CN101679237A

CN101679237A - The method of preparation (R)-2-crassitude and (S)-2-crassitude and tartrate thereof

Info

Publication number: CN101679237A
Application number: CN200880021225A
Authority: CN
Inventors: 迈克尔·克里斯蒂; 约瑟夫·J·佩特雷蒂斯
Original assignee: Cephalon LLC
Current assignee: Cephalon LLC
Priority date: 2007-05-03
Filing date: 2008-05-02
Publication date: 2010-03-24
Also published as: UA99913C2; NZ580948A; IL201627A; JP5698887B2; EA200971019A1; ZA200907643B; CA2686033A1; KR20100017565A; EA019031B1; JP2010526142A; WO2008137087A1; AU2008248168B2; EP2152669A1; IL201627A0; AU2008248168A1; MX2009011787A; BRPI0810330A2

Abstract

The invention provides simple and direct, safety, cheapness and commercial scalable method from 2-methylpyrroline preparation (R)-or (S)-2-crassitude, this method does not need to separate synthetic intermediate.

Description

The method of preparation (R)-2-crassitude and (S)-2-crassitude and tartrate thereof

The cross reference of related application

Present patent application requires the U.S. Provisional Application No.60/927 that submitted on May 3rd, 2007,356 rights and interests, this application to incorporate this paper in full into as a reference.

Background of invention

(R)-and (S)-the 2-crassitude is the parent material that can be used for synthetic multiple medicament production.For example, (R)-the 2-crassitude can be used for preparing many H ₃Receptors ligand.For this reason, very interested for the cost-effective approach of exploitation preparation (R)-and (S)-2-crassitude.But, program that before is developed or the expensive parent material of use, or need many tediously long synthesis steps.

People such as Pu (Org.Process Res.﹠amp; Dev., 2005,9,45-50) disclose by under the condition that exists at L-tartrate, racemic 2-crassitude is carried out fractional crystallization prepare (R)-2-crassitude L-tartrate.The cost of racemic 2-crassitude is about 20 a dollars/gram.

People (Recl.Trav.Chim.Pays-Bas such as Van de Kuil, 1994,113,267-277) disclose from 2-methylpyrroline (about 5 dollars/gram), synthetic (the R)-2-crassitude L-tartrate of four (4) steps with (S)-2-crassitude D-tartrate.Yet this method has several unfavorable factors.The first, this method requires three intermediates of preparation, wherein two must be separated.In addition, this method need be removed Glacial acetic acid and 37% excessive aqueous hydrochloric acid takes separation of intermediates HCl salt by vacuum, and it is time-consuming, expensive and have corrodibility.In addition, this synthesizes and need come separation of intermediates by carry out twice successive flash distillation from potassium hydroxide.

People such as Ku (Tetrahedron, 2006,62,4584-4589) disclose from synthetic (the R)-2-crassitude hydrochloride of N-Boc-L-dried meat ammonia alcohol four (4) steps.This method has several unfavorable factors.The first, this method need prepare and separate three different synthetic intermediates.The second, this method has been utilized environmentally harmful methylene chloride, and corrosive gaseous hydrochloric acid and phosphoric acid.The 3rd, this method is used expensive lithium iodide (about 13 dollars/gram).In addition, the water absorbability of consequent hydrochloride is very big.

People such as Zhao (J.Org.Chem., 2006,71,4336-4338) disclose from synthetic (the R)-2-crassitude benzene sulfonate of N-Boc-L-proline(Pro) four (4) steps.This method has several unfavorable factors.The first, this method need prepare and separate three (3) individual independent synthetic intermediates.The second, this method adopt corrosive reagents such as phosphoric acid, etherate of trifluoroboron, sodium hydroxide, sodium borohydride and

For brief, safety, cheapness, commercial scalable scale and need not to separate the method for the preparation (R) that a plurality of synthetic intermediates can carry out-and (S)-2-crassitude, exist demand.

Summary of the invention

We are unexpected to find, can divide two steps, from the 2-methylpyrroline of cheapness, use non-aggressive reagent to prepare (R)-2-crassitude L-tartrate and (S)-2-crassitude D-tartrate, and needn't separate any synthetic intermediate.In one embodiment, the invention provides the method that is used for preparation (R)-2-crassitude L-tartrate, this method may further comprise the steps:

(a) hydrogenation 2-methylpyrroline in the mixture that comprises alcoholic solvent and hydrogenation catalyst;

(b) optionally remove hydrogenation catalyst from mixture;

(c) L-tartrate is dissolved in the mixture to form solution;

(d) make (R)-2-crassitude L-tartrate from solution crystallization; With

(e) fractional crystallization (R)-2-crassitude L-tartrate.

Hydrogenation catalyst is platinum catalyst preferably.Platinum catalyst is platinum oxide (IV) preferably.Platinum catalyst is more preferably 5%Pt-C.

Alcoholic solvent is ethanol and methanol mixture preferably.Alcoholic solvent is more preferably the mixture that ethanol and methyl alcohol exist with about 2: 1 to about 3: 1 (v/v) ratios.

Step (a) preferably around envrionment temperature carry out.

Platinum catalyst preferably removes by filter in step (b).

Isolating (R)-2-crassitude L-tartrate preferably has the optical purity that is at least 50%ee.

This method is also optional to be may further comprise the steps:

(f) make isolating (R)-2-crassitude L-tartrate recrystallization;

(g) (R)-2-crassitude L-tartrate of separation recrystallization; With

(h) optional repeating step (f) and step (g).

This method comprises randomly that also (the R)-2-crassitude L-tartrate that makes isolated recrystallization and alkali reaction are to provide (R)-2-the step of crassitude.

This method also preferably includes (the R)-2-crassitude L-tartrate that will be produced and changes into pharmaceutical composition, preferred H ₃Receptors ligand, preferred 2-(6-{2-[(2R)-2-methyl isophthalic acid-tetramethyleneimine-1-yl] ethyl }-2-naphthalene-2-yl)-step of 2H-pyridazin-3-one:

In one embodiment, the invention provides prepare 6-{4-[3-((R)-2-methyl-tetramethyleneimine-1-yl)-propoxy-]-phenyl-method of 2H-pyridazin-3-one:

May further comprise the steps:

(1a) hydrogenation 2-methylpyrroline in the mixture that comprises alcoholic solvent and hydrogenation catalyst;

(1b) optionally remove hydrogenation catalyst from mixture;

(1c) L-tartrate is dissolved in the mixture to form solution;

(1d) make (R)-2-crassitude L-tartrate from solution crystallization;

(1e) fractional crystallization (R)-2-crassitude L-tartrate; With

(2) make (R)-2-crassitude L-tartrate and alkali reaction to form (R)-2-crassitude free alkali; With

(3) make (R)-2-crassitude and 6-[4-(3-halogen-propoxy-)-phenyl]-the 2H-pyridazin-3-one to be to be enough to form (R)-6-{4-[3-(2-methyl-tetramethyleneimine-1-yl)-propoxy-]-phenyl }-react under time of 2H-pyridazin-3-one and the condition.

Preferably, 6-[4-(3-halogen-propoxy-)-phenyl]-the 2H-pyridazin-3-one prepares by following steps:

(a) make 1-(4-hydroxyl-phenyl)-ethyl ketone and 1,3-two Halopropanes are to be enough to form 1-[4-(3-halogen-propoxy-)-phenyl]-contact under time of ethyl ketone and the condition; With

(b) make 1-[4-(3-halogen-propoxy-)-phenyl]-ethyl ketone is being enough to generate 6-[4-(3-halogen-propoxy-)-phenyl with oxoethanoic acid]-contact under time of 2H-pyridazin-3-one and the condition.

The present invention also provides the method for preparation (S)-2-crassitude D-tartrate, and this method may further comprise the steps:

(b) optionally remove hydrogenation catalyst from mixture;

(c) D-tartrate is dissolved in the mixture to form solution;

(d) make (S)-2-crassitude D-tartrate from solution crystallization; With

(e) fractional crystallization (S)-2-crassitude D-tartrate.

Step (a) is preferably carried out under the envrionment temperature around.

Platinum catalyst preferably removes by filter in step (b).

Isolating (S)-2-crassitude D-tartrate preferably has the optical purity that is at least 50%ee.

This method is also optional to be may further comprise the steps:

(f) make isolating (S)-2-crassitude D-tartrate recrystallization;

(g) (S)-2-crassitude D-tartrate of separation recrystallization; With

(h) optional repeating step (f) and step (g).

This method is also optional to comprise that (the S)-2-crassitude D-tartrate that makes separated recrystallization and alkali reaction are to provide (S)-2-the step of crassitude.

This method changes into H with prepared (S)-2-crassitude D-tartrate also optional comprising ₃Receptors ligand, preferred 2-(6-{2-[(2S)-2-methyl isophthalic acid-tetramethyleneimine-1-yl] ethyl }-2-naphthalene-2-yl)-step of 2H-pyridazin-3-one:

Detailed Description Of The Invention

Definition

" pact " is meant the numerical range of set-point ± 10%; For example, word " about 50 " comprise 50 ± 10%, or be 45 to 55.

" alcoholic solvent " is meant C ₁-C ₆Alkyl alcohol or C ₁-C ₆The mixture of alkyl alcohol.

" commercial size " is meant a collection of at least 500 grams that are.

Crystallization " be meant cause crystal formation.

" H ₃Receptors ligand " be meant as antagonist, agonist or partial agonist and histamine H ₃The compound of acceptor interaction.

" different-phase catalyst " is meant the hydrogenation catalyst that is insoluble in the alcoholic solvent.

" homogeneous catalyst " is meant the hydrogenation catalyst that dissolves in the alcoholic solvent.

" hydrogenation catalyst " is meant and is suitable for catalysis 2-methylpyrroline and H-H reaction to form the composition of 2-crassitude.

" separation " is meant separated portion from mixture (for example reagent or product).

" optical purity " is meant the ratio of a kind of enantiomorph in mixture of enantiomers, and with enantiomeric excess (%ee) expression, and it is defined as (| R-S|/(R+S)) * 100%, and wherein R and S are the marks separately of enantiomorph, thereby make R+S=1,

" medicament production " is meant disease, the patient's condition or disorderly compound or the composition that can be used for treating the people.

" platinum catalyst " is meant bag platiniferous hydrogenation catalyst.

" purifying " is meant the purity that increases compound.

" purity " is meant the weight percentage of a kind of component in mixture.

" solution " is meant the solvent that comprises partly soluble at least one or more materials; And it can comprise insoluble one or more (for example solid) materials.

For all purposes, all publications of quoting herein are incorporated herein by reference in full with it.

Describe

The invention provides the method for preparation (R)-2-crassitude L-tartrate or (S)-2-crassitude D-tartrate, may further comprise the steps:

(b) randomly remove hydrogenation catalyst from mixture;

(c) L-tartrate or D-tartrate are dissolved in the mixture to form solution;

(d) make (R)-2-crassitude L-tartrate or (S)-2-crassitude D-tartrate from solution crystallization; With

(e) fractional crystallization (R)-2-crassitude L-tartrate or (S)-2-crassitude D-tartrate.

Step (a)

In step (a), the 2-methylpyrroline is hydrogenated in the mixture that comprises alkyl alcohol solvent and hydrogenation catalyst.2-methylpyrroline used in hydrogenation can be available from commercial source (for example, Sigma-Aldrich Corp.; St.Louis, MO).The important benefits of the inventive method is other parent material costliness that the 2-methylpyrroline is not produced (R)-and (S)-2-crassitude.

Used hydrogenation catalyst can be available from commercial source (for example, Sigma-Aldrich Corp. in this reaction; St.Louis, MO).Hydrogenation catalyst can be homogeneous catalyst or different-phase catalyst.The example of hydrogenation catalyst includes but not limited to platinum catalyst.The example of platinum catalyst includes but not limited to that charcoal carries platinum (Pt/C), platinum oxide (IV) and composition thereof.The example of homogeneous catalyst includes but not limited to three (triphenylphosphine) rhodium chloride (Wilkinson (Wilkinson ' s) catalyzer) with at United States Patent (USP) 4,581, disclosed catalyzer in 417,4,631,315 and 5,670,437.Hydrogenation catalyst is platinum oxide (IV) preferably.Hydrogenation catalyst is more preferably 5%Pt-C.

Used alcoholic solvent is C in described reaction ₁-C ₆Alkyl alcohol or C ₁-C ₆The mixture of alkyl alcohol.C ₁-C ₆The example of alkyl alcohol includes but not limited to methyl alcohol, ethanol, Virahol and propyl carbinol.Alcoholic solvent preferably comprises ethanol.Alcoholic solvent preferably comprises methyl alcohol.Alcoholic solvent is more preferably ethanol and methanol mixture.Alcoholic solvent is more preferably the mixture that ethanol and methyl alcohol exist with about 0.5: 1 to about 10: 1 (v/v) ratio.Alcoholic solvent is more preferably the mixture that ethanol and methyl alcohol exist with about 1: 1 to about 5: 1 (v/v) ratio.Alcoholic solvent is more preferably the mixture that ethanol and methyl alcohol exist with about 2: 1 to about 3: 1 (v/v) ratios.Alcoholic solvent is more preferably the mixture that ethanol and methyl alcohol exist with about 2.4: 1 (v/v) ratios.

Alcoholic solvent can any suitable amount be present in step (a) reaction mixture.Alcoholic solvent preferably account for reaction mixture at least about 50% (w/w).Alcoholic solvent more preferably account for reaction mixture at least about 70% (w/w).Alcoholic solvent more preferably account for reaction mixture at least about 90% (w/w).Alcoholic solvent more preferably account for reaction mixture at least about 95% (w/w).Particularly, compare C with acetate ₁-C ₆Alkyl alcohol is easier to be removed from reaction mixture.In addition, C ₁-C ₆Alkyl alcohol is noncorrosive.

Used hydrogen (H in hydrogenation ₂) can be used as gas and join in the reaction mixture, such as by under nitrogen atmosphere, reacting, perhaps can generate in the original place, such as by using NaBH ₄Handle H ₂PtCl ₆Or RhCl ₃(referring to Brown and Sivasankaran, J.Am.Chem.Soc.1962,84,2828).In certain embodiments, hydrogenation is undertaken by gaseous hydrogen is joined in the reaction mixture.In preferred embodiments, hydrogenation is carried out being higher than under the barometric point.In some embodiments, reaction is undertaken by original place generation hydrogen.

Hydrogenation can carry out in any suitable temperature.Reaction is preferably carried out at ambient temperature.

The advantage of the inventive method is that hydrogenation carries out in noncorrosive alkyl alcohol solvent.Another advantage of the inventive method is the product (being the 2-crassitude) that directly obtains hydrogenation, need not preparation or separation of intermediates, such as intermediate salt.

Step (b)

Step (b) is an optional step.In step (b), from hydrogenation mixture, remove hydrogenation catalyst.Preferably from hydrogenation mixture, remove hydrogenation catalyst afterwards in step (a).Step (b) is preferably carried out before in step (d), particularly when hydrogenation catalyst is different-phase catalyst.The appropriate means that is used to remove hydrogenation catalyst includes but not limited to filtration, decant and centrifugal.In some embodiments, hydrogenation catalyst is filtered and removes.When hydrogenation catalyst during generally based on precious metal, the advantage of the inventive method be hydrogenation catalyst can from mixture, remove, in follow-up hydrogenation, be recycled and re-use (for example, referring to, US5,554,353 (people such as Schneider); EP 1 739 104 A1 (people such as Kobayashi); Setty-Fichman waits the people, J.Mol.Cat.A:Chem., 1999,144 (1), 159-163.

Step (c)

In step (c), L-tartrate or D-tartrate are dissolved in the hydrogenation mixture to form solution.If required product is (R)-2-crassitude, then use L-tartrate.If required product is (S)-2-crassitude, then use D-tartrate.Used in the methods of the invention L-tartrate or D-tartrate can be available from commercial source (for example, Sigma-Aldrich Corp.; St.Louis, MO).

The solution that forms in step (c) is homogeneous preferably.If solution is not homogeneous (for example, comprising undissolved particle), then preferred heated solution is to promote dissolving.

The advantage of the inventive method is that it need not be separated in prepared 2-crassitude in the hydrogenation before adding tartrate from reaction mixture.This makes present method compare simpler, quicker, more cheap with the method for prior art and less waste more.

Step (d)

In step (d), make (R)-2-crassitude L-tartrate or (S)-2-crassitude D-tartrate crystallization in the prepared solution from step (c).If in step (c), add L-tartrate, then (R)-2-crassitude L-tartrate crystallization from the solution of step (d).If in step (c), add D-tartrate, then (S)-2-crassitude D-tartrate crystallization from the solution of step (d).Can use any appropriate means to make (R)-2-crassitude L-tartrate or (S)-2-crassitude D-tartrate from solution crystallization.In some embodiments, the solution heating to promote dissolving, is cooled off with induced crystallization then.

