip acetic acid (50mL) solution of aceticanhydride (97mL), and drip and finish, stirring is spent the night, and after the TLC detection reaction is complete, adds dense H again
2SO
4(132mL), Paraformaldehyde 96 (HCHO)
n(31g), stirring at room is after 5 days, and the TLC detection reaction is complete, uses the aqueous solution, ammoniacal liquor (200mL) neutralization of NaOH (600g) successively, uses ethyl acetate extraction then, extracting solution saturated common salt water washing, anhydrous Na
2SO
4Drying, concentrating and obtaining the oily matter product is compound 4 (285g).Yield is 100%.
Embodiment 2
2, compound 5:1 '-benzyl-1,2,3,4-tetrahydrochysene-spiral shell [isoquinoline 99.9-4,4 '-piperidines] synthetic:
(285g 0.853mol) is dissolved among the 6N HCl (600mL), heats back 1 stream 5 hours will to go up the final oily matter product of example 1 gained, after the TLC detection reaction is complete, regulates PH with NaOH (400g) and proper ammonia and be about 9, use dichloromethane extraction, extracting solution saturated common salt water washing, anhydrous Na
2SO
4Dry concentrate faint yellow solid (1 '-benzyl-1,2,3,4-tetrahydrochysene-spiral shell [isoquinoline 99.9-4,4 '-piperidines]).
Embodiment 3
3, compound 6:1 '-benzyl-2-BOC-1,2,3,4-tetrahydrochysene-spiral shell [isoquinoline 99.9-4,4 '-piperidines] synthetic
To go up example 2 described solids and be dissolved in the methylene dichloride (1500mL), ice bath drips Et
3N (30mL) drips (Boc) again
2O (175g, 0.811mol) after, drip Et again
2N (45mL), PH is about 9, stir spend the night after, add methylene dichloride (1000mL), use successively again 2N NaOH (2 * 300mL), 1N HCl washing is to acid, uses the saturated common salt water washing to neutral at last, anhydrous Na
2SO
4Drying, concentrate white solid (1 '-benzyl-2-BOC-1,2,3,4-tetrahydrochysene-spiral shell [isoquinoline 99.9-4,4 '-piperidines]).
1HNMR (400MHz, CD
3OD): δ 7.05～7.43 (m, 9H), 4.59 (s, 2H), 4.14 (s, 2H), 3.69 (s, 2H), 3.30～3.40 (m, 2H), 2.70～3.1 (m, 4H), 1.60～1.70 (m, 2H), 1.43～1.47 (s, 9H); FAB-MS calculated value: C
25H
32N
2O
2, 392; Test value: 393.1 (M+H)
Embodiment 4
4, compounds ib: 2-BOC-1,2,3,4-tetrahydrochysene-spiral shell [isoquinoline 99.9-4,4 '-piperidines] synthetic:
To go up example 3 gained white solids and be dissolved in the methyl alcohol (1600mL), add Pd (OH)
2/ C (15g), hydrogenation removed by filter catalyzer (recyclable applying mechanically) after 48 hours under 3～4 atmospheric pressure, after mother liquor concentrates, get white solid (2-BOC-1,2,3 with methyl alcohol-anhydrous diethyl ether crystallization, 4-tetrahydrochysene-spiral shell [isoquinoline 99.9-4,4 '-piperidines]) be 226g, productive rate 78%.
1HNMR(400MHz，CD
3OD)：δ7.56～7.54(d，1H)，7.29～7.19(m，2H)，7.0～7.10(d，1H)，4.62(s，2H)，3.72(s，2H)，3.50～3.48(m，2H)，3.31～3.18(m，2H)，2.58～2.55(m，2H)，1.84～1.77(m，2H)，1.47(s，9H)。
Embodiment 5
5, compound 7:2-ethanoyl-1,2,3,4-tetrahydrochysene-spiral shell [isoquinoline 99.9-4,4 '-piperidines] synthetic:
(41g 0.1mol) is dissolved in the 500mL methyl alcohol, adds 2g catalyst P d/C, behind shortening 24hr under the 3-4 normal atmosphere, filters, and removes catalyzer with example 1 gained oily matter.After mother liquor concentrated, obtain yellow oil (2-ethanoyl-1,2,3,4-tetrahydrochysene-spiral shell [isoquinoline 99.9-4,4 '-piperidines]) (28g, 90%).