Step (e)

In step (e), isolate crystallization (R)-2-crassitude L-tartrate or (S)-2-crassitude D-tartrate.If in step (c), add L-tartrate, then (R)-2-crassitude L-tartrate crystallization and separated in step (e) from the solution of step (d).If in step (c), add D-tartrate, then (S)-2-crassitude D-tartrate crystallization and separated in step (e) from the solution of step (d).The proper method that is used for fractional crystallization (R)-2-crassitude L-tartrate or (S)-2-crassitude D-tartrate includes but not limited to filtration, decant and centrifugal.The advantage of the inventive method is that product can be separated by simple filtering.(R)-2-crassitude L-tartrate or (S)-2-crassitude D-tartrate preferably is filtered separation.Be appreciated that, isolating (R)-2-crassitude L-tartrate may comprise (S)-2-crassitude L-tartrate, and isolating (S)-2-crassitude D-tartrate may comprise (R)-2-crassitude D-tartrate, and it will reduce the optical purity of separated product.Isolating (R)-2-crassitude L-tartrate or (S)-2-crassitude D-tartrate preferably has the optical purity of 40%ee at least.Isolating (R)-2-crassitude L-tartrate or (S)-2-crassitude D-tartrate more preferably has the optical purity of 50%ee at least.Isolating (R)-2-crassitude L-tartrate or (S)-2-crassitude D-tartrate more preferably has the optical purity of 55%ee at least.

Optional additional step

The advantage of the method for the present invention preparation (R)-2-crassitude L-tartrate or (S)-2-crassitude D-tartrate is, it adopts cheap and noncorrosive reagent and solvent, can and carry out at an easy rate in the convenience of the temperature between 0 ℃-25 ℃, only need to prepare a kind of midbody compound, do not require and separate the synthetic intermediate, allow catalyst recycle, and the product that can separate and be used for then subsequent technique by simple filtering is provided.

Isolating product is the tartrate additive salt of (R)-or (S)-2-crassitude free alkali.If desired, described salt can be converted into (R)-or (S)-2-crassitude free alkali.The free alkali of gained can adopt technology known in the art to separate.Free alkali preferably can generate in the original place and need not to separate promptly to can be used for next synthesis step.Method as herein described both had been applicable to isolating 2-crassitude free alkali, was applicable to autochthonous 2-crassitude free alkali in reaction mixture again.

Therefore, in certain embodiments, described method is further comprising the steps of: make isolating (R)-2-crassitude L-tartrate or (S)-2-crassitude D-tartrate and alkali reaction, so that (R)-2-crassitude or (S)-2-crassitude to be provided.The suitable alkali that is used for this reaction includes but not limited to ammonium hydroxide, alkali metal hydroxide (for example, sodium hydroxide, potassium hydroxide), alkylamine (for example, triethylamine, diisopropylethylamine) and composition thereof.The appropriate solvent that is used for this reaction includes but not limited to diethyl ether and methylene dichloride.In addition, can use process known in the art, make spent ion exchange resin, generate 2-crassitude free alkali from corresponding tartrate.

(the R)-2-crassitude L-tartrate that makes, (S)-2-crassitude D-tartrate, (R)-2-crassitude or (S)-2-crassitude preferably has the optical purity of 50%ee at least.This is meant that main enantiomorph accounts for 75% of mixture, and less important enantiomorph accounts for 25% (50%ee=((0.75-0.25)/(0.75+0.25) * 100%).This purity level is for enough usually for the product that uses as reagent in the building-up process subsequently.For example, when (the R)-2-crassitude L-tartrate that has an optical purity of 50% when use prepares the compound with other stereocenter, reaction will generate the mixture of diastereomer, and during the main diastereomer that normal purifying is formed by (R)-2-crassitude, can remove the less important diastereomer that forms by (S)-2-crassitude.

Higher if desired optical purity level, then can be with (R)-2-crassitude L-tartrate of obtaining or (S)-2-crassitude D-tartrate carries out recrystallization.Therefore, in certain embodiments, described method also can may further comprise the steps:

(f) make isolating (R)-2-crassitude L-tartrate or (S)-2-crassitude D-tartrate recrystallization;

(g) separate (R)-2-crassitude L-tartrate of recrystallization or (S)-2-crassitude D-tartrate; With

(h) optional repeating step (f) and step (g).

Step (f)

In step (f), will be in step (e) isolating (R)-2-crassitude L-tartrate or (S)-2-crassitude D-tartrate carry out recrystallization.The appropriate means that isolating (R)-2-crassitude L-tartrate or (S)-2-crassitude D-tartrate carries out recrystallization includes but not limited to, isolating tartrate is dissolved in the appropriate solvent, then with the solution cooling to promote crystallization.Suitable recrystallization solvent includes but not limited to alcoholic solvent.Recrystallization solvent preferably comprises the alcoholic solvent at least about 70% (v/v) ethanol and methyl alcohol.Recrystallization solvent is more preferably and comprises at least about 70% (v/v) with the ethanol of (v/v) ratio existence in about 1: 1 to about 5: 1 and the alcoholic solvent of methyl alcohol.Recrystallization solvent is more preferably and comprises at least about 70% (v/v) with the ethanol of (v/v) ratio existence in about 2: 1 to about 3: 1 and the alcoholic solvent of methyl alcohol.Recrystallization solvent is more preferably and comprises at least about the ethanol of 90% (v/v) and the alcoholic solvent of methyl alcohol.Recrystallization solvent is more preferably and comprises at least about 90% (v/v) with the ethanol of (v/v) ratio existence in about 1: 1 to about 5: 1 and the alcoholic solvent of methyl alcohol.Recrystallization solvent is more preferably and comprises at least about 90% (v/v) with the ethanol of (v/v) ratio existence in about 2: 1 to about 3: 1 and the alcoholic solvent of methyl alcohol.

Step (g)

In step (g), separate (R)-2-crassitude L-tartrate of recrystallization or (S)-2-crassitude D-tartrate.The proper method that is used to separate the tartrate of recrystallization includes but not limited to filtration, decant and centrifugal.(R)-2-crassitude L-tartrate of recrystallization or (S)-2-crassitude D-tartrate preferably is filtered separation.

Make in step (e) isolating tartrate according to step (f) and (g) experience single recrystallization order, isolating (R)-2-crassitude L-tartrate with 80%ee optical purity at least or (S)-2-crassitude D-tartrate preferably is provided.Isolating (R)-2-crassitude L-tartrate or (S) in step (g)-2-crassitude D-tartrate has the optical purity of 85%ee at least.What the optical purity of 85%ee was meant that main enantiomorph accounts for mixture is higher than 92%, less important enantiomorph is lower than 8%, and (84%ee=((0.925-0.075)/(0.925+0.075) * 100%), this is normally enough for the purity that is used for building-up process subsequently.

Step (h)

Higher if desired optical purity then can repeat recrystallization order (that is, step (f) and (g)) one or many, thus the optical purity of increase (R)-2-crassitude L-tartrate or (S)-2-crassitude D-tartrate.Behind twice recrystallization, (R)-2-crassitude L-tartrate or (S)-2-crassitude D-tartrate preferably has the optical purity of 90%ee at least.(R)-2-crassitude L-tartrate of isolating recrystallization or (S)-2-crassitude D-tartrate more preferably has the optical purity of 93%ee at least.Behind three (3) inferior recrystallizations, (R)-2-crassitude L-tartrate or (S)-2-crassitude D-tartrate preferably has the optical purity of 95%ee at least.(R)-2-crassitude L-tartrate of isolating recrystallization or (S)-2-crassitude D-tartrate more preferably has the optical purity of 97%ee at least.Behind four (4) inferior recrystallizations, (R)-2-crassitude L-tartrate or (S)-2-crassitude D-tartrate preferably has the optical purity of 98%ee at least.

Free alkali

Method also can be chosen wantonly and comprise that (R)-2-crassitude L-tartrate of making isolating recrystallization or (S)-2-crassitude D-tartrate and alkali reaction are to provide the step of (R)-2-crassitude or (S)-2-crassitude.The suitable alkali that is used for this reaction includes but not limited to ammonium hydroxide, alkali metal hydroxide (for example, sodium hydroxide, potassium hydroxide), alkylamine (for example, triethylamine, diisopropylethylamine) and composition thereof.The appropriate solvent that is used for this reaction includes but not limited to diethyl ether and methylene dichloride.In addition, can use program known in the art, make spent ion exchange resin, generate 2-crassitude free alkali from corresponding tartrate.

The free alkali of gained can adopt technology known in the art to separate.Free alkali preferably generates in the original place and need not to separate and promptly can be used for next synthesis step.Method as herein described both had been applicable to isolating 2-crassitude free alkali, was applicable to autochthonous 2-crassitude free alkali in reaction mixture again.

Additional compounds

Except the facilitated method that preparation (R)-and (S)-2-crassitude and tartrate separately thereof are provided, the present invention also provides the 2-crassitude has been incorporated into method in the useful compound of other compound, particularly pharmacy.Can use at step (e), (g) or (the R)-2-crassitude L-tartrate that (h) obtains afterwards or (S)-2-crassitude D-tartrate.In certain embodiments, the initial step that transforms is by reacting with alkali or ion exchange resin, can be with (R)-2-crassitude L-tartrate or (S)-2-crassitude D-tartrate form is converted into corresponding free alkali form (that is, being respectively (R)-2-crassitude or (S)-2-crassitude).Should (R)-2-crassitude or (S)-the 2-crassitude, no matter isolating still original place preparation all can be used for preparing many medical compoundss known in the art then, for example, histamine-3 receptors ligand.

For example, or (S) by (R)-2-crassitude of method for preparing-the 2-crassitude can be converted into the H of formula (I) ₃Receptor antagonist and/or inverse agonist, or its pharmacologically acceptable salts:

Wherein

R ¹Be

R ²Be

Be described among WO2007/009741 from the appropriate means of 2-crassitude preparation formula (I) compound, and can adapt, be used for according to (R)-2-crassitude of preceding method preparation or (S)-the 2-crassitude.For example, can provide the 4-{4-[(3-chloropropyl that is dissolved in the 2-butanone) the oxygen base] phenyl }-solution of 3-oxo-1-piperazinecarboxylic acid-1,1 dimethyl ethyl ester.Can add salt of wormwood, potassiumiodide and (R)-2-crassitude or (S)-2-crassitude free alkali, with mixture 80 ℃ of heating 24 hours.Can and between EtOAc and water, distribute the reaction cool to room temperature then.Can be with organic phase dry and concentrate, resistates by purification by flash chromatography, is merged suitable fraction and concentrates, so that the amine of being protected by BOC of formula (II) to be provided:

R wherein ²Be

(promptly, compound 4-(4-{[3-(2R-methyl isophthalic acid-pyrrolidyl) propyl group] the oxygen base } phenyl)-3-oxo-1-piperazinecarboxylic acid-1,1-dimethyl ethyl ester or 4-(4-{[3-(2S-methyl isophthalic acid-pyrrolidyl) propyl group] the oxygen base } phenyl)-3-oxo-1-piperazinecarboxylic acid-1,1-dimethyl ethyl ester).Can remove the BOC protecting group (for example) in formula (II) compound then by reacting with trifluoroacetic acid, to form the amine of formula (III):

R wherein ²Be The amine of formula (III) then can be selected from the compound that following carboxylic acid reaction forms formula (I): 4-cyanobenzoic acid, 4-(1-azelidinyl carbonyl) phenylformic acid, 2, the 4-difluoro-benzoic acid, 3, the 5-difluoro-benzoic acid, the 4-fluorobenzoic acid, 1-methyl isophthalic acid H-1,2,3-triazole-4-formic acid, 1,5-dimethyl-1H-pyrazoles-3-formic acid, 1-methyl-5-oxo-3-pyrrolidinecarboxylic acid, 3,5-dimethyl-4-isoxazole carboxylic acid, 1,3-dimethyl-1H-pyrazoles-5-formic acid, 2,3-difluoro-benzoic acid, 2, the 5-difluoro-benzoic acid, 2,6-difluoro-benzoic acid and 3,4-difluoro-benzoic acid.

In the amine of being protected by BOC of preparation formula (II) used 1; 1-dimethyl ethyl-4-{4-[(3-chloropropyl) oxygen base] phenyl }-3-oxo-1-piperazinecarboxylic acid ester can be by making 1-bromo-3-chloropropane and 1; 1-dimethyl ethyl-4-(4-hydroxy phenyl)-3-oxo-1-piperazinecarboxylic acid ester reaction is produced; 1; 1-dimethyl ethyl-4-(4-hydroxy phenyl)-3-oxo-1-piperazinecarboxylic acid ester can be by 1; 1-dimethyl ethyl-3-oxo-4-{4-[(phenyl methyl) oxygen base] phenyl }-1-piperazinecarboxylic acid ester carries out catalytic hydrogenolysis and preparation; 1; 1-dimethyl ethyl-3-oxo-4-{4-[(phenyl methyl) oxygen base] phenyl }-1-piperazinecarboxylic acid ester can be by making methylsulfonyl chloride and 1; 1-dimethyl ethyl-(2-hydroxyethyl) [2-oxo-2-({ 4-[(phenyl methyl) oxygen base] phenyl } amino) ethyl] urethane reaction is produced; 1,1-dimethyl ethyl-(2-hydroxyethyl) [2-oxo-2-({ 4-[(phenyl methyl) oxygen base] phenyl } amino) ethyl] carbamate can pass through N ²-(2-hydroxyethyl)-N1-{4-[(phenyl methyl) oxygen base] phenyl } G-NH2 carries out BOC protection and is produced N ²-(2-hydroxyethyl)-N ¹-{ 4-[(phenyl methyl) oxygen base] phenyl } G-NH2 can be by making the 4-[(phenyl methyl) the oxygen base] aniline and chloroacetyl chloride reaction, prepare with the reaction of 2-monoethanolamine then.

Replace BOC, can use other nitrogen-protecting group known in the art.The case description of suitable nitrogen-protecting group is in Green, T.W.; Wutz, P.G.M.Protective Groups inOrganic Synthesis, 2d ed.; John Wiley and Sons:New York, 1991.

Therefore, one embodiment of the invention relate to the method for the compound of preparation formula (I):

R wherein ¹And R ²Definition as mentioned above, said method comprising the steps of:

(1b) optionally remove hydrogenation catalyst from mixture;

(1c) L-tartrate is dissolved in the mixture to form solution;

(1d) make (R)-2-crassitude L-tartrate from solution crystallization;

(1e) fractional crystallization (R)-2-crassitude L-tartrate; With

(2a) isolating (R)-2-crassitude L-tartrate is converted into the compound of formula I.

This method also can be chosen wantonly and may further comprise the steps:

(1f) make isolating (R)-2-crassitude L-tartrate recrystallization;

(1g) (R)-2-crassitude L-tartrate of separation recrystallization; With

(1h) optional repeating step (f) and step (g).

In another embodiment, the present invention relates to the method for the compound of preparation formula (I):

R wherein ¹And R ²Definition as mentioned above, may further comprise the steps:

(1b) optionally remove hydrogenation catalyst from mixture;

(1c) L-tartrate is dissolved in the mixture to form solution;

(1d) make (R)-2-crassitude L-tartrate from solution crystallization;

(1e) fractional crystallization (R)-2-crassitude L-tartrate;

(1f) make (R)-2-crassitude L-tartrate and alkali reaction so that (R)-2-to be provided crassitude;

(2) make the protected amine reaction of (R)-2-crassitude and formula (Ia):

Wherein PG is a protecting group, to form the protected amine of formula (II):

(3) remove the protecting group of the protected amine of formula (II), form the amine of formula (III):

With

(4) amine that makes formula (III) be selected from following carboxylic acid reaction to form the compound of formula (I): 4-cyanobenzoic acid, 4-(1-azelidinyl carbonyl) phenylformic acid, 2, the 4-difluoro-benzoic acid, 3, the 5-difluoro-benzoic acid, the 4-fluorobenzoic acid, 1-methyl isophthalic acid H-1,2,3-triazole-4-formic acid, 1,5-dimethyl-1H-pyrazoles-3-formic acid, 1-methyl-5-oxo-3-pyrrolidinecarboxylic acid, 3,5-dimethyl-4-isoxazole carboxylic acid, 1,3-dimethyl-1H-pyrazoles-5-formic acid, 2,3-difluoro-benzoic acid, 2, the 5-difluoro-benzoic acid, 2,6-difluoro-benzoic acid and 3,4-difluoro-benzoic acid.

This method also can be chosen wantonly and may further comprise the steps:

(1f) make isolating (R)-2-crassitude L-tartrate recrystallization;

(1g) (R)-2-crassitude L-tartrate of separation recrystallization; With

(1h) optional repeating step (f) and (g).

Protecting group is BOC preferably.

Another shows that the active compound of histamine-3 receptors ligand is 2-(6-{2-[(2R)-2-methyl isophthalic acid-tetramethyleneimine-1-yl]-ethyl }-2-naphthalene-2-yl)-the 2H-pyridazin-3-one.A kind of method that is used for preparing this compound is described in US 2005/0256127.

6-bromo-naphthalene-2-alcohol can provide three fluoro-methylsulfonic acid 6-bromo-naphthalenes-2-base ester with any suitable trifluoromethanesulfonic acid class agent treated in the presence of organic bases.The example of suitable trifluoromethanesulfonic acid class reagent is, for example, and trifluoromethanesulfanhydride anhydride; trifluoromethanesulfchloride chloride, N-phenyl trifluoromethanesulfonate methylsulfonyl imines, trifyl-1-H-imidazoles; trifluoromethanesulfonic acid aniline, trifluoromethanesulfonic acid-2-nitrophenyl ester, trifluoromethanesulfonic acid-4-nitrophenyl ester.The example of organic bases is a triethylamine for example, diisopropylamine, and diisopropylethylamine, 2,6-lutidine, pyridine and 1,8-diazabicyclo be [5.4.0] 11 carbon-7-alkene (DBU) also.

Described reaction can be finished in any suitable organic solvent.The example of appropriate solvent is CH ₂Cl ₂, dimethyl ether (DME) and toluene.React under the two-phase condition that also can use mineral alkali therein and carry out.For example, suitable mineral alkali is K ₃PO ₄, NaHCO ₃, Na ₂CO ₃, NaOH etc.Preferred solvent is a toluene.Typically, be reflected at for example to use in the two-phase condition under toluene and the 30% potassiumphosphate low temperature and carry out.The preferred range of reaction is-5 ℃ to about 0 ℃ approximately.

Three fluoro-methylsulfonic acid-6-bromo-naphthalene-2-base ester by with vinyl three fluoroborates (ester) reagent react, be converted into 2-bromo-6-vinyl-naphthalene.Suitable vinyl three fluoroborates (ester) reagent is vinyl three potassium fluoborates for example, 2-vinyl-4,4,5,5-tetramethyl--1,3,2-two oxa-pentaboranes, dibutyl vinyl boric acid ester.The usage quantity of this reagent is that about 1.0 molar equivalents are to about 1.5 molar equivalents with respect to three fluoro-methylsulfonic acid 6-bromo-naphthalenes-2-base ester.Typically, being reflected at for example pure and mild basic solution of polar organic solvent for example carries out in the metal carbonate solution.Preferred solvent is an ethanol.The example that can be used for other solvent of this reaction is n-propyl alcohol, Virahol, methyl alcohol and other suitable alcohol.Metal carbonate is cesium carbonate preferably.Perhaps, also can use other salt, for example Na ₂CO ₃And K ₃PO ₄The amount that is used for the metal carbonate of this reaction is that about 2 molar equivalents are to about 4 molar equivalents with respect to three fluoro-methylsulfonic acid 6-bromo-naphthalenes-2-base ester.Be reflected at palladium catalyst and organic amino bases is for example finished under the condition such as existence such as triethylamine, diisopropylamines.The example that is used for the palladium catalyst of this reaction includes but not limited to tetrakis triphenylphosphine palladium, PdCl ₂(dppf) ₂, PdCl ₂(Ph ₃P) ₂And PdCl ₂(CH ₃CN) ₂Preferred palladium catalyst is a tetrakis triphenylphosphine palladium.

2-bromo-6-vinyl-naphthalene can provide 1-[2-(6-bromo-naphthalene-2-yl)-ethyl in order to (R)-2-crassitude anionic treatments of n-Butyl Lithium generation]-(R)-2-methyl-tetramethyleneimine.Can be improved by preparation (R) according to the method described above-and/or (S)-2-crassitude in the method described in the US2005/0256127.2-bromo-6-vinyl-naphthalene then can with (R)-2-crassitude negatively charged ion or any other suitable alkali reaction of producing with n-Butyl Lithium, so that 1-[2-(6-bromo-naphthalene-2-yl)-ethyl to be provided]-2R-methyl-tetramethyleneimine.(R)-2-crassitude anionic treatments that 2-bromo-6-vinyl-naphthalene can produce in order to n-Butyl Lithium is to provide 1-[2-(6-bromo-naphthalene-2-yl)-ethyl]-(R)-2-methyl-tetramethyleneimine.Preferably, about 1.2 (the R)-2-crassitudes to about 2.5 molar equivalents are used in this reaction.Reaction is typically at organic solvent for example THF, methyl-tertbutyl ether (MTBE), Et ₂Finish among O and the DME.Preferred solvent is tetrahydrofuran (THF) (THF).In a controlled manner, typically in the dropping mode, n-Butyl Lithium is joined in the THF solution of (R)-2-crassitude.The THF solution that in this solution, adds 2-bromo-6-vinyl-naphthalene.Perhaps, also be fit in the solution of (R)-2-crassitude and n-Butyl Lithium, add the THF solution of 2-bromo-6-vinyl-naphthalene.Be reflected to be lower than under the room temperature and finish, typically in about 0 ℃ to about-20 ℃ temperature range, finish.With respect to 2-bromo-6-vinyl naphthalene compound, use about 0.3 n-Butyl Lithium to about 0.7 molar equivalent.Resulting compound is 1-[2-(6-bromo-naphthalene-2-yl)-ethyl]-(R)-2-methyl-tetramethyleneimine.

1-[2-(6-bromo-naphthalene-2-yl)-ethyl]-(R)-2-methyl-tetramethyleneimine can react with the 2H-pyridazin-3-one then, so that required 2-{6-[2-((R) 2-methyl-tetramethyleneimine-1-yl)-ethyl to be provided]-naphthalene-2-yl }-2H-pyridazin-3-one compound, it can be further processed to prepare suitable salt.This reaction uses 2H-pyridazin-3-one, oxine, copper catalyst to finish in the presence of alkali.With respect to 1-[2-(6-bromo-naphthalene-2-yl)-ethyl]-(R)-and 2-methyl-tetramethyleneimine, use about 1.0 (2H)-pyridazin-3-ones to about 1.5 molar equivalents.Copper catalyst can be any suitable copper catalyst, for example copper (I) catalyzer.The suitable catalyzer example that is used for this reaction includes but not limited to copper (0) powder, cupric chloride (I), cupric bromide (I), cupric iodide (I), cupric oxide (I), venus crystals (I), cupric chloride (II), cupric bromide (II), cupric iodide (II), cupric oxide (II) or venus crystals (II).Preferred copper catalyst is cupric chloride (I).With respect to 1-[2-(6-bromo-naphthalene-2-yl)-ethyl]-(R)-and 2-methyl-tetramethyleneimine, use about 0.02 copper catalyst to about 1.0 molar equivalents.The suitable part example that is used for this reaction includes but not limited to right-dimethyl aminopyridine, pyridine, 3-picoline, 4-picoline, oxine, 7-methyl-oxine, 7-just-propyl group-oxine, 1,10-phenanthroline and 2,2 '-dipyridyl.Preferred part is an oxine, and its consumption is with respect to 1-[2-(6-bromo-naphthalene-2-yl)-ethyl]-(R)-2-methyl-tetramethyleneimine is about 0.02 to about 2.0 molar equivalents.Alkali is metal carbonate or metal alkoxide preferably, for example, and cesium carbonate, salt of wormwood, yellow soda ash and sodium tert-butoxide.Preferred alkali is salt of wormwood, and its consumption is with respect to 1-[2-(6-bromo-naphthalene-2-yl)-ethyl]-(R)-2-methyl-tetramethyleneimine is about 1.0 to about 2.0 molar equivalents.Reaction is finished in polar organic solvent at elevated temperatures.The example of appropriate solvent includes but not limited to N, N '-dimethyl formamide, N-Methyl pyrrolidone, N, N '-N,N-DIMETHYLACETAMIDE, pyridine, 3-picoline, 4-picoline etc.Preferred solvent is dimethyl formamide (DMF).Reaction the typical case finish under nitrogen atmosphere, reaction mixture is heated to about 100 ℃ arrives about 160 ℃ temperature.The reaction typical case can finish in about 48 hours about 10.When reaction is finished and be cooled to 25 ℃, add not miscible solvent, for example ethyl acetate with water.For example 25% NaCl solution or other suitable salts solution wash several times to organic solution with salt brine solution.Organic solution is dry and be concentrated into driedly, obtain product.

Perhaps, 2-(6-{2-[(2R)-2-methyl isophthalic acid-tetramethyleneimine-1-yl]-ethyl }-2-naphthalene-2-yl)-2H-pyridazin-3-one promoting agent can be according to the US 7 that submitted on October 22nd, 2003,153, program preparation described in 889, for example, at least general process and example 31 described preparations, perhaps any other suitable being used to provide the program preparation of stabilizing active agent.In brief, for example, use BH ₃-THF is with the reduction of 6-bromo-2-naphthoate, so that corresponding alcohol to be provided.6-bromo-naphthalene-2-base-methyl alcohol is with 3 (2H)-pyridazinones, copper powder and alkaline purification, with provide 2-[6-(2-hydroxyl-ethyl)-naphthalene-2-base-]-the 2H-pyridazin-3-one, it activates such as tosylate with sulphonate.Provide according to the above-mentioned step (a) that has or do not have an optional step (f) to (h) to (e) and make (R)-2-crassitude L-tartrate and alkali reaction prepare (R)-2-crassitude so that (R)-2-crassitude to be provided, with sulphonate and the reaction of described (R)-2-crassitude so that 2-(6-{ (2R) 2-methyl isophthalic acid-tetramethyleneimine-1-yl }-ethyl)-2-naphthalene-2-yl to be provided)-the 2H-pyridazin-3-one.

Therefore, one embodiment of the invention relate to and prepare 2-{6-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-naphthalene-2-yl }-method of 2H-pyridazin-3-one, may further comprise the steps:

(1b) optionally remove hydrogenation catalyst from mixture;

(1c) L-tartrate or D-tartrate are dissolved in the mixture to form solution;

(1d) make (R)-2-crassitude L-tartrate or (S)-2-crassitude D-tartrate from solution crystallization;

(1e) fractional crystallization (R)-2-crassitude L-tartrate or (S)-2-crassitude D-tartrate; With

(R)-2-crassitude L-tartrate is contacted with alkali with formation (R)-2-crassitude free alkali, or (S)-2-crassitude D-tartrate is contacted with alkali to form (S)-2-crassitude;

(3a) three fluoro-methylsulfonic acid 6-bromo-naphthalenes-2-base ester is converted into 2-bromo-6-vinyl-naphthalene;

(3b) make 2-bromo-6-vinyl-naphthalene with (R)-2-crassitude or (S)-2-crassitude reacts in the presence of n-Butyl Lithium, so that 1-[2-(6-bromo-naphthalene-2-yl)-ethyl to be provided]-2R-methyl-tetramethyleneimine or 1-[2-(6-bromo-naphthalene-2-yl)-ethyl]-2S-methyl-tetramethyleneimine; With

(3c) make 1-[2-(6-bromo-naphthalene-2-yl)-ethyl]-2-methyl-tetramethyleneimine and the reaction of 2H-pyridazin-3-one, so that 2-{6-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl to be provided]-naphthalene-2-yl }-the 2H-pyridazin-3-one.

This method also can be chosen wantonly and may further comprise the steps:

(1f) make isolating (R)-2-crassitude L-tartrate recrystallization;

(1g) (R)-2-crassitude L-tartrate of separation recrystallization; With

(1h) optional repeating step (f) and (g).

In addition, three fluoro-methylsulfonic acid 6-bromo-naphthalenes-2-base ester can followingly obtain: 6-bromo-naphthalene-2-alcohol is provided; With make 6-bromo-naphthalene-2-alcohol and suitable trifluoromethanesulfonic acid class reagent react.

Can use the exemplary compounds of the inventive method preparation to comprise:

WO 2005/11786 has also described the histamine-3-receptors ligand that comprises 2-methyl-pyrrolidyl part shown in the following general formula III:

Wherein A is selected from:

Wherein:

M is 0,1 or 2;

N is 0,1 or 2;

R ³Be hydrogen or low alkyl group;

T is 1 or 2;

R ⁴Be hydrogen or low alkyl group;

X is O, S or N-R ⁸, R wherein ⁸Be hydrogen or low alkyl group;

P is 0,1 or 2;

R ⁶Be low alkyl group;

S is 0,1 or 2; With

R ⁷Be low alkyl group.

The compound of formula III can prepare according to reaction scheme 1:

Reaction scheme 1

The coupling of carboxylic acid and amine extensively described in the literature and this process be well known by persons skilled in the art (for the reaction conditions of this reaction of describing in the literature of realization can referring to, for example: Comprehensive Organic Transformations:A Guide to FunctionalGroup Preparations, 2nd Edition, Richard C.Larock.John Wiley﹠amp; Sons, New York, NY.1999).6-hydroxyl-2-naphthoic acid can by with according to above-mentioned steps (a) to (e) (have or do not have optional step (f)) to (h) and make (R)-2-crassitude L-tartrate and alkali reaction with (R) that provide (R)-2-crassitude to prepare-or (S)-2-crassitude coupling, be converted into corresponding amide easily.Can use any suitable coupling agent to realize this conversion.For example, can use coupling agent as 1 equally well, 1 '-carbonyl dimidazoles (CDI), N, N '-dicyclohexylcarbodiimide (DCC), 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDCI), 1-[two (dimethylamino) methylene radical]-1H-1,2,3-triazolo [4,5-b] pyridine-3-oxygen base hexafluorophosphate (HATU), L-hydroxyl-1,2,3-benzotriazole (HOBT), O-benzotriazole-1-base-N, N, N ', N '-tetramethyl-urea a tetrafluoro borate (TBTU) waits realizes this conversion.

Character for solvent for use is not specifically limited, and condition is that described solvent does not have adverse influence to the reagent that reacts or involved, and it can dissolve described reagent at least to a certain extent.The example of appropriate solvent comprises: DMF, methylene dichloride (DCM) ， diox, THF etc.Typically, alkali uses with coupling agent.Character to used alkali in this stage is not specifically limited, and can use any alkali that is generally used for this class reaction here equally.The example of this class alkali comprises triethylamine and diisopropylethylamine etc.Reaction can be carried out in wide temperature range, and accurate temperature of reaction is not conclusive for the present invention.Be heated to backflow from surrounding temperature and can be convenient to the carrying out that react.Reacting required time also can be according to many factors, particularly temperature of reaction and reagent character, and significantly changes.Yet 0.5 hour to several days period enough produces amide derivatives usually.

An exemplary process that is used for preparing (6-hydroxyl-naphthalene-2-yl)-(2-methyl-tetramethyleneimine-1-yl)-ketone is as described below.Preparation 6-hydroxyl-2-naphthoic acid, 2-(1H-benzotriazole-1-yl)-1 in 10mL DMF, 1,3, the mixture of 3-tetramethyl-urea a tetrafluoro borate, 2.3mL N-ethyl diisopropyl amine and or (S)-2-methyl-tetramethyleneimine according to (R) of said process preparation, and at room temperature stirred 16 hours.Then mixture is concentrated into dry doubling and adds 50mL ethyl acetate, 30mL water and 20mL NaHCO ₃The aqueous solution (10%).Water can be used the 50mL ethyl acetate extraction then, and the organic layer that merges is carried out purifying with the silicon-dioxide column chromatography.The product fraction is concentrated into dry doubling and 20mL diethyl ether/heptane 1/1 grinds twice, and resistates is carried out vacuum-drying at 50 ℃.Use according to (R)-2-crassitude of methods described herein preparations or (S)-the 2-crassitude puts into practice this method, can generate (6-hydroxyl-naphthalene-2-yl)-(2R-methyl-tetramethyleneimine-1-yl)-ketone or (6-hydroxyl-naphthalene-2-yl)-(2S-methyl-tetramethyleneimine-1-yl)-ketone, it can be used for preparing histamine-3-receptors ligand then.