Embodiment 6
6, compound 8:1 '-BOC-2-ethanoyl-1,2,3,4-tetrahydrochysene-spiral shell [isoquinoline 99.9-4,4 '-piperidines] synthetic:
(16g 0.05mol) is dissolved in the 100ml methylene dichloride, adds triethylamine (6g will to go up example 5 gained oily matter, 0.06mol), the two carbonic acid tert-butyl esters of dropping under ice bath (13g, 0.06mol), after stirring is spent the night, add the 100ml methylene dichloride, saturated sodium bicarbonate solution, saturated common salt water washing, dry back concentrate, and obtain faint yellow oily thing (1 '-benzyl-2-BOC-1,2,3,4-tetrahydrochysene-spiral shell [isoquinoline 99.9-4,4 '-piperidines]) (21g, 94%).
Embodiment 7
7, Compound I a:1 '-BOC-1,2,3,4-tetrahydrochysene-spiral shell [isoquinoline 99.9-4,4 '-piperidines] synthetic:
To go up example 6 compounds (18g 0.043mol) is dissolved in the 100ml methyl alcohol, add entry 60mL after, water-bath adds down 18gK
2CO
3After, stirring is spent the night, and steams except that after usefulness dichloromethane solution extracting behind the methyl alcohol, concentrating, be dissolved in 100mL formic acid, under the ice bath, behind the adding 10N methyl alcohol hydrogen chloride solution 4.5mL, solution is after concentrating, behind methyl alcohol, ether recrystallization, obtain faint yellow solid (1 '-BOC-1,2,3,4-tetrahydrochysene-spiral shell [isoquinoline 99.9-4,4 '-piperidines]) (12g, 79%).
1HNMR(400MHz，CD
3OD)：δ7.41～7.38(d，1H)，7.36～7.34(m，2H)，7.32～7.24(m，1H)，4.40(s，2H)，4.15～4.12(d，2H)，3.48(s，2H)，2.99～2.92(m，2H)，2.05～1.93(m，4H)，1.47(s，9H)。
Embodiment 8
8,1 '-BOC-7-methyl isophthalic acid, 2,3,4-tetrahydrochysene-spiral shell [isoquinoline 99.9-4,4 '-piperidines] and 2-BOC-7-methyl-1,
2,3,4-tetrahydrochysene-spiral shell [isoquinoline 99.9-4,4 '-piperidines] synthetic:
Adopt and preparation 1 '-BOC-1,2,3,4-tetrahydrochysene-spiral shell [isoquinoline 99.9-4,4 '-piperidines] and 2-BOC-1,2,3,4-tetrahydrochysene-spiral shell [isoquinoline 99.9-4,4 '-piperidines] is operational path similarly.Initial reactant adopts methyl benzonitrile.The reactant consumption should carry out according to the reaction equivalent.
Embodiment 9
9,1 '-BOC-7-fluoro-1,2,3,4-tetrahydrochysene-spiral shell [isoquinoline 99.9-4,4 '-piperidines] and 2-BOC-7-fluorine
-1,2,3,4-tetrahydrochysene-spiral shell [isoquinoline 99.9-4,4 '-piperidines] synthetic:
Adopt and preparation 1 '-BOC-1,2,3,4-tetrahydrochysene-spiral shell [isoquinoline 99.9-4,4 '-piperidines] and 2-BOC-1,2,3,4-tetrahydrochysene-spiral shell [isoquinoline 99.9-4,4 '-piperidines] is operational path similarly.Initial reactant adopts p-Fluorophenyl cyanide.The reactant consumption should carry out according to the reaction equivalent.