In order to prepare histamine-3-receptors ligand, above-mentioned (R) or (S) the alcohol reaction of intermediate and formula HO-A (wherein the definition of A as mentioned above) are to form ether.Ether synthetic extensively described in the literature and this program is well known by persons skilled in the art.(for the reaction conditions of the described reaction of describing in the literature of realization, for example, referring to: Comprehensive OrganicTransformations:A Guide to Functional Group Preparations, 2nd Edition, Richard C.Larock.John Wiley﹠amp; Sons, New York, NY.1999).Can by use generally adopted in the what is called well known by persons skilled in the art " Mitsunobu reaction " and by broadly described reaction conditions, realize this conversion (Hughes, David L.The Mitsunobureaction.Organic Reactions (New York) (1992), 42,335-656.).Use trialkyl phosphine such as tributylphosphine, triphenylphosphine etc. and diazonium compound such as diethyl-azodiformate (DEAD), di-isopropyl azodiformate (DIAD) (optional conjugated polymer), tetramethyl-Cellmic C 121 etc. to transform the generally condition in the solvent of use such as tetrahydrofuran (THF) (THF), toluene, the methylene dichloride etc. of institute at this.Character for solvent for use is not specifically limited, and condition is that described solvent does not have adverse influence to the reagent that reacts or involved, and it can dissolve described reagent at least to a certain extent.Reaction can be carried out in wide temperature range, and accurate temperature of reaction is not conclusive for the present invention.Ambient temperature generally is suitable to refluxing.Reacting required time also can be according to many factors, particularly temperature of reaction and reagent character, and significantly changes.Yet 0.5 hour to several days period will enough produce required compound usually.

As an alternative, can use following route of synthesis:

Reaction scheme 2

Shown in reaction scheme 2, initial pure HO-A, wherein A reacts under the Mitsunobu reaction conditions with methyl ester as mentioned above, carries out the cracking of ester then.The acid of intermediate formation then with according to above-mentioned steps (a) to (e) (have or do not have optional step (f)) to (h) and make (R)-2-crassitude L-tartrate and alkali reaction (R)-2-crassitude to be provided or to make (S)-2-crassitude D-tartrate and alkali reaction carries out coupling to provide (S)-2-crassitude to prepare (R)-or (S)-2-crassitude, to obtain required compound.Suitable coupling agent and condition are as mentioned above.

Therefore, one embodiment of the invention relate to the method for preparing the formula III compound:

Wherein each variable as mentioned above, described method comprises:

(1b) optionally remove hydrogenation catalyst from mixture;

(1c) L-tartrate or D-tartrate are dissolved in the mixture to form solution;

(R)-2-crassitude L-tartrate is contacted with alkali to form (R)-2-crassitude free alkali or (S)-2-crassitude D-tartrate is contacted with alkali to form (S)-2-crassitude;

(3a) make the carboxylic acid of following formula

Contact with under time of being enough to form corresponding amide phenol and the condition with (R)-or (S)-2-crassitude; With

(3b) make the alcohol of acid amides phenol and formula HO-A, wherein A contacts under the time that is enough to provide corresponding amide ether and condition as mentioned above.

This method also can be chosen wantonly and may further comprise the steps:

(1f) make isolating (R)-2-crassitude L-tartrate or (S)-2-crassitude D-tartrate recrystallization;

(1g) separate (R)-2-crassitude L-tartrate of recrystallization or (S)-2-crassitude D-tartrate; With

(1h) optional repeating step (f) and step (g).

Another embodiment relates to the method for preparing the formula III compound:

Wherein each variable as mentioned above, described method comprises:

(1b) optionally remove hydrogenation catalyst from mixture;

(1c) L-tartrate or D-tartrate are dissolved in the mixture to form solution;

(3a) make the ester phenol of following formula:

With the alcohol of formula HO-A, wherein A contacts with under time of being enough to form corresponding ether-ether and the condition as mentioned above; With

(3b) ether-ether and (R)-or (S)-2-crassitude is contacted with under time of being enough to form corresponding amide ether and the condition.

This method also can be chosen wantonly and may further comprise the steps:

(1h) optional repeating step (f) and step (g).

Can use the particularly preferred compound of method preparation of the present invention to comprise:

(2-methyl-tetramethyleneimine-1-yl)-6-[2-(1-methyl-tetramethyleneimine-2-yl)-oxyethyl group]-naphthalene-2-yl }-ketone;

[6-(1-sec.-propyl-tetramethyleneimine-3-base oxygen base)-naphthalene-2-yl]-(2-methyl-tetramethyleneimine-1-yl)-ketone;

[6-(1-sec.-propyl-piperidin-4-yl oxygen base-) naphthalene-2-yl]-(2-methyl-tetramethyleneimine-1-yl)-ketone; With

[6-(1-isobutyl--piperidin-4-yl oxygen base)-naphthalene-2-yl]-(2-methyl-tetramethyleneimine-1-yl)-ketone.

Can be from (R)-2-crassitude of producing according to methods described herein or (S)-another group compound of 2-crassitude preparation is disclosed in the US 2008/0027041A1.The compound of general formula I V specifically, is disclosed in this application:

And pharmacologically acceptable salt;

Wherein:

R ¹For

X and X ^aBe CH or N independently of one another;

Y is S (O) _q, O or NR ¹⁵

R ²For

Wherein:

As X and X ^aWhen all being CH, R then ²Be positioned at Y-(CHR ⁴) _m-R ¹Position or contraposition between group; With

As X or X ^aOne of when being N, R then ²Be positioned at Y-(CHR ⁴) _m-R ¹The contraposition of group;

Each R ³Be independently:

H, F, Cl, Br, I, OR ²¹, NR ²³R ²⁴, NO ₂, CN, CF ₃, C ₁-C ₆Alkyl, C (=O) R ²¹, CO ₂R ²¹Or C (=O) NR ²³R ²⁴Perhaps

Work as R ³With R ²Be ortho position and R ²For (i), (ii), (iv), (vi) or (ix) time, R then ³And R ¹⁴Formation-(CH together ₂) _s-,-CH ₂Z-,-ZCH ₂-,-ZCH ₂CH ₂-or CH ₂CH ₂Z-; Wherein Z is O, S (O) _yOr NR ²⁷Perhaps

Work as R ³With R ²Be ortho position and R ²For (iv), (v) or (viii) the time, R then ³And R ¹³Formation-(CH together ₂) _s-,-CH ₂Z-,-ZCH ₂-,-ZCH ₂CH ₂-or CH ₂CH ₂Z-; Perhaps

Work as R ³With R ²Be ortho position and R ²For (viii) the time, R then ³And R ^13bCan form together-(CH ₂) _s-,-CH ₂Z-,-ZCH ₂-,-ZCH ₂CH ₂-or CH ₂CH ₂Z-; Perhaps

Work as R ³With X ^aBe ortho position and R ²With R ³Be ortho position and and X ^aWhen position between being, then R ²And R ³Can form together:

Each R ⁴Be H independently, C ₁-C ₆Alkyl or OR ²¹, wherein alkyl is optional by 1-3 R ²⁰Group replaces;

R ¹²Be H, C ₁-C ₆Alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, Heterocyclylalkyl, C (=O) R ²⁷Or CO ₂R ²⁷, alkyl wherein, cycloalkyl, aryl, arylalkyl, heteroaryl base or Heterocyclylalkyl are optional by 1-3 R ²⁰Group replaces;

R ¹³And R ¹⁴Be H independently of one another, C ₁-C ₆Alkyl, aryl, arylalkyl C ₁-C ₆Alkoxyl group, S (=O) _y-C ₁-C ₆Alkyl, cycloalkyl, Heterocyclylalkyl or heteroaryl;

R ^13a, R ^13b, R ^13cAnd R ^14aBe H independently of one another, C ₁-C ₆Alkyl; Perhaps R ¹³And R ¹⁴Form the condensed phenyl with the carbon atom that they connected, thienyl, pyrryl ， oxazolyl, pyridyl or C ₃-C ₆Cycloalkyl ring; Perhaps R ^13bAnd R ¹⁴, perhaps R ¹³And R ^14a, perhaps R ^13bAnd R ^14a, perhaps R ^13cAnd R ^14aForm condensed C with the carbon atom that they connected ₃-C ₆Cycloalkyl ring; Perhaps R ¹³And R ^13a, perhaps R ¹⁴And R ^14a, form C with the carbon atom that they connected ₃-C ₈Cycloalkyl ring; Condition is R ¹³And R ¹⁴, R ^13bAnd R ¹⁴, R ¹³And R ^14a, R ^13bAnd R ^14a, R ^13cAnd R ^14a, R ¹³And R ^13aAnd R ¹⁴And R ^14aIn be no more than and a pair ofly connect or their institute's bonded carbon atoms form ring with them; And condensed phenyl wherein, thienyl, pyrryl ， oxazolyl, pyridyl or cycloalkyl ring are optional by 1-3 R ²⁰Group replaces;

R ¹⁵Be H, C ₁-C ₆Alkyl, C (=O) R ²⁵, CO ₂R ²⁵

R ²⁰Be H in each case independently, F, Cl, Br, I, OR ²¹, OR ²², NR ²³R ²⁴, NHOH, NO ₂, CN, CF ₃, optional by OR ²⁶The C that replaces ₁-C ₆Alkyl, C ₂-C ₆Thiazolinyl, C ₂-C ₆Alkynyl, C ₃-C ₇Cycloalkyl C ₀-C ₄Alkyl, the Heterocyclylalkyl C of 3-7 unit ₀-C ₄Alkyl, phenyl, 5 or 6 yuan of heteroaryl C ₀-C4 alkyl, arylalkyl, (=O), C (=O) R ²¹, CO ₂R ²¹, OC (=O) R ²¹, C (=O) NR ²³R ²⁴, NR ²⁷C (=O) R ²¹, NR ²⁷C (=O) OR ²¹, OC (=O) NR ²³R ²⁴, NR ²⁷C (=S) R ²¹Or S (O) _qR ²¹

Each R ²¹Be H independently, C ₁-C ₆Alkyl, aryl or arylalkyl;

Each R ²²Be the residue of amino acid after removing the hydroxyl of decarboxylate independently;

Each R ²³And R ²⁴Be independently selected from H, C ₁-C ₆Alkyl and aryl, or R ²³And R ²⁴Form randomly by=3-7 unit heterocycle that O replaces with the nitrogen-atoms that they connected;

R ²⁵Be C ₁-C ₆Alkyl, aryl or alkylaryl;

R ²⁶Be H, C ₁-C ₆Alkyl, aryl or alkylaryl;

R ²⁷Be H or C ₁-C ₆Alkyl;

Work as R ¹When connecting by nitrogen-atoms, m is 1,2,3,4 or 5, and when R1 connected by carbon atom, m was 0,1,2,3,4 or 5;

N is 1,2 or 3;

Q is 0,1 or 2;

S is 1,2 or 3; With

Y is 0,1 or 2.

The specific examples of this compounds that use 2-crassitude preparation method according to the present invention can prepare comprises:

The 2-methyl-6-{4-[(R)-2-methyl-3-((R)-2-methyl-tetramethyleneimine-1-yl)-propoxy-]-phenyl }-the 2H-pyridazin-3-one;

6-{3,5-two fluoro-4-[3-((R)-2-methyl-tetramethyleneimine-1-yl)-propoxy-]-phenyl }-2-methyl-2H-pyridazin-3-one;

6-{3-chloro-4-[3-((R)-2-methyl-tetramethyleneimine-1-yl)-propoxy-]-phenyl }-2-methyl-2H-pyridazin-3-one;

2,6-dimethyl-5-{4-[3-((R)-2-methyl-tetramethyleneimine-1-yl)-propoxy-]-phenyl }-the 2H-pyridazin-3-one;

6-methyl-5-{4-[3-((R)-2-methyl-tetramethyleneimine-1-yl)-propoxy-]-phenyl }-the 2H-pyridazin-3-one;

2-methyl-5-{4-[3-((R)-2-methyl-tetramethyleneimine-1-yl)-propoxy-]-phenyl }-the 2H-pyridazin-3-one;

5-{4-[3-((R)-2-methyl-tetramethyleneimine-1-yl)-propoxy-]-phenyl }-2-pyridine-2-base-2H-pyridazin-3-one;

2-(6-methyl-pyridine-2-yl)-5-{4-[3-((R)-2-methyl-tetramethyleneimine-1-yl)-propoxy-]-phenyl }-the 2H-pyridazin-3-one;

2-(3-methyl-pyridine-2-yl)-5-{4-[3-((R)-2-methylpyrrolidin-1-yl)-propoxy-]-phenyl }-the 2H-pyridazin-3-one;

6-methyl-5-{4-[3-((R)-2-methyl-tetramethyleneimine-1-yl)-propoxy-]-phenyl }-2-pyridine-2-base-2H-pyridazin-3-one;

6-methyl-2-(3-methyl-pyridine-2-yl)-5-{4-[3-((R)-2-methyl-tetramethyleneimine-1-yl)-propoxy-]-phenyl }-the 2H-pyridazin-3-one;

6-methyl-5-{4-[3-((R)-2-methyl-tetramethyleneimine-1-yl)-propoxy-]-phenyl }-2-thiene-3-yl--2H-pyridazin-3-one;

5-{4-[3-((S)-2-methyl-tetramethyleneimine-1-yl)-propoxy-]-phenyl }-2-pyridine-2-base-2H-pyridazin-3-one;

6-{4-[3-((R)-2-methyl-tetramethyleneimine-1-yl)-propoxy-]-phenyl }-5-pyridine-2-base-4,5-dihydro-2H-pyridazin-3-one;

6-{4-[3-((R)-2-methyl-tetramethyleneimine-1-yl)-propoxy-]-phenyl }-5-pyridine-2-base-2H-pyridazin-3-one;

2-(2-fluoro-ethyl)-6-{4-[3-((R)-2-methyl-tetramethyleneimine-1-yl)-propoxy-]-phenyl }-the 2H-pyridazin-3-one;

6-{3-fluoro-4-[3-((R)-2-methyl-tetramethyleneimine-1-yl)-propoxy-]-phenyl }-the 2H-pyridazin-3-one;

4-methyl-6-{4-[3-((R)-2-methyl-tetramethyleneimine-1-yl)-propoxy-]-phenyl }-4,5-dihydro-2H-pyridazin-3-one;

4-methyl-6-{4-[3-((R)-2-methyl-tetramethyleneimine-1-yl)-propoxy-]-phenyl }-the 2H-pyridazin-3-one;

2-methyl-4-{3-[3-((R)-2-methyl-tetramethyleneimine-1-yl)-propoxy-]-phenyl }-2,5,6,7-tetrahydrochysene-ring penta [d] pyridazine-1-ketone;

2-sec.-propyl-5-{4-[3-((R)-2-methyl-tetramethyleneimine-1-yl)-propoxy-]-phenyl }-the 2H-pyridazin-3-one;

2-[3-((R)-2-methyl-tetramethyleneimine-1-yl)-propoxy-]-5-(6-oxo-1,6-dihydro-pyridazine-3-yl)-cyanobenzene;

2-(2-hydroxyethyl)-6-{4-[3-((R)-2-methyl-tetramethyleneimine-1-yl)-propoxy-]-phenyl }-the 2H-pyridazin-3-one;

6-{4-[(S)-2-methyl-3-((R)-2-methyl-tetramethyleneimine-1-yl)-propoxy-]-phenyl }-the 2H-pyridazin-3-one;

6-{3-methoxyl group-4-[3-((R)-2-methyl-tetramethyleneimine-1-yl)-propoxy-]-phenyl }-the 2H-pyridazin-3-one;

6-{4-[3-((R)-2-methyl-tetramethyleneimine-1-yl)-propoxy-]-phenyl }-2-pyrimidine-2-base-2H-pyridazin-3-one;

6-{6-[3-((R)-2-methyl-tetramethyleneimine-1-yl)-propoxy-]-pyridin-3-yl }-the 2H-pyridazin-3-one;

6-{4-[3-((R)-2-methyl-tetramethyleneimine-1-yl)-propoxy-]-phenyl }-2-(2,2,2-three fluoro-ethyls)-4,5-dihydro-2H-pyridazin-3-one;

6-{4-[3-((R)-2-methyl-tetramethyleneimine-1-yl)-propoxy-]-phenyl }-2-(2,2,2-three fluoro-ethyls)-2H-pyridazin-3-one;

5-{4-[3-((R)-2-methyl-tetramethyleneimine-1-yl)-propoxy-]-phenyl }-3,4-diaza-dicyclo is [4.2.0] suffering-4-alkene-2-ketone also;

4-{4-[3-((R)-2-methyl-tetramethyleneimine-1-yl)-propoxy-]-phenyl }-2,4a, 5,6,7,7a-six hydrogen-ring penta [d] pyridazine-1-ketone;

6-{4-[3-((R)-2-methyl-tetramethyleneimine-1-yl)-propoxy-]-phenyl }-4,5-dihydro-2H-pyridazin-3-one;