Embodiment 10
10,1 '-CBZ-1,2,3,4-tetrahydrochysene-spiral shell [isoquinoline 99.9-4,4 '-piperidines] and 2-CBZ-1,2,3, the 4-tetrahydrochysene-
Synthesizing of spiral shell [isoquinoline 99.9-4,4 '-piperidines]:
Adopt and preparation 1 '-BOC-1,2,3,4-tetrahydrochysene-spiral shell [isoquinoline 99.9-4,4 '-piperidines] and 2-BOC-1,2,3,4-tetrahydrochysene-spiral shell [isoquinoline 99.9-4,4 '-piperidines] is operational path similarly.Wherein, use chloroformic acid benzyl ester (CBZCl) to replace two carbonic acid tert-butyl esters ((BOC)
2O).The reactant consumption should carry out according to the reaction equivalent.
Embodiment 11
11,1 '-CBZ-7-fluoro-1,2,3,4-tetrahydrochysene-spiral shell [isoquinoline 99.9-4,4 '-piperidines] and 2-CBZ-7-fluorine
-1,2,3,4-tetrahydrochysene-spiral shell [isoquinoline 99.9-4,4 '-piperidines] synthetic:
Adopt and preparation 1 '-BOC-1,2,3,4-tetrahydrochysene-spiral shell [isoquinoline 99.9-4,4 '-piperidines] and 2-BOC-1,2,3,4-tetrahydrochysene-spiral shell [isoquinoline 99.9-4,4 '-piperidines] is operational path similarly.Wherein, initial reactant adopts fluorophenyl acetonitrile, uses chloroformic acid benzyl ester (CBZCl) to replace two carbonic acid tert-butyl esters ((BOC)
2O).The reactant consumption should carry out according to the reaction equivalent.
Embodiment 12
9,1 '-CBZ-7-methyl isophthalic acid, 2,3,4-tetrahydrochysene-spiral shell [isoquinoline 99.9-4,4 '-piperidines] and 2-CBZ-7-methyl
-1,2,3,4-tetrahydrochysene-spiral shell [isoquinoline 99.9-4,4 '-piperidines] synthetic:
Adopt and preparation 1 '-BOC-1,2,3,4-tetrahydrochysene-spiral shell [isoquinoline 99.9-4,4 '-piperidines] and 2-BOC-1,2,3,4-tetrahydrochysene-spiral shell [isoquinoline 99.9-4,4 '-piperidines] is operational path similarly.Wherein, initial reactant adopts the methylbenzene acetonitrile, uses chloroformic acid benzyl ester (CBZCl) to replace two carbonic acid tert-butyl esters ((BOC)
2O).The reactant consumption should carry out according to the reaction equivalent.
Embodiment 13
13,1 '-BOC-7-methoxyl group-1,2,3,4-tetrahydrochysene-spiral shell [isoquinoline 99.9-4,4 '-piperidines] and 2-BOC-7-methoxy
Base-1,2,3,4-tetrahydrochysene-spiral shell [isoquinoline 99.9-4,4 '-piperidines] synthetic:
Adopt and preparation 1 '-BOC-1,2,3,4-tetrahydrochysene-spiral shell [isoquinoline 99.9-4,4 '-piperidines] and 2-BOC-1,2,3,4-tetrahydrochysene-spiral shell [isoquinoline 99.9-4,4 '-piperidines] is operational path similarly.Wherein, initial reactant adopts PARA METHOXY PHENYL ACETONITRILE.The reactant consumption should carry out according to the reaction equivalent.
Embodiment 14
14,1 '-CBZ-7-methoxyl group-1,2,3,4-tetrahydrochysene-spiral shell [isoquinoline 99.9-4,4 '-piperidines] and 2-CBZ-7-methoxy
Base-1,2,3,4-tetrahydrochysene-spiral shell [isoquinoline 99.9-4,4 '-piperidines] synthetic:
Adopt and preparation 1 '-BOC-1,2,3,4-tetrahydrochysene-spiral shell [isoquinoline 99.9-4,4 '-piperidines] and 2-BOC-1,2,3,4-tetrahydrochysene-spiral shell [isoquinoline 99.9-4,4 '-piperidines] is operational path similarly.Wherein, initial reactant adopts PARA METHOXY PHENYL ACETONITRILE, uses chloroformic acid benzyl ester (CBZCl) to replace two carbonic acid tert-butyl esters ((BOC)
2O).The reactant consumption should carry out according to the reaction equivalent.