4,4-dimethyl-6-{4-[3-((R)-2-methyl-tetramethyleneimine-1-yl)-propoxy-]-phenyl }-4,5-dihydro-2H-pyridazin-3-one;

6-{3-fluoro-4-[3-((R)-2-methyl-tetramethyleneimine-1-yl)-propoxy-]-phenyl }-4,5-dihydro-2H-pyridazin-3-one;

5,5-dimethyl-6-{4-[3-((R)-2-methyl-tetramethyleneimine-1-yl)-propoxy-]-phenyl }-4,5-dihydro-2H-pyridazin-3-one;

6-{4-[3-((R)-2-methyl-tetramethyleneimine-1-yl)-propoxy-]-phenyl }-2-pyridine-2-base-4,5-dihydro-2H-pyridazin-3-one;

6-{3,5-two fluoro-4-[3-((R)-2-methyl-tetramethyleneimine-1-yl)-propoxy-]-phenyl }-the 2H-pyridazin-3-one;

6-{3,5-two bromo-4-[3-((R)-2-methyl-tetramethyleneimine-1-yl)-propoxy-]-phenyl }-the 2H-pyridazin-3-one;

6-{3,5-two fluoro-4-[3-((R)-2-methyl-tetramethyleneimine-1-yl)-propoxy-]-phenyl }-4,5-dihydro-2H-pyridazin-3-one;

5-methyl-6-{4-[3-((R)-2-methyl-tetramethyleneimine-1-yl)-propoxy-]-phenyl }-4,5-dihydro-2H-pyridazin-3-one racemoid;

5-methyl-6-{4-[3-((R)-2-methyl-tetramethyleneimine-1-yl)-propoxy-]-phenyl }-4,5-dihydro-2H-pyridazin-3-one diastereomer;

6-{ (R)-2-methyl-4-[3-(2-methyl-tetramethyleneimine-1-yl)-propoxy-]-phenyl }-4,5-dihydro-2H-pyrazine-3-ketone;

2-{4-[3-((R)-2-methyl-tetramethyleneimine-1-yl)-propoxy-]-phenyl }-6-phenyl-2H-pyridazin-3-one;

6-methyl-2-{4-[3-((R)-2-methyl-tetramethyleneimine-1-yl)-propoxy-]-phenyl }-the 2H-pyridazin-3-one;

2-{4-[3-((R)-2-methyl-tetramethyleneimine-1-yl)-propoxy-]-phenyl }-2H-phthalazines-1-ketone;

2-{4-[3-((R)-2-methyl-tetramethyleneimine-1-yl)-propoxy-]-phenyl }-6-pyridin-3-yl-2H-pyridazin-3-one;

3-methyl-4-{4-[3-((R)-2-methyl-tetramethyleneimine-1-yl)-propoxy-]-phenyl }-6H-isoxazole [3,4-d] pyridazine-7-ketone also;

8-[3-((R)-2-methyl-tetramethyleneimine-1-yl)-propoxy-]-5,6-dihydro-2H-benzo [h] cinnolines-3-ketone;

5-methyl-6-{4-[3-((R)-2-methyl-tetramethyleneimine-1-yl)-propoxy-]-phenyl }-the 2H-pyridazin-3-one;

5-ethyl-6-{4-[3-((R)-2-methyl-tetramethyleneimine-1-yl)-propoxy-]-phenyl }-the 2H-pyridazin-3-one;

8-[3-(2-methyl-tetramethyleneimine-1-yl)-propoxy-]-4,4a, 5,6-tetrahydrochysene-2H-benzo [h] cinnolines-3-ketone;

6-{2-methoxyl group-4-[3-((R)-2-methyl-tetramethyleneimine-1-yl)-propoxy-]-phenyl }-the 2H-pyridazin-3-one;

6-{2-fluoro-4-[3-((R)-2-methyl-tetramethyleneimine-1-yl)-propoxy-]-phenyl }-the 2H-pyridazin-3-one;

6-{4-[3-((R)-2-methyl-tetramethyleneimine-1-yl)-propoxy-]-phenyl }-2-pyridine-2-base-2H-pyridazin-3-one;

6-{4-[3-((R)-2-methyl-tetramethyleneimine-1-yl)-propoxy-]-phenyl }-4-pyridine-2-base-4,5-dihydro-2H-pyridazin-3-one;

6-{4-[3-((R)-2-methyl-tetramethyleneimine-1-yl)-propoxy-]-phenyl }-4-pyridine-2-base-2H-pyridazin-3-one;

8-[3-((R)-2-methyl-tetramethyleneimine-1-yl)-propoxy-]-5,6-dihydro-3H-benzo [f] cinnolines-2-ketone;

5-{4-[3-((R)-2-methyl-tetramethyleneimine-1-yl)-propoxy-]-phenyl }-the 2H-pyridazin-3-one;

2-methoxymethyl-5-{4-[3-((R)-2-methyl-tetramethyleneimine-1-yl)-propoxy-]-phenyl }-the 2H-pyridazin-3-one;

5-{4-[(S)-2-methyl-3-((R)-2-methyl-tetramethyleneimine-1-yl)-propoxy-]-phenyl }-the 2H-pyridazin-3-one;

5-{4-[(R)-2-methyl-3-((R)-2-methyl-tetramethyleneimine-1-yl)-propoxy-]-phenyl }-the 2H-pyridazin-3-one;

5-{3,5-two bromo-4-[3-((R)-2-methyl-tetramethyleneimine-1-yl)-propoxy-]-phenyl }-the 2H-pyridazin-3-one;

2-methoxymethyl-5-{2-methyl-4-[3-((R)-2-methyl-tetramethyleneimine-1-yl)-propoxy-]-phenyl }-the 2H-pyridazin-3-one;

5-{2-methyl-4-[3-((R)-2-methyl-tetramethyleneimine-1-yl)-propoxy-]-phenyl }-the 2H-pyridazin-3-one;

4-methoxyl group-2-methoxymethyl-5-{4-[3-((R)-2-methyl-tetramethyleneimine-1-yl)-propoxy-]-phenyl }-the 2H-pyridazin-3-one;

5-methoxyl group-2-methoxymethyl-4-{4-[3-((R)-2-methyl-tetramethyleneimine-1-yl)-propoxy-]-phenyl }-the 2H-pyridazin-3-one;

5-methoxyl group-4-{4-[3-((R)-2-methyl-tetramethyleneimine-1-yl)-propoxy-]-phenyl }-the 2H-pyridazin-3-one;

6-{4-[3-((S)-2-methyl-tetramethyleneimine-1-yl)-propoxy-]-phenyl }-the 2H-pyridazin-3-one;

5-{4-[3-((R)-2-methyl-tetramethyleneimine-1-yl)-propoxy-]-phenyl-3,4-diaza-dicyclo also [4.1.0] heptan-4-alkene-2-ketone;

5-{4-[(S)-2-methyl-3-((R)-2-methyl-tetramethyleneimine-1-yl)-propoxy-]-phenyl-3,4-diaza-dicyclo also [4.1.0] heptan-4-alkene-2-ketone;

5-{4-[3-((R)-2-methyl-tetramethyleneimine-1-yl)-propoxy-]-phenyl-3,4-diaza-dicyclo also [4.1.0] heptan-4-alkene-2-ketone individual isomer;

6-{4-[2-hydroxyl-3-((R)-2-methyl-tetramethyleneimine-1-yl)-propoxy-]-phenyl }-the 2H-pyridazin-3-one;

6-{4-[(S)-2-hydroxyl-3-((R)-2-methyl-tetramethyleneimine-1-yl)-propoxy-]-phenyl }-the 2H-pyridazin-3-one;

6-{4-[(R)-2-hydroxyl-3-((R)-2-methyl-tetramethyleneimine-1-yl)-propoxy-]-phenyl }-the 2H-pyridazin-3-one;

With

6-cyclopropyl-2-{4-[3-((R)-2-methyl-tetramethyleneimine-1-yl)-propoxy-]-phenyl }-the 2H-pyridazin-3-one;

Or the mixture or the pharmacologically acceptable salts of its stereoisomeric forms in any ratio, stereoisomeric forms in any ratio.

Preferred compound in these is selected from:

5-methyl-6-{4-[3-((R)-2-methyl-tetramethyleneimine-1-yl)-propoxy-]-phenyl }-4,5-dihydro-diastereomer of 2H-pyridazin-3-one;

5-methyl-6-{4-[3-((R)-2-methyl-tetramethyleneimine-1-yl)-propoxy-]-phenyl }-4,5-dihydro-2H-pyridazin-3-one; With

6-{4-[3-((R)-2-methyl-tetramethyleneimine-1-yl)-propoxy-]-phenyl }-the 2H-pyridazin-3-one;

Particularly preferred compound is 6-{4-[3-((R)-2-methyl-tetramethyleneimine-1-yl)-propoxy-in above-mentioned]-phenyl }-mixture or the pharmacologically acceptable salts of 2H-pyridazin-3-one or its stereoisomeric forms in any ratio, stereoisomeric forms in any ratio.This compound can be from (the R)-2-crassitude preparation according to above-described method preparation.Reaction scheme 3 has been described preparation 6-{4-[3-((R)-2-methyl-tetramethyleneimine-1-yl)-propoxy-]-phenyl }-illustrative methods of 2H-pyridazin-3-one.

Reaction scheme 3

According to reaction scheme 3, in step 1,1-(4-hydroxy phenyl) ethyl ketone and 3-bromo-n-propyl chloride are at CH ₃COCH ₃In mixture be heated to 65 ℃ and spend the night.Mixture is filtered, use washing with acetone, and be concentrated into dried.Crude product is dissolved in CH ₂Cl ₂In, use saturated NaHCO ₃, the NaCl solution washing, and use Na ₂SO ₄Dry.Vacuum concentration obtains product to doing.

The mixture of the product of step 1 and oxoethanoic acid monohydrate stirred 2 hours at 100 ℃ in 15mL acetate.Evaporating solvent adds entry and is cooled to 0 ℃ in resistates, add dense NH simultaneously ₄The OH aqueous solution is to pH8.In this mixture, add hydrazine hydrate and be heated to 100 ℃ and last 1 hour.The solid that obtains can be through filtering and washing with water.Roughage dissolves in CH ₂Cl ₂Among/the MeOH, and use CH ₂Cl ₂To the CH that contains 10%MeOH ₂Cl ₂In carry out the column chromatography purifying.

The product of step 2, K ₂CO ₃, the NaI of 100mg and the mixture of R-2-crassitude hydrochloride in acetonitrile be heated to 80 ℃ and last 2 days.Then reaction mixture is filtered, use CH ₂Cl ₂Washing, and concentrate.Resistates is dissolved in CH ₂Cl ₂In, use saturated NaHCO ₃, saturated NaCl washing, use Na ₂SO ₄Dry and concentrated.Use 100%CH ₂Cl ₂To containing 5%MeOH: 95%CH ₂Cl ₂2-aminopropane, then with containing 10%MeOH: 90%CH ₂Cl ₂2-aminopropane resistates is carried out ISCO step chromonere purifying, obtain product.The free alkali of product is by being dissolved among the MeOH and adding the EtOH that contains 0.5N HCl, then evaporating solvent and from MeOH:Et ₂The O crystallization can be converted into HCl salt.

Therefore, one embodiment of the invention relate to the method for preparation formula IV compound:

Particularly (R)-or (S)-6-{4-[3-(2-methyl-tetramethyleneimine-1-yl)-propoxy-]-phenyl }-the 2H-pyridazin-3-one,

Wherein each variable as mentioned above, described method comprises:

(1b) optionally remove hydrogenation catalyst from mixture;

(1c) L-tartrate or D-tartrate are dissolved in the mixture to form solution;

(3a) make 1-(4-hydroxyl-phenyl)-ethyl ketone and 1,3-two Halopropanes are to be enough to form 1-[4-(3-halogen-propoxy-)-phenyl]-contact under time of ethyl ketone and the condition;

(3b) make 1-[4-(3-halogen-propoxy-)-phenyl]-ethyl ketone is being enough to generate 6-[4-(3-halogen-propoxy-)-phenyl with oxoethanoic acid]-contact under time of 2H-pyridazin-3-one and the condition; With

(3c) make 6-[4-(3-halogen-propoxy-)-phenyl]-2H-pyridazin-3-one and (R)-or (S)-2-crassitude to be to be enough to form corresponding (R)-or (S)-6-{4-[3-(2-methyl-tetramethyleneimine-1-yl)-propoxy-]-phenyl }-contact under time of 2H-pyridazin-3-one and the condition.

This method also can be chosen wantonly and may further comprise the steps:

(1h) optional repeating step (f) and (g).

More generally, aforesaid method can be suitable for preparing the compound described in the US 2008/0027041A1, by with according to (R) of the preparation of method above or (S) 2-crassitude hydrochloride, K ₂CO ₃And NaI, at CH ₃The compound of formula V is provided among the CN:

And recovery product.

Another embodiment of the invention relates to the method that is used for preparation formula IV compound:

Wherein each variable as mentioned above, described method comprises:

(1b) optionally remove hydrogenation catalyst from mixture;

(1c) L-tartrate or D-tartrate are dissolved in the mixture to form solution;

(3a) or (S) with (R)-2-crassitude-the 2-crassitude is converted into the compound of formula IV.

This method also can be chosen wantonly and may further comprise the steps:

(1h) optional repeating step (f) and (g).

Can comprise according to the exemplary compound of these method preparations (R)-or (S)-6-{4-[3-(2-methyl-tetramethyleneimine-1-yl)-propoxy-]-phenyl }-the 2H-pyridazin-3-one:

Compound is 6-{4-[3-((R)-2-methyl-tetramethyleneimine-1-yl)-propoxy-preferably]-phenyl }-the 2H-pyridazin-3-one.

Can use according to (R) of methods described herein preparations or (S) another group histamine-3-receptors ligand of 2-crassitude preparation in WO 2006/059778, describe.These compounds comprise the compound of general formula VI:

And pharmacologically acceptable salt;

Wherein Y is (R) or (S) 2-crassitude;

R ¹Represent hydrogen atom independently of one another, hydroxyl, halogen atom, low alkyl group, junior alkyl halides, lower alkoxy, halogenated lower alkoxy, lower alkoxy-low alkyl group, or halogenated lower alkoxy-low alkyl group;

P is 0 to 4 integer;

R ²The expression hydroxyl, halogen atom, low alkyl group, junior alkyl halides, lower alkoxy, halogenated lower alkoxy, lower alkoxy-low alkyl group, or halogenated lower alkoxy-low alkyl group, or

R ²Expression

Group, wherein A represents the compound of formula (III-1) or formula (III-2)

R wherein ³Represent hydrogen atom or the optional cycloalkyl that is replaced by low alkyl group, junior alkyl halides, cycloalkyl, halogen atom or hydroxyl; And R ⁴The expression hydrogen atom, hydroxyl, halogen atom, low alkyl group, junior alkyl halides, lower alkoxy, halogenated lower alkoxy, lower alkoxy-low alkyl group, or halogenated lower alkoxy-low alkyl group;

M is 0 or 1; N is 0,1 or 2; With

X ¹-X ⁴The optional carbon atom that is replaced by low alkyl group, lower alkoxy, halogenated lower alkoxy or halogen atom of expression independently of one another.

Can comprise according to concrete disclosed compound in this group of methods described herein preparation:

1-methyl-4-{4-[3-((2S)-2-methyl isophthalic acid-pyrrolidyl) propoxy-] phenyl }-2 (1H)-pyridones; With

1-methyl-4-{4-[3-((2R)-2-methyl isophthalic acid-pyrrolidyl) propoxy-] phenyl }-2 (1H)-pyridones.

These compounds can be prepared as follows: provide wherein that Y is the midbody compound of the formula (VI) of Cl, and make this compound with according to (R) of method preparation above or (S) 2-crassitude, K ₂CO ₃With NaI at CH ₃React among the CN, and reclaim product, described similar with top compound about US 2008/0027041A1.

Therefore, another embodiment of the invention relates to the method for preparation formula VI compound:

Wherein each variable as mentioned above, described method comprises:

(1b) optionally remove hydrogenation catalyst from mixture;

(1c) L-tartrate or D-tartrate are dissolved in the mixture to form solution;

(3a) making Y wherein is that compound and (R)-or (S)-2-crassitude of the formula VI of Cl contacts with under time of being enough to form corresponding amide and the condition.

This method also can be chosen wantonly and may further comprise the steps:

(1h) optional repeating step (f) and (g).

Another application of having described the histamine-3-receptors ligand that comprises 2-crassitude part is WO 2007/105053.This application has been described the preparation of the compound of following formula VII:

Wherein

A is (R) or (S) 2-crassitude;

Z, Y, Q, X are nitrogen or carbon independently;

R ³Be hydrogen, (C ₁-C ₈) alkyl, (C ₁-C ₈) alkoxyl group, halogen, 5-6 unit aryl, 5-6 unit heteroaryl, hydroxyl, methylene radical hydroxyl ,-(C=O) NR ⁴R ⁵And S (O) _p(C ₁-C ₄) alkyl, wherein p is 1 or 2;

R wherein ⁴And R ⁵Be independently selected from:

Hydrogen; Randomly by the (C of 1-4 halogen replacement ₁-C ₈) alkyl; (C ₁-C ₈) alkyl, its optional following substituting group replacement: OH, 1-4 (C of being selected from ₁-C ₄) alkyl, (C ₃-C ₇) cycloalkyl, (C ₁-C ₄) dialkyl amido, optional replaced by halogen and choose quilt (C ₆-C ₁₀) aryloxy ((C ₆-C ₁₀) aryloxy is optional is replaced by 1-2 halogen) (the C of replacement ₆-C ₁₀) aryl and optional by (C ₆-C ₁₀) aryl replacement and optional by 1-3 (C ₁-C ₄) the 5-10 unit heteroaryl that replaces of alkyl; (C ₃-C ₇) cycloalkyl; (C ₆-C ₁₄) aryl; Optional by (C ₁-C ₃) the alkyl replacement-(C ₂-C ₃) alkyl-O-(C ₁-C ₃) alkyl;-(C ₁-C ₃) alkyl-C (=O) O-(C ₁-C ₃) alkyl; Optional by one or more (C ₁-C ₄) the 3-8 unit Heterocyclylalkyl that replaces of alkyl-carbonyl; Optional by one or more (C ₁-C ₂) alkyl replacement (C ₆-C ₁₄) aryl sulfonyl; 5-10 unit heteroaryl; (C ₆-C ₁₄) aryl-(C ₀-C ₄) alkylidene group-O-(C ₀-C ₄) alkyl, wherein each (C ₀-C ₄) alkyl and each (C ₀-C ₄) alkylidene group is optional by 1-4 (C ₁-C ₄) the alkyl replacement; Perhaps randomly, R ⁴And R ⁵Form 4-6 unit heterocycle with the nitrogen that they connected, wherein with described assorted nuclear nitrogen at interval one of the described assorted nuclear carbon of at least two atoms randomly by O or NR ⁶Substitute R wherein ⁶Be hydrogen, (C ₁-C ₃) alkyl or-C (=O) (C ₁-C ₃) alkyl; Optional with wherein said heterocycle by halogen, (C ₁-C ₃) alkyl or hydroxyl replacement;

R ⁷Be hydrogen;

Or randomly, R ³And R ⁷Two adjacent atoms that they were connected in the ring that comprises Z, Y, Q and X form 5 or 6 yuan of heterocycles; Wherein one of the described assorted nuclear carbon of at least two atoms is optional by O or NR at interval with described assorted nuclear nitrogen ⁸Substitute; R wherein ⁸Be hydrogen or (C ₁-C ₃) alkyl.

Reaction scheme 4 has illustrated the method for preparing the compound of the foundation structure with formula VII, wherein A, R ³, Y, Q, Z and X definition the same.Referring to following reaction scheme 4, compound (III) can be prepared as follows: use according to (R) of method for preparing or (S) 2-crassitude and suitable reductive agent such as NaHB (OAc) ₃, at solvent such as CH ₂Cl ₂Or among the DCE, arrive under the temperature of room temperature at-5 ℃, preferably under about room temperature, the bromo-tetralone compound of processing formula (I) is to generate the compound of required formula (III).Other the suitable reductive agent that is used for this reaction comprises NaCNBH ₃Or NaBH ₄, in solvent such as MeOH or EtOH.Other the suitable condition that is used for this conversion comprises, use (R) of the program preparation according to the present invention-or (S)-the 2-crassitude, at CH ₂Cl ₂Or among the DCE,

Under the condition that molecular sieve and alkali such as TEA exists, at room temperature, handle the tetralone of corresponding formula (I), use NaBH then ₄Or NaHB (OAc) ₃Handle.

Compound III then can be at suitable palladium catalyst such as 1, under the condition that the aqueous solution of 1-two (diphenylphosphine) ferrocene Palladous chloride (II) and suitable alkali such as yellow soda ash exists, with solvent such as glycol dimethyl ether in, from room temperature under about 100 ℃ temperature, preferably under about 90 ℃, handle with the boric acid that the quilt of formula (IV) suitably replaces, generate the compound of required formula V.Other felicity condition that is used for this conversion comprises uses tetrakis triphenylphosphine palladium (0) and yellow soda ash at ethanol/water mixture, under 30 ℃-110 ℃ temperature, preferably under about reflux temperature, the boric acid that the quilt of the compound of processing formula (III) and formula (IV) suitably replaces is to generate the compound of corresponding formula V.

Reaction scheme 4

Therefore, one embodiment of the invention relate to the method for preparation formula VII compound:

Wherein each variable as mentioned above, described method comprises:

(1b) optionally remove hydrogenation catalyst from mixture;

(1c) L-tartrate or D-tartrate are dissolved in the mixture to form solution;

(3a) make 6-halogen-3,4-dihydro-1H-naphthalene-2-ketone and (R)-or (S)-2-crassitude contacted with condition with the time that is enough to form corresponding amine; With

(3b) make the boric acid of acid amides and following formula,

Wherein each variable contacts under the time that is enough to provide formula VII compound and condition as mentioned above.

This method also can be chosen wantonly and may further comprise the steps:

(1h) optional repeating step (f) and (g).

Reaction scheme 5 has illustrated the alternative approach for preparing the compound of the foundation structure with formula VII, wherein R ³Be CONR ⁴R ⁵And the definition of Y, Z, Q and X is the same.Referring to reaction scheme 5, the coupling of the suitable acid reagent of bromide (III) and formula (VI) can be carried out described in the reaction scheme 4 as top, generates the compound of required formula (VIII).In methylene dichloride, at room temperature handle the tertiary butyl ester derivative of corresponding formula (VIII) with trifluoroacetic acid, generate the corresponding carboxylic acid (not shown).Use formula NHR ⁴R ⁵Amine, under the condition that suitable coupling agent such as HOBT and EDCI and tertiary amine such as triethylamine exist, handle carboxylic acid, can generate the compound of required formula (IX).

Reaction scheme 5

Perhaps, the compound of formula (IX) also can be by with chlorination 2-chloro-1, and 3-methylimidazole and suitable alkali such as diisopropyl ethyl amine are handled carboxylic acid in such as methylene dichloride and suitable amine prepares at solvent.

Another embodiment is the method for the compound of preparation formula VII:

Wherein the definition of each variable as mentioned above, described method comprises:

(1b) optionally remove hydrogenation catalyst from mixture;

(1c) L-tartrate or D-tartrate are dissolved in the mixture to form solution;

(3a) make the boric acid of 1-(6-halogen-1,2,3,4-tetrahydrochysene-naphthalene-2-yl)-(R)-2-methyl-tetramethyleneimine or 1-(6-halogen-1,2,3,4-tetrahydrochysene-naphthalene-2-yl)-(S)-2-methyl-tetramethyleneimine and following formula,

Wherein each variable contacts under the time that is enough to provide following formula: compound and condition as mentioned above:

With

Make the compound of following formula,

Contact with under time of being enough to form formula VII compound and the condition with amine.

This method also can be chosen wantonly and may further comprise the steps:

(1h) optional repeating step (f) and (g).

Can comprise according to the specific examples of the compound of these methods preparation:

(S, R)-3-[6-(2-methyl-tetramethyleneimine-1-yl)-5,6,7,8-tetrahydrochysene-naphthalene-2-yl]-pyridine;

(R, R)-3-[6-(2-methyl-tetramethyleneimine-1-yl)-5,6,7,8-tetrahydrochysene-naphthalene-2-yl]-pyridine;

(R, R)-3[6-(2-methyl-tetramethyleneimine-1-yl)-5,6,7,8-tetrahydrochysene-naphthalene-2-yl]-benzamide; With

(S, R) 3-[6-(2-methyl-tetramethyleneimine-1-yl)-5,6,7,8-tetrahydrochysene-naphthalene-2-yl]-benzamide.

Compound described in the WO 2006/066197 also can more easily use (R) of the present invention-and (S) 2-crassitude synthesis method prepare.WO 2006/066197 has described following formula VIII and the compound of formula IX:

And pharmacologically acceptable salt; With its enantiomorph, diastereomer, hydrate, solvate and pharmacologically acceptable salts, ester and acid amides

Wherein

L is 1 or 2 for-O-and n; Perhaps L be-C ≡ C-or-CH ₂CH ₂-and n be 0 or 1;

R ¹For-H or be C _1-6Alkyl C _3-7Cycloalkyl ,-COOC _1-6Alkyl, or-the COO benzyl, optional separately by Ra one replacement, two replacements or three replacements;

Wherein Ra is selected from :-OH ,-OC _1-6Alkyl, optional quilt-OC _1-4The phenyl that alkyl or halogen replace ,-CN ,-NO ₂,-N (R ^b) R ^c,-C (O) N (R ^b) R ^c,-N (R ^b) C (O) R ^b,-N (R ^b) SO ₂C _1-6Alkyl ,-C (O) C _1-6Alkyl ,-S (O) _0-2-C _1-6Alkyl ,-SO ₂N (R ^b) ^Rc,-SCF ₃, halogen ,-CF ₃,-OCF ₃,-COOH and-COOC _1-6Alkyl; R wherein ^bAnd R ^cBe independently of one another-H or-C _1-6Alkyl;

R ⁴For-OH ,-OC _1-6Alkyl ,-CF ₃,-C _1-6Alkyl, or halogen; Two R ⁴Substituting group can connect together and form methylene radical or ethylidene;

M is 0,1 or 2;

R ⁵Be selected from :-C _1-6Alkyl ,-OH ,-OC _1-6Alkyl ,-SC _1-6Alkyl and halogen;

Ar ¹For being selected from following aryl or hetero-aromatic ring:

A) phenyl, optional by R ^jOne replace, two replace or three replace and quilt-OC on adjacent carbons randomly _1-4Alkylidene group O-two replaces-OC _1-4Alkylidene group O-optional by fluorine ,-(CH ₂) _2-3NH-,-(CH ₂) _1-2NH (CH ₂)-,-(CH ₂) _2-3N (C _1-4Alkyl)-or-(CH ₂) _1-2N (C _1-4Alkyl) (CH ₂)-one replaces or two replacements;

R wherein ^jBe selected from:

1)-and OH ,-C _1-6Alkyl is randomly replaced or trisubstituted-OC by halogen one replacement, two _1-6Alkyl ,-C _2-6Thiazolinyl ,-OC _3-6Thiazolinyl, optional by trimethyl silyl replacement-C _2-6Alkynyl ,-OC _3-6Alkynyl ,-C _3-6Cycloalkyl ,-OC _3-6Cycloalkyl ,-CN ,-NO ₂,-N (R ^k) R ^l,-N (R ^k) C (O) R ^l,-N (R ^k) SO ₂C _1-6Alkyl ,-C (O) C _1-6Alkyl ,-S (O) _0-2C _1-6Alkyl ,-C (O) N (R ^m) R ⁿ, SO ₂N (R ^m) R ⁿ,-SCF ₃, halogen ,-CF ₃,-COOH ,-COOC _1-6Alkyl and-COOC _3-7Cycloalkyl;

R wherein ^kAnd R ^lBe independently of one another-H or-C _1-6Alkyl;

R wherein ^mAnd R ⁿBe independently of one another-H or-C _1-6Alkyl, or R ^mAnd R ⁿForming 4-8 unit heterocycle with the nitrogen that they connected, described heterocycle has 1 or 2 and is selected from＞O,＞S (O) _0-2,＞NH and＞NC _1-6The heteroatoms of alkyl has 0 or 1 two key, has 0 or 1 carbonyl member;

2)-G-Ar ², wherein G be key ,-O-or-S-, and Ar ²For phenyl or have the monocyclic aromatic alkyl of five or six annular atomses, a carbon atom quilt＞O of described monocyclic aromatic alkyl,＞S,＞NH or＞N (C1.4 alkyl) substitutes, the optional quilt-N=of other carbon atom substitutes at the most, chooses wantonly by R separately ^pOne replacement, two replaces or three replacements; R wherein ^pFor being independently selected from following substituting group :-OH ,-C _1-6Alkyl ,-OC _1-6Alkyl, phenyl ,-CN ,-NO ₂,-N (R ^q) R ^r-,-C (O) N (R ^q) R ^r,-N (R ^q) C (O) R ^r,-N (R ^q) SO ₂C _1-6Alkyl ,-C (O) C _1-6Alkyl ,-S (O) _0-2-C _1-6Alkyl ,-SO ₂N (R ^q) R ^r,-SCF ₃, halogen ,-CF ₃,-OCF ₃,-OCHF ₂,-COOH and-COOC _1-6Alkyl;

R wherein ^qAnd R ^rBe selected from-H-C independently of one another _1-6Alkyl and-C _2-6Thiazolinyl; With

3) 4-8 unit heterocycle saturated or fractional saturation, have 1 or 2 to be selected from＞O,＞S (O) _0-2,＞NH and＞NC _1-6The heteroatoms member of alkyl has 0 or 1 carbonyl member, and described ring is randomly by R ^pOne replacement, two replaces or three replacements;

B) partly condense forming the phenyl or the pyridyl of five yuan of aromatic rings of condensed at two adjacent carbons ring members places and ternary hydrocarbon, a carbon atom quilt＞O of described part,＞S,＞NH or＞N (C _1-4Alkyl) replace, and the optional quilt-N=replacement of maximum other carbon atoms of this part, described condensed ring is optional by R ^tOne replacement, two replaces or three replacements; R wherein ^tFor being independently selected from following substituting group :-OH ,-C _1-6Alkyl ,-OC _1-6Alkyl, phenyl ,-CN ,-NO ₂,-N (R ^u) R ^v,-C (O) N (R ^u) R ^v,-N (R ^u) C (O) R ^v,-N (R ^u) SO ₂C _1-6Alkyl ,-C (O) C _1-6Alkyl ,-S (O) _0-2-C _1-6Alkyl ,-SO ₂N (R ^u) R ^v,-SCF ₃, halogen ,-CF ₃,-OCF ₃,-OCHF ₂,-COOH and-COOC _1-6Alkyl;

R wherein ^uAnd R ^vBe independently of one another-H or-C _1-6Alkyl;

C) partly condense to form the phenyl of the hexa-atomic aromatic ring of condensed at two adjacent carbons ring members places and quaternary hydrocarbon, one or two carbon atom quilt-N=of described part replaces, and this condensed ring is optional by R ^tOne replacement, two replaces or three replacements;

D) naphthyl, optional by R ^tOne replacement, two replaces or three replacements;

E) have the monocyclic aromatic hydrocarbyl group of five annular atomses, have carbon atom as tie point, have a carbon atom quilt＞O,＞S,＞NH or＞N (C _1-4Alkyl) substitutes, have the optional quilt-N=of maximum other carbon atoms and substitute, choose wantonly by R ^jOne replaces or two replaces and choose that benzo-fused or pyrido condenses at two adjacent carbons places wantonly, and wherein benzo-fused or pyrido condensed is partly optional by R ^tOne replacement, two replaces or three replacements; With

F) have the monocyclic aromatic alkyl of six annular atomses, have carbon atom, have one or two carbon atom quilt-N=and replace as tie point, optional by R ^jOne replaces or two gets and choose wantonly that benzo-fused or pyrido condenses at two adjacent carbons places, wherein acene condense or the pyrido condensed partly optional by R ^jOne replaces or two replacements.

These compounds can be according to for example reaction scheme 6 preparations.