Claims (9)
1, the preparation of volution class template compound has related to " 1,2,3,4-tetrahydrochysene-spiral shell [isoquinoline 99.9-4,4 '-piperidines] " ring spirocyclic medicament template compound, and chemical structural formula is as follows:
Synthesizing of (Compound I), wherein, R in the formula
1For replacing functional group, as H, C
1～C
6Alkyl, C
1～C
6Alkoxyl group, halogen (F, Cl, I etc.); R in the formula
2, R
3Be amino substituted radical, as H, C
1～C
3Alkyloyl, formic acid ring butyl ester, t-butyl formate, formic acid ring pentyl ester, benzyl formate, chloroformic acid benzyl ester (CBZCl), two carbonic acid tert-butyl ester (BOC)
2O; Wherein, R
1The position of substitution can be ortho position (5 on the phenyl ring; 8); between the position (6 on the phenyl ring; 7); the basic raw material that adopts is a benzyl cyanide as benzyl cyanide; to (; adjacent) methyl benzonitrile; to (; adjacent) fluorobenzonitrile; to (; adjacent) the anisole formonitrile HCN; under the alkaline matter effect, obtain piperidines 1 with the reaction of nitrogen benzyl two (2-halogen ethane) amine; behind catalytic hydrogenating reduction, obtain compound 2 then; after acidylate, obtain compound 3; it is characterized in that; compound 3 adopts conventional reagent to carry out the mannich ring-closure reaction of aromatic hydrocarbons; obtain " 1; 2; 3,4-tetrahydrochysene-spiral shell [isoquinoline 99.9-4,4 '-piperidines] " compound ring series
At this moment, R
3For-Bn, R
2For-COR, conventional reagent is: adopt formalin, methylal, Paraformaldehyde 96, reaction solvent is chosen hydrochloric acid, hydrochloric acid-ethanol, acetic acid, acetic acid-vitriol oil; Temperature of reaction is 25～120 ℃, and this compound can be used as midbody product can derive serial spirocyclic medicament template compound.
2, the preparation of a kind of volution class template compound according to claim 1 is characterized in that reaction formula is as follows:
3, the preparation of volution class template compound according to claim 1 and 2, it is characterized in that, benzyl cyanide obtains in the reaction of piperidines 1 with the reaction of nitrogen benzyl two (2-halogen ethane) amine under the alkaline matter effect, alkaline matter is potassium hydroxide, lithium hydroxide, sodium hydroxide, hydrolith, di-isopropyl amination lithium, methyl two silicon amination lithiums, and reaction solvent is selected water, tetrahydrofuran (THF) or normal hexane, ether for use; Temperature of reaction is 0～120 ℃; The alkaline matter consumption is 3～5 equivalent moles; Carry out shortening to changing platform thing 1, get compound 2 after the hydrogenation, wherein, adopt catalytic hydrogenation and chemical hydrogenation method in this step reaction, catalyzer adopts Raney's nickel, and consumption is 5～10% mole numbers of reaction substrate, reaction solvent is methyl alcohol, ethanol, water, and the adding alkaline matter, as, ammonia, ammoniacal liquor, triethylamine, dimethylamine etc.; Reaction pressure is 2～5 normal atmosphere, and temperature of reaction is 25～40 ℃; (COR) protect the amido of compound 2, obtain compound 3, wherein, R is the aliphatic group or the aromatic substituents of 0～5 carbon atom, or the halogenated aliphatic compound of 0～5 carbon atom to adopt different acylations groups.