Reaction scheme 6

Referring to reaction scheme 6, the reagent of formula A1, A2 and A5 is commercially available or prepares according to currently known methods.3-5 hydroxy benzaldehyde derivative A1 and pure A2 use suitable alkali such as K according to Williamson ether synthetic schemes ₂CO ₃, Na ₂CO ₃Or NaH, solvent such as acetonitrile in, react under the condition of catalytic KI or NaI having or do not have, form ether A3.Perhaps, the ether of formula A3 therein A2 comprise protected hydroxyl and replace being produced under the substituent Mitsunobu condition of bromide.The reduction amination of the aldehyde functionality of compound A-13 provides the compound of formula A4.Aldehyde can use suitable reductive agent such as NaBH adding or not adding under activator such as protonic acid or the lewis acidic condition ₄, NaCNBH ₃Or NaHB (OAc) ₃, handle with the suitable amine that contains R1.Preferred condition comprises NaBH ₄In methyl alcohol.Under the condition of tertiary amine base such as TEA or DIPEA existence, in appropriate solvent such as THF or DCM, finish amine A4 and form ketone A6 with α-Lu Daitong A5 alkylation.Cyclisation involves the cyclisation of tetrahydroisoquinoline salt to generate tetrahydroisoquinoline A7, is by being exposed to or not having the suitable protonic acid of solvent such as DCM or Lewis acid such as methylsulfonic acid (MSA), trifluoroacetic acid (TFA), an AlCl ₃, TiCl ₄Or BF ₃* OEt ₂Realize down.Preferred condition is that pure MSA or MSA are in DCM.Intermediate salt can use the reductive agent of standard such as NaCNBH ₃In the acidic methanol medium, be reduced.Perhaps, ketone A6 can at first adopt currently known methods, comprise NaBH ₄Be reduced into their alcohol accordingly.Intermediate ethanol is handled in DCM with MSA, obtains encircling substance A 7.At last, side chain primary alcohol group in compd A 7 can followingly be converted into corresponding amine A9: is activated and forms suitable leavings group (such as methanesulfonates or bromide), use then (R) prepared in accordance with the present invention-or (S)-2-crassitude displacement leavings group.This displacement can use suitable alkali such as Na ₂CO ₃, polar solvent such as propyl carbinol in, carry out under the condition of catalytic KI or NaI having or do not have.Perhaps, amine A9 can be produced by the oxidation of alcohol and the reduction amination of gained aldehyde.

Therefore, one embodiment of the invention relate to the method for preparation formula VIII and IX compound:

(1b) optionally remove hydrogenation catalyst from mixture;

(1c) L-tartrate or D-tartrate are dissolved in mixture to form solution;

(3a) make the compound of following formula

Wherein each variable contacts with under time of the compound that is enough to form formula VIII or IX and the condition with (R)-or (S)-2-crassitude as mentioned above.

This method also can be chosen wantonly and may further comprise the steps:

(1h) optional repeating step (f) and (g).

The compound that perhaps, can comprise the 2-crassitude according to reaction scheme 7 preparations:

Reaction scheme 7

Referring to reaction scheme 7, the ether of formula A3 can at first use (R) prepared in accordance with the present invention-or (S)-2-crassitude, is converted into corresponding optional protected amine B 1 according to reaction scheme A is described.Phenyl aldehyde B 1 can use the reduction amination scheme of reaction scheme A then, is converted into diamines B2, and wherein Q is (R)-or (S)-2-methylpyrrole alkyl.Shown in reaction scheme 6, finish alkylation to form ketone B3 and cyclisation compound with production A12.

Another embodiment of the invention relates to the method for preparation formula VIII and IX compound, comprising:

(1b) optionally remove hydrogenation catalyst from mixture;

(1c) L-tartrate or D-tartrate are dissolved in mixture to form solution;

(3a) make the compound of following formula,

Wherein each variable contacts with under time of being enough to form corresponding amine and the condition with (R)-or (S)-2-crassitude as mentioned above;

(3b) amine is converted into the compound of formula VIII or IX.

This method also can be chosen wantonly and may further comprise the steps:

(1h) optional repeating step (f) and (g).

Can use the exemplary compound of the inventive method preparation to be: 4-(4-methoxyl group-phenyl)-2-methyl-7-[3-(2-methyl-tetramethyleneimine-1-yl)-propoxy-]-1,2,3,4-tetrahydrochysene-isoquinoline 99.9.

Method of the present invention also can be used for preparing as the following formula X of description among the WO 06/078775 and the compound of XI:

And pharmacologically acceptable salts, wherein:

N is 2,3,4 or 5;

R is R ³-aryl, R ³-heteroaryl, R ³-cycloalkyl, R ³-Heterocyclylalkyl, alkyl, haloalkyl ,-OR ⁴,-SR ⁴Or-S (O) _1-2R ⁵

R ¹Be H and R ²Be R ⁶-phenyl or

: perhaps R ¹Be R ⁶-phenyl or

And R ²Be H; Perhaps R ¹And R ²Be independently selected from R ⁶-phenyl; With X be-O-or-S-;

Perhaps R ¹And R ²Form with the carbon atom that they connected

With X be-O-,-S-or-NR ⁷

R ³For 1-3 is independently selected from following substituting group: H, alkyl, halogen, OH, alkoxyl group and-NR ¹¹R ¹²,

R ⁴Be alkyl, arylalkyl or cycloalkyl;

R ⁵Be alkyl ,-NR ¹¹R ¹², R ³-aryl or R ³-arylalkyl;

R ⁶Be independently selected from following substituting group: H, alkyl ,-CF for 1-3 is individual ₃, halogen ,-NO ₂,-CN ,-C (O) OR ¹³,-C (O) NR ¹¹R ¹²,-NR ¹⁴R ¹⁵,-OR ¹³And haloalkyl;

R ⁷Be H, alkyl ,-c (O) OR ¹³,-C (O) NR ¹¹R ¹²Or-C (O) R ¹³

R ¹¹And R ¹²Be independently selected from: H, alkyl, cycloalkyl, aryl and arylalkyl;

R ¹³Be H, alkyl, cycloalkyl or arylalkyl;

R ¹⁴Be H, alkyl, cycloalkyl or arylalkyl; With

R ¹⁵Be H, alkyl, cycloalkyl ,-C (O) OR ¹³,-C (O) NR ¹¹R ¹²Or-CO) R ¹³

The compound of formula X and XI can be according to following reaction scheme 8 preparations.

Reaction scheme 8

Referring to reaction scheme 8, compound 1 and anils 2 react under the temperature of realization response, preferred 50-150 ℃ being enough in appropriate solvent such as THF Huo diox, preferred Zai diox, provide compound 3.The nitro of compound 3 uses hydrogen at suitable catalyzer such as Pd/C, PtO ₂, under nickel (Raney nickel) exists in the protein, preferably nickel exists in protein the condition, in appropriate solvent such as methyl alcohol, ethanol or Virahol, preferably in methyl alcohol or ethanol, be reduced into amine 4.Well known to a person skilled in the art that other method of reducing also is suitable for.

The primary amine of compound 4 is under the condition of coupling agent such as DEC and HOBT existence, at appropriate solvent such as ether, THF or CH ₂Cl ₂In, preferably at CH ₂Cl ₂In, by carrying out acidylate, provide compound 5 with carboxylic acid reaction.Perhaps, amine can by chloride of acid under the condition that alkali exists by acidylate.Compound 5 is heated the time that is enough to take place cyclisation in acetate.In step 5, if protecting group is present on the radicals X, then it is removed at this moment.The suitable protecting group of X=O, N or S and the method for removing thereof can be referring to Green ' s Protecting Groups in OrganicSynthesis.Compound 6 in appropriate solvent such as acetone, THF, ether etc., preferably in acetone, at alkali such as Na ₂CO ₃Or K ₂CO ₃Exist, preferably at K ₂CO ₃Under the condition that exists, under 0-65 ℃ temperature, with α, ω-saturated dihalide reacts, and provides compound 7, and wherein Y is a halogen.

Compound 7 in appropriate solvent such as CH ₃In CN, THF, the ether etc., preferably at CH ₃Solution among the CN uses tertiary amine base such as Et ₃Processing such as N, DIPEA is preferably handled with DIPEA, use then (R) prepared in accordance with the present invention-or (S)-processing of 2-crassitude.Reaction is then 0-100 ℃ of heating, to provide compound 8.

Perhaps, can follow following reaction scheme 9.

Reaction scheme 9

Referring to reaction scheme 9, in the literature compound known 9 in appropriate solvent such as acetone, THF, ether etc., preferably in acetone, at alkali such as Na ₂CO ₃Or K ₂CO ₃Exist, preferably at K ₂CO ₃Under the condition that exists, under 0 to 65 ℃ temperature, with α, ω-saturated dihalide reacts, and provides compound 10.Compound 10 in appropriate solvent such as CH ₃In CN, THF, the ether etc., preferably at CH ₃Solution among the CN uses tertiary amine base such as Et ₃Processing such as N, DIPEA is preferably handled with DIPEA, use then (R) prepared in accordance with the present invention-or (S)-processing of 2-crassitude.Reaction is heated under 0-100 ℃ temperature then, to provide compound 11.

As an alternative, compound can be produced according to following reaction scheme 10.

Reaction scheme 10

Referring to reaction scheme 10, compound 12 in appropriate solvent such as acetone, THF etc., preferably in acetone, at alkali such as Na ₂CO ₃Or K ₂CO ₃Exist, preferably at K ₂CO ₃Under the condition that exists, under 0-65 ℃ temperature, with α, ω-saturated dihalide reacts, and provides compound 13, and wherein Y is a halogen.Compound 13 in appropriate solvent such as CH ₃In CN, THF, the ether etc., preferably at CH ₃Solution among the CN uses tertiary amine base such as Et ₃Processing such as N, DIPEA is preferably handled with DIPEA, use then (R) prepared in accordance with the present invention-or (S)-processing of 2-crassitude.Reaction is heated under 0-100 ℃ temperature then, to provide compound 14.The nitro of compound 14 is at suitable catalyzer such as Pd/C, PtO ₂, under nickel exists in the protein, preferably nickel exists in protein the condition, in appropriate solvent such as methyl alcohol, ethanol or Virahol, preferably in methyl alcohol or ethanol, use hydrogen reducing to become amine 15.Well known to a person skilled in the art that other method of reducing also is suitable for.

Still referring to reaction scheme 10, appropriate solvent such as THF Huo diox in, in the preferred Zai diox, be enough to the temperature of realization response, preferably under 50-150 ℃, compound 15 and 16 reacts, and provides compound 17.The nitro of compound 17 is reduced into amine, and provides compound 18 subsequently.Amine 18 is handled 0 to 100 ℃ temperature, preferred 25 to 75 ℃ with thio-carbonyldiimidazole (Q=S) or 1,1 '-carbonyl dimidazoles (Q=O) in appropriate solvent such as THF, ether etc., provides compound 19.

19 solution in appropriate solvent such as DMSO, DMF etc., 0 to 100 ℃, preferably under 25 to 75 ℃ temperature, with alkali such as K ₂CO ₃Deng and alkylating agent R ⁴L or methanesulfonates or sulphonate are handled, and wherein L is Cl, Br or I, provides 20.

Therefore, one embodiment of the invention relate to the method for preparation formula X and XI compound:

Wherein each variable as mentioned above;

Comprise:

(1a) hydrogenation 2-methylpyrroline in comprising alcoholic solvent and mixture of catalysts;

(1b) optionally remove hydrogenation catalyst from mixture;

(1c) L-tartrate or D-tartrate are dissolved in the mixture to form solution;

(3a) (R)-or (S)-2-crassitude is converted into the compound of formula VIII or IX.

This method also can randomly may further comprise the steps:

(1h) repeating step (f) and (g) randomly.

The same compound that is fit to the inventive method is at following formula XII described in the WO 2007/099423 and the compound of XIII:

Or its pharmacologically acceptable salts, wherein

R ³Be (C _1-6)-alkyl, aryl or heteroaryl, optional by maximum 3 fluorine atoms replacements;

R ⁴Be hydrogen, halogen, (C _1-6)-alkyl or (C _3-7)-cycloalkyl, (C _1-6)-alkoxyl group or (C _3-7)-cycloalkyloxy (optional) by maximum 3 fluorine atoms replacements, aryl, heteroaryl;

R ⁵Be (CR ⁶R ⁹) _m-(CR ¹⁰R ¹¹) _p-B, wherein R ⁶, R ⁹, R ¹⁰And R ¹¹With the carbon atom that they connected, form the loop systems of 3-10 unit's monocycle or dicyclo;

B comprises maximum 3 heteroatomic 4-7 first Heterocyclylalkyl (for example, azetidine, tetramethyleneimine, piperidines, azepines that are selected from N, O, S

Morpholine, thiomorpholine, piperazine or 1-4 diaza

) or NR ¹²R ¹³

R ⁸, R ⁹, R ¹⁰, R ¹¹, R ¹²And R ¹³Be independently selected from: hydrogen, C _1-6Alkyl, (C _1-6Alkyl)-and aryl, (C _1-6Alkyl)-heteroaryl; Perhaps

R ¹²And R ¹³Form loop systems (for example, the azepine of 3-10 unit monocycle or dicyclo with the nitrogen that they connected

, piperidines, tetramethyleneimine or morpholine), condition is NR ¹²R ¹³Not NH ₂

M is 0,1,2,3 or 4;

N is 0,1,2 or 3; With

P is 0 to 3.

These compounds can be by the preparation of the general procedure shown in the following reaction scheme 11.

Reaction scheme 11

Referring to reaction scheme 11, the ketone of general formula I I, wherein (OH) not protected, (R) that has prepared with the present invention-or (S)-2-crassitude reaction is to generate the amino-phenol of general formula III for hydroxyl.This conversion can use obtainable one or more methods of those skilled in the art and program to finish.For example, the ketone of formula II and 2-crassitude can merge in inert aprotic solvent such as chloroform or methylene dichloride, at Lewis acid reagent such as titanium tetrachloride (TiCl ₄) or the titanium isopropylate existence is down, generates the intermediate imines by dehydration.Perhaps, II and the solution of 2-crassitude in solvent such as toluene, reflux under the condition that the tosic acid of catalytic amount exists, condition is to use Dean-Stark trap (Dean-Stark trap) or activated molecular sieve to remove and anhydrates, and also can be used for generating effectively the intermediate imines.But this imines original place then transforms, and perhaps transforms in other step in its separated back, becomes amino-phenol intermediate III.This can be by using for example borane reagent such as sodium borohydride (NaBH ₄), sodium cyanoborohydride (NaBH ₃CN), sodium triacetoxy borohydride etc., in the solvent such as methylene dichloride, methyl alcohol, THF or diox of reactionlessness, the two keys of C=N were also finished originally.Perhaps, this imines can use the catalytic hydrogenation condition to be reduced, and for example, uses hydrogen (H ₂) and proper metal catalyzer such as protein in nickel (RaNi), charcoal carry palladium (Pd/C) or similar catalyzer, in reaction-inert solvent such as methyl alcohol or ethanol, with about 20 ℃ under temperature up to the boiling point of solvent for use, in the individual atmospheric scope of about 1-5 of hydrogen, carry out.Other related example that is used for this conversion can be referring to document.

Still referring to reaction scheme 11, the phenol OH base that exists in the intermediate of formula III can be under the condition that alkali exists and as in the reaction-inert solvent shown in the approach b, by using general formula R ⁵The reagent of-A is converted into the III alkylation ether products of general formula I, wherein R ⁵The same and A of definition be leavings group, comprise halogen (for example, Cl, Br, I), methanesulfonates (promptly-OSO ₂CH ₃Or-OMs) or tosylate (that is ,-OSO ₂C ₆H ₅Or-OTs).Suitable alkali comprises the carbonate of sodium, potassium or caesium, the supercarbonate of sodium or potassium, the tert butoxide of sodium or potassium, the oxyhydroxide of sodium or potassium etc., preferred cesium carbonate.Appropriate solvent comprises DMF, DMSO, DMA, THF etc., preferred DMSO.

Therefore, one embodiment of the invention relate to the method for preparation formula XII and XIII compound:

The definition of each variable as mentioned above, described method comprises:

(1b) optionally remove hydrogenation catalyst from mixture;

(1c) L-tartrate or D-tartrate are dissolved in mixture to form solution;

(3a) make the compound of following formula,

Contact with under time of being enough to form corresponding amine phenol and the condition with (R)-or (S)-2-crassitude; With

(3b) amine phenol and alcohol are contacted under time of the compound that is enough to provide formula XII or XIII and condition.

This method also can be chosen wantonly and may further comprise the steps:

(1h) optional repeating step (f) and (g).

The compound of general formula X II of the present invention and XIII also can be produced by the route shown in the following reaction scheme 12.