4, the preparation of volution class template compound according to claim 1 is characterized in that R
2Replace COR by H, remove the acylations blocking group of compound 4 after, obtain compound 5; This step reaction adopts alkaline matter as sodium hydroxide, potassium hydroxide, ammonia soln etc.; Temperature of reaction is 80～120 ℃, and its chemical equation is as follows:
5, according to the preparation of claim 1 or 4 described volution class template compounds, it is characterized in that, use suitable acylating reagent to handle compound 5, obtain compound 6; Wherein acylating reagent has carboxylamine ring butyl ester, t-butyl carbamate, carboxylamine ring pentyl ester, benzyl carbamate, chloroformic acid benzyl ester (CBZCl), two carbonic acid tert-butyl ester (BOC)
2O, its chemical equation is as follows:
6, the preparation of volution class template compound according to claim 5 is characterized in that, compound 6 re-uses the catalytic hydrogenation method and removes benzyl, obtain final compounds ib, catalyzer is 5-20%Pd/C etc., and reaction solvent is methyl alcohol, ethanol etc., and hydrogenation pressure is 2～4 normal atmosphere; Temperature of reaction is 25～40 ℃, and its chemical equation is as follows:
7, the preparation of volution class template compound according to claim 1 and 2 is characterized in that, after compound 4 is removed benzyl earlier, obtains compound 7; Catalyzer is 5-20%Pd/C etc., and reaction solvent is methyl alcohol, ethanol etc., and hydrogenation pressure is 2～4 normal atmosphere; Temperature of reaction is 25～40 ℃, and its chemical equation is as follows:
8, the preparation of volution class template compound according to claim 7 is characterized in that, uses suitable acylting agent to handle compound 7, just obtains compound 8; Wherein acylating reagent has carboxylamine ring butyl ester, the carboxylamine tertiary butyl, carboxylamine ring pentyl ester, benzyl carbamate, chloroformic acid benzyl ester (CBZCl), two carbonic acid tert-butyl ester (BOC)
2O, its chemical equation is as follows:
9, the preparation of volution class template compound according to claim 8 is characterized in that, after compound 8 is removed the acylations blocking group again, treatedly just can get Compound I a, wherein, treatment process with alkaline matter as Na
2CO
3, K
2CO
3Alcoholic solution remove blocking group, with hydrochloric acid neutralization and salify, its chemical equation is as follows then:
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB031163122A CN1297557C (en) | 2003-04-10 | 2003-04-10 | Preparation of spirocyclic template compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB031163122A CN1297557C (en) | 2003-04-10 | 2003-04-10 | Preparation of spirocyclic template compound |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1535967A true CN1535967A (en) | 2004-10-13 |
| CN1297557C CN1297557C (en) | 2007-01-31 |
Family
ID=34320304
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB031163122A Expired - Fee Related CN1297557C (en) | 2003-04-10 | 2003-04-10 | Preparation of spirocyclic template compound |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1297557C (en) |
Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7696201B2 (en) | 2006-08-15 | 2010-04-13 | Vertex Pharmaceuticals Incorporated | Modulators of muscarinic receptors |
| US7786141B2 (en) | 2004-08-19 | 2010-08-31 | Vertex Pharmaceuticals Incorporated | Dihydrospiroindene modulators of muscarinic receptors |
| US7786107B2 (en) | 2006-08-18 | 2010-08-31 | Vertex Pharmaceuticals Incorporated | Modulators of muscarinic receptors |
| US7858790B2 (en) | 2006-06-29 | 2010-12-28 | Vertex Pharmaceuticals Incorporated | Modulators of muscarinic receptors |
| US7858635B2 (en) | 2005-12-22 | 2010-12-28 | Vertex Pharmaceuticals Incorporated | Spiro compounds as modulators of muscarinic receptors |
| US7863449B2 (en) | 2004-11-29 | 2011-01-04 | Vertex Pharmaceuticals Incorporated | Modulators of muscarinic receptors |
| US7879834B2 (en) | 2004-08-19 | 2011-02-01 | Vertex Pharmaceuticals Incorporated | Spiroindoline modulators of muscarinic receptors |
| US7973162B2 (en) | 2007-10-03 | 2011-07-05 | Vertex Pharmaceuticals Incorporated | Modulators of muscarinic receptors |
| US8003660B2 (en) | 2006-02-22 | 2011-08-23 | Vertex Pharmaceuticals Incorporated | Modulators of muscarinic receptors |
| US8263605B2 (en) | 2006-02-22 | 2012-09-11 | Vertex Pharmaceutical Incorporated | Modulators of muscarinic receptors |
| WO2016177472A1 (en) * | 2015-05-05 | 2016-11-10 | Laboratorios Del Dr. Esteve, S.A. | Spiro-isoquinoline-4,4'-piperidine compounds having multimodal activity against pain |
| CN114907216A (en) * | 2022-06-28 | 2022-08-16 | 万华化学集团股份有限公司 | Hydrogenation method of dicyanoethyl tertiary amine |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SK282166B6 (en) * | 1992-12-11 | 2001-11-06 | Merck & Co., Inc. | Spiropiperinde derivatives, method for their preparation and pharmaceutical preparation containing them |
| US5578593A (en) * | 1992-12-11 | 1996-11-26 | Merck & Co., Inc. | Spiro piperidines and homologs promote release of growth hormone |
-
2003
- 2003-04-10 CN CNB031163122A patent/CN1297557C/en not_active Expired - Fee Related
Cited By (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7879834B2 (en) | 2004-08-19 | 2011-02-01 | Vertex Pharmaceuticals Incorporated | Spiroindoline modulators of muscarinic receptors |
| US7786141B2 (en) | 2004-08-19 | 2010-08-31 | Vertex Pharmaceuticals Incorporated | Dihydrospiroindene modulators of muscarinic receptors |
| US8497295B2 (en) | 2004-08-19 | 2013-07-30 | Vertex Pharmaceuticals Incorporated | Spiroindoline modulators of muscarinic receptors |
| US8367691B2 (en) | 2004-08-19 | 2013-02-05 | Vertex Pharmaceutical Incorporated | Modulators of muscarinic receptors |
| US8258148B2 (en) | 2004-08-19 | 2012-09-04 | Vertex Pharmaceutical Incorporated | Spiroindoline modulators of muscarinic receptors |
| US7863449B2 (en) | 2004-11-29 | 2011-01-04 | Vertex Pharmaceuticals Incorporated | Modulators of muscarinic receptors |
| US7858635B2 (en) | 2005-12-22 | 2010-12-28 | Vertex Pharmaceuticals Incorporated | Spiro compounds as modulators of muscarinic receptors |
| US8003660B2 (en) | 2006-02-22 | 2011-08-23 | Vertex Pharmaceuticals Incorporated | Modulators of muscarinic receptors |
| US8263605B2 (en) | 2006-02-22 | 2012-09-11 | Vertex Pharmaceutical Incorporated | Modulators of muscarinic receptors |
| US8304423B2 (en) | 2006-02-22 | 2012-11-06 | Vertex Pharmaceutical Incorporated | Modulators of muscarinic receptors |
| US7858790B2 (en) | 2006-06-29 | 2010-12-28 | Vertex Pharmaceuticals Incorporated | Modulators of muscarinic receptors |
| US7696201B2 (en) | 2006-08-15 | 2010-04-13 | Vertex Pharmaceuticals Incorporated | Modulators of muscarinic receptors |
| US7786107B2 (en) | 2006-08-18 | 2010-08-31 | Vertex Pharmaceuticals Incorporated | Modulators of muscarinic receptors |
| US7973162B2 (en) | 2007-10-03 | 2011-07-05 | Vertex Pharmaceuticals Incorporated | Modulators of muscarinic receptors |
| WO2016177472A1 (en) * | 2015-05-05 | 2016-11-10 | Laboratorios Del Dr. Esteve, S.A. | Spiro-isoquinoline-4,4'-piperidine compounds having multimodal activity against pain |
| US10508114B2 (en) | 2015-05-05 | 2019-12-17 | Esteve Pharmaceuticals, S.A. | Spiro-isoquinoline-4,4′-piperidine compounds having multimodal activity against pain |
| CN114907216A (en) * | 2022-06-28 | 2022-08-16 | 万华化学集团股份有限公司 | Hydrogenation method of dicyanoethyl tertiary amine |
| CN114907216B (en) * | 2022-06-28 | 2024-02-02 | 万华化学集团股份有限公司 | Hydrogenation method of dicyanoethyl tertiary amine |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1297557C (en) | 2007-01-31 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1297557C (en) | Preparation of spirocyclic template compound | |
| CN1069635C (en) | Novel phenylalkylaminoalcohol carbamates and process for prepn. of same | |
| WO2009064476A1 (en) | Preparation of sitagliptin intermediate | |
| CN1414966A (en) | Process and intermediates for preparation of imidazolidinone alpha U protein antagonists | |
| CN111018803B (en) | Preparation method of Barosavir intermediate | |
| CN1800179A (en) | Method for preparing candestartan | |
| CN114573500A (en) | Preparation method of lefenacin intermediate | |
| CN103159633B (en) | The preparation method of tapentadol hydrochloride and the compound for the preparation of tapentadol hydrochloride | |
| CN107602559B (en) | A method of the asymmetric ciprofloxacin eye drops synthesis of chiral ternary carbocyclic nucleoside caused by Michael's addition | |
| CN1923801A (en) | Preparation method of phenyl (S)-N-ethyl-N-methyl-3-[1-(dimethyamino)ethyl]-amidoformate (I) and tartrate thereof (II) | |
| CN112110897B (en) | Preparation method of deuterated crizotinib and derivative thereof | |
| CN108640884B (en) | 2-morpholinone salt, preparation method thereof and preparation method of 2-morpholinone | |
| CN103183673A (en) | Synthesizing method of (S,S)-2,8-diazabicyclo[4.3.0]nonane | |
| CN102050748B (en) | Method for preparing expectorant, namely ambroxol key intermediate trans-4-[(2-amino benzyl) amino]-cyclohexanol | |
| CN1150160C (en) | Process for synthesizing Tuoteluodin L-tartrate | |
| CN112457204B (en) | Preparation method of S-configuration phenethylamine hydrochloride compound | |
| CN102344431A (en) | Method for preparing nebivolol hydrochloride | |
| CN115215814A (en) | Synthetic method of isoxazolidine compounds | |
| CN1023121C (en) | Crystal of hydrochloric salt of etoposide-2-dimethylamino compounds and process for preparing them | |
| CN1842523A (en) | Process for the asymmetric hydrogenation of beta-amino ketones | |
| CN1293031C (en) | Method for preparing indan-1,3-dicarboxylic acid | |
| CN108409731B (en) | Chiral resolution of aryl-substituted 1H-pyridine [3,4-b ] indole-3-carboxylic acid methyl ester | |
| CN107827916B (en) | Synthesis method of (R) - (1-amino-3-methyl) butyl-1-pinanediol borate | |
| CN102260224B (en) | Method for synthesizing 2-morpholone derivatives | |
| CN100432044C (en) | New process for preparing levo-albuterol |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| ASS | Succession or assignment of patent right |
Owner name: TIANJIN YAOMING KANGDE NEW DRUGS DEVELOPMENT CO., Free format text: FORMER OWNER: SHANGHAI YAOMING KANGDE NEW MEDICINE DEVELOPMENT CO., LTD. Effective date: 20070209 |
|
| C41 | Transfer of patent application or patent right or utility model | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20070209 Address after: 300457 No. 111 Huang Hai Road, Tianjin Economic Development Zone Patentee after: Tianjin Yaoming Kangde New Medicine Development Co., Ltd. Address before: 200131 Shanghai City, Pudong Waigaoqiao Free Trade Zone Aidoulu 253 No. 4 No. 2 parts of A Patentee before: Shanghai Yaoming Kangde New Medicine Development Co., Ltd. |
|
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20070131 Termination date: 20150410 |
|
| EXPY | Termination of patent right or utility model |