Reaction scheme 12

Referring to reaction scheme 12, the phenolic ketone of general formula I I can be converted into ether (approach c) by the general known method of those skilled in the art.For example, phenol II can be under the condition that alkali exists, described in the approach b of reaction scheme 1, with general formula R ⁵The reagent of-A reacts, to generate the ketone of general formula I V.Perhaps, the ketone of general formula VII, wherein L ₁Be suitable leavings group (that is, F ,-OMs etc.), can with general formula R ⁵The reagent of-OH reacts in the presence of suitable alkali and in inert solvent, to generate the intermediate (approach e) of general formula I V.The ketone IV that obtains like this can use the reduction amination condition described in reaction scheme 11 before to be converted into the product (approach d) of required general formula I then.In some cases, also may advantageously use reductive agent at first such as NaBH ₄, in solvent such as methyl alcohol, the phenylcarbinol (approach f) with intermediate ketone IV is converted into corresponding general formula V activates phenylcarbinol V (approach g) intermediate with production VI, wherein L then ²Be leavings group (for example, OMs, OTs, Cl), and last with (R)-or (S)-2-crassitude displacement leavings group (approach h), described (R)-or (S)-2-crassitude according to above-mentioned steps (a) to (e) (have or do not have optional step (f)) to (h) and make (R)-2-crassitude L-tartrate and alkali reaction (R)-2-crassitude to be provided or to make (S)-2-crassitude D-tartrate and alkali reaction prepares with generation (S)-2-crassitude.

Therefore, another embodiment of the invention relates to the method for preparation formula XII and XIII compound:

The definition of each variable as mentioned above, described method comprises:

(1b) optionally remove hydrogenation catalyst from mixture;

(1c) L-tartrate or D-tartrate are dissolved in mixture to form solution;

(3a) make the compound of following formula,

With formula R ⁵The compound of-LG, wherein LG is a leavings group, contact with under time of being enough to form following formula: compound and the condition,

With

(3b) make the compound of following formula,

Contact with under time of being enough to form formula XII or XIII compound and the condition with (R)-or (S)-2-crassitude.

This method also can be chosen wantonly and may further comprise the steps:

(1h) optional repeating step (f) and (g).

Can use the exemplary compounds of the inventive method preparation to be: 1-{3-[1-(2-methyl-tetramethyleneimine-1-yl)-indane-5-base oxygen base]-propyl group } azepan.

Method of the present invention also is suitable for preparing such as for example formula XIV that describes in WO 2007/094962 and the compound of XV.

Wherein

X is O or NR ₇

Y is 0,1 or 2;

R ₃Be selected from following group for 0-2 is individual: halogen, (C _1-8) alkyl, (C _1-8) alkoxyl group, (C _3-7) cycloalkyl, (C _3-7) cycloalkyl-(C _1-6) alkyl, comprise 1-3 heteroatomic Heterocyclylalkyl and (C that is selected from O, S _1-5) alkyl-O-(C _1-5) alkyl;

R ₄And R ₆Be independently selected from: (C _1-8) alkyl, (C _1-8) alkoxyl group, (C _3-7) cycloalkyl, (C _3-7) cycloalkyl-(C _1-6) alkyl, comprise 1-3 heteroatomic Heterocyclylalkyl that is selected from O, S, N, (C _1-5) alkyl-O-(C _1-5) alkyl, acid amides, (C _1-5) alkyl-aryl, and CF ₃

R ₅Be selected from: hydrogen, (C _1-8) alkyl, aryl, (C _1-5) alkyl-O-(C _1-5) alkyl and (C _1-5) alkyl-aryl, perhaps

R ₅And R ₄The atom that is connected with them forms the loop systems of condensed 5-6 unit's saturated carbon ring or 10 yuan of dicyclos of condensed, such as

Perhaps

R ₅And R ₆The atom that is connected with them forms the loop systems of condensed 5-6 unit's saturated carbon ring or 10 yuan of dicyclos of condensed, such as

Perhaps

R ₅And R ₄The atom that is connected with them forms condensed 5-6 unit saturated carbon ring, and this is carbocyclic fused 6 yuan of aromatic rings, such as

Perhaps

R ₅And R ₆The atom that is connected with them forms the saturated carbocyclic ring of condensed 5-6 unit, and this is carbocyclic fused 6 yuan of aromatic rings, such as

Perhaps

R ₅And R ₆The atom that is connected with them forms condensed thionaphthene or condensed cumarone loop systems, such as

Wherein X is NR ₇, R ₇And R ₂Lump together and be-(CH ₂CH ₂)-comprise the ring of two nitrogen with formation, wherein y is that 0 (piperazine) or y are 1 (high piperazine) and R wherein ₁As defined above, and pharmacologically acceptable salts.

Above-described compound with 2-methylpyrrole groups can be according to following reaction scheme preparation.(R) prepared in accordance with the present invention-or (S)-the 2-crassitude can be with 1 under condition known in the art, the reaction of 3-propylene dichloride, and to generate (R)-or (S)-1-(3-chloro-propyl group)-2-methyl-tetramethyleneimine, it can be used in the following reaction scheme.

Reaction scheme 13

Reaction scheme 14

Reaction scheme 15

Reaction scheme 16

Reaction scheme 17

Reaction scheme 18

Reaction scheme 19

Therefore, one embodiment of the invention relate to the method for preparation formula XIV and XV compound:

Wherein each variable as mentioned above, described method comprises:

(1b) optionally remove hydrogenation catalyst from mixture;

(1c) L-tartrate or D-tartrate are dissolved in mixture to form solution;

(3a) (R)-or (S)-2-crassitude is converted into 1-(3-halogen-propyl group)-(R)-2-methyl-tetramethyleneimine or 1-(3-halogen-propyl group)-(S)-2-methyl-tetramethyleneimine; With

(3b) 1-(3-halogen-propyl group)-(R)-2-methyl-tetramethyleneimine or 1-(3-halogen-propyl group)-(S)-2-methyl-tetramethyleneimine are converted into the compound of formula XII or XIII.

This method also can be chosen wantonly and may further comprise the steps:

(1h) optional repeating step (f) and (g).

Exemplary compound that can be prepared according to the methods of the invention comprises:

The 3-methyl isophthalic acid-and 4-[3-(2R-methylpyrrolidin-1-yl) propoxy-] phenyl }-4,5-dihydro-1H-benzo [g] indazole;

5-methyl-2-{4-[3-(2R-methylpyrrolidin-1-yl) propoxy-] phenyl }-2H-pyrazoles-3-carboxylic acid cyclohexyl amide;

1-{4-[3-(2-(R)-methyl-tetramethyleneimine-1-yl)-propoxy-]-phenyl }-5-phenyl-3-Trifluoromethyl-1 H-pyrazoles;

The 3-methyl isophthalic acid-4-[3-(2-methyl-tetramethyleneimine-1-yl)-propoxy-]-phenyl)-1H-benzo [4,5] thieno-[3,2-c] pyrazoles; With

3-{4-[3-(2-methyl-tetramethyleneimine-1-yl)-propoxy-]-phenyl }-1-trifluoromethyl-3H-8-oxa--2,3-diaza-ring penta [a] indenes.

Other compound that can benefit from preparation 2-crassitude method as herein described is included in the formula XVI of description among the WO 2007/048595 and the compound of formula XVII:

And pharmacologically acceptable salts;

A wherein ¹Be CH, the C-halogen, or;

A ²Be nitrogen or sulphur;

R ^2aBe hydrogen, aryl, C _1-6Alkoxyl group, amino, C _1-6Alkyl, C _2-6Thiazolinyl, heteroaryl, C _3-8Cycloalkyl, 3-8 unit Heterocyclylalkyl, acyl group, C _1-6-alkylaryl, C _1-6-alkyl, heteroaryl, C _1-6-alkyl-cycloalkyl, C _1-6-alkyl heterocycle alkyl, carboxyl, alkoxy carbonyl, aminocarboxyl, C _1-6-alkyl carboxyl, C _1-6-alkyl acyl, C _1-6-alkyl alkoxy, C _1-6-alkyl alkoxy carbonyl, C _1-6-alkyl amino-carbonyl, C _1-6-alkyl acyl amino, acyl amino, C _1-6-alkyl urea groups, C _1-6-alkyl carbamate, C _1-6-alkylamino, C _3-8-cycloalkyl amino, hydroxyl, C _1-6Alkyl hydroxy, halogen or cyano group;

R ^2bBe hydrogen, halogen, C _1-8-alkyl or C _3-8Cycloalkyl;

Perhaps R ^2aAnd R ^2bConnect together and form C _3-8Cycloalkyl, 3-8 unit's Heterocyclylalkyl or oxo group;

R ³Be hydrogen, halogen, C _1-4Alkyl or C _1-4Alkoxyl group;

R ⁴Be hydrogen, halogen, C _1-4Alkyl or C _1-4Alkoxyl group;

L ¹For-(O) _v-(CR ^9aR ^9b) _m-(CH ₂) _z

R ^9aBe hydrogen or unsubstituted C _1-8Alkyl;

R ^9bBe C _1-6-alkylaryl or unsubstituted C _1-8Alkyl;

N is for equaling 0,1 or 2 integer;

T is for equaling 2,3 or 4 integer;

W is for equaling 2,3 or 4 integer;

V equals 0 or 1 integer;

M equals 0 or 1 integer; With

Z is for equaling 0,1,2 or 3 integer;

Similar compounds, such as the compound of in WO 2006/103045, describing, but also the method according to this invention preparation, incorporating this paper into is used for all purposes in full in described application.

Above-described compound can prepare according to reaction scheme 20:

Reaction scheme 20

R wherein ³Be H, F or Cl, and Y ¹Be I or Br.

These reactions can use catalyzer such as two cupric iodides or acid chloride, with part such as 1,2-diamines (anti-form-1 for example, the 2-diamino-cyclohexane), phosphine (for example 1,1 '-two (diphenylphosphine) ferrocene or 2-(dicyclohexylphosphontetrafluoroborate)-2 '-(N, the N-dimethylamino)-and xenyl) or amino acid is (for example, glycine) associating, at solvent (such as diox, tetrahydrofuran (THF), dimethyl formamide or toluene) in, under the condition that alkali (such as potassiumphosphate or sodium tert-butoxide) exists, carry out 25-120 ℃ temperature with under inert atmosphere (argon gas or nitrogen).Perhaps, this reaction can be according to people such as Klapars A. at J.Am.Chem.Soc.2002, and the method described in 124,7421 is carried out.

Can use (R) prepared according to the methods of the invention or (S)-2-crassitude at the compound of formula Ia described in the reaction scheme 20 and Ib, according to reaction scheme 21 preparations.

Reaction scheme 21

These reactions can be under the condition that alkali such as triethylamine or salt of wormwood exist, and carries out in as solvent at acetonitrile or acetone, perhaps carries out according to any ordinary method well known by persons skilled in the art.

Therefore, one embodiment of the invention relate to the method for preparation formula XVI and XVII compound;

Wherein each variable as mentioned above, described method comprises:

(1b) optionally remove hydrogenation catalyst from mixture;

(1c) L-tartrate or D-tartrate are dissolved in the mixture to form solution;

(3a) make the compound of following formula,

Wherein Y1 is

Contact with under time of being enough to form formula XVI compound and the condition with (R)-or (S)-2-crassitude.

This method also can be chosen wantonly and may further comprise the steps:

(1h) optional repeating step (f) and (g).

Perhaps, can implement following reaction scheme 22, wherein from according to above-mentioned (a) to (e) (have or do not have optional step (f)) to (h) and make (R)-2-crassitude L-tartrate contact with alkali with (R)-2-crassitude is provided or make (S)-2-crassitude D-tartrate and alkali reaction with by (S)-2-crassitude, preparation 2-crassitude alkoxyl group, its then with reagent such as halogen-oxyalkylation reaction.

Reaction scheme 22

Reaction described in the reaction scheme 22 can be under the condition that alkali such as potassium tert.-butoxide, cesium carbonate or sodium hydride exist, in solvent such as dimethyl formamide or tetrahydrofuran (THF), in the presence of catalyzer based on palladium or copper, according to people such as Penning at J.Med.Chem.2000,43,721 described methods are carried out.

Therefore, another embodiment of the invention comprises the method for preparation formula XVI and XVII compound:

Wherein each variable as mentioned above, described method comprises:

(1b) optionally remove hydrogenation catalyst from mixture;

(1c) L-tartrate or D-tartrate are dissolved in the mixture to form solution;

(3a) (R)-or (S)-2-crassitude is converted into corresponding 2-methylpyrrole alkyl alkyl-OH;

(3a) make the compound of following formula,

Wherein Y1 is

Contact with under time of being enough to form formula XVI compound and the condition with (R)-or (S)-2-methylpyrrole alkyl alkyl-OH.

This method also can randomly may further comprise the steps:

(1h) optional repeating step (f) and step (g).

Can exemplary compounds prepared according to the methods of the invention comprise:

1-[3-(4-{4-[(2-methylpyrrolidin-1-yl) methyl]-1,3-oxazole-2-yl } phenoxy group) the propyl group piperidines;

2-[(2-{4-[3-(2-methylpyrrolidin-base) propoxy-] phenyl }-1,3-oxazole-4-yl) methyl]-2-azaspiro [5.5] undecane;

4-[(2-methylpyrrolidin-1-yl) methyl]-2-{4-[3-(2-methylpyrrolidin-1-yl) propoxy-] phenyl }-1, the 3-oxazole;

1-sec.-propyl-4-[3-(4-{4-[(2-methyl piperidine-1-yl) methyl]-1,3-oxazole-2-yl } phenoxy group) propyl group] piperazine;

4-methyl isophthalic acid-[3-(4-{4-[(2-methylpyrrolidin-1-yl) methyl]-1,3-oxazole-2-yl } phenoxy group) propyl group] piperidines;

2-methyl isophthalic acid-[3-(4-{4[(2-methylpyrrolidin-1-yl) methyl]-1,3-oxazole-2-yl } phenoxy group) propyl group] piperidines;

4-[(2-methylpyrrolidin-1-yl) methyl]-2-(4-{3-[2-(tetramethyleneimine-1-yl) ethyl) tetramethyleneimine-1-yl] propoxy-} phenyl)-1, the 3-oxazole;

1-cyclopentyl-4-[3-(4-{4-[(2-methylpyrrolidin-1-yl) methyl]-1,3 oxazole-2-yl } phenoxy group) propyl group] piperazine;

N, N-dimethyl-1-[4-(4-{4-[(2-methylpyrrolidin-1-yl) methyl]-1,3-oxazole-2-yl } phenoxy group) butyl] tetramethyleneimine-3-amine;

1-[2-(4-{4-[(2-methylpyrrolidin-1-yl) methyl]-1,3-oxazole-2-yl } phenoxy group) ethyl]-4-(2-tetramethyleneimine-1-base ethyl) piperazine;

2-{4-[3-(2-methylpyrrolidin-1-yl) propoxy-]-[3-4-(2-oxo-2-tetramethyleneimine-1-base ethyl)-1,3-oxazole;

1-[(2-{4-[3-(2-methylpyrrolidin-1-yl) propoxy-] phenyl]-1,3-oxazole-4-yl) methyl] pyrrolidin-2-one;

N-[(2-{4-[3-(2-methylpyrrolidin-1-yl) propoxy-] phenyl }-1,3-oxazole-4-yl) methyl]-the N-phenyl amine;

2-{4-[3-(2-methylpyrrolidin-1-yl) propoxy-]-[3-4-(2-tetramethyleneimine-1-base ethyl)-1,3-oxazole;

4-[(2-methyl isophthalic acid H-imidazoles-1-yl) methyl]-2-{4-[3-(2-methylpyrrolidin-base) propoxy-] phenyl }-1, the 3-oxazole;

1-[(2-{4-[3-(2-methylpyrrolidin-1-yl) propoxy-] phenyl }-1,3-oxazole-4-yl) methyl]-1H-1,2, the 4-triazole;

1-[(2-{4-[3-(2-methylpyrrolidin-1-yl) propoxy-] phenyl-1,3-oxazole-4-yl) methyl] piperidines;

1-[3-(4-[4-[(2-methylpyrrolidin-1-yl) methyl]-1,3-oxazole-2-yl) phenoxy group) propyl group) azepan;

1-(3-{4-[4-methyl-5-(piperidines-1-yl) methyl)-1,3-oxazole-2-yl] phenoxy group } propyl group) piperidines;

(2R)-and 4-methyl-2-{[(2-{4-[3-(2-methylpyrrolidin-1-yl) propoxy-] phenyl }-1,3-oxazole-4-yl) methyl] amino } penta-1-alcohol;

N-[(2-{4-[3-(2-methylpyrrolidin-1-yl) propoxy-] phenyl }-1,3-oxazole-4-yl) methyl] cyclopentamine;

1-[4-(4-{4-[(2-methylpyrrolidin-1-yl) methyl]-1,3-oxazole-2-yl } phenoxy group) butyl] azepan;

1-[2-(4-{4-[(2-methylpyrrolidin-1-yl) methyl }-1,3-oxazole-2-yl } phenoxy group) ethyl] azepan;

N-(1, the 3-dimethylbutyl)-N-[(2-{4-[3-(2-methylpyrroline-1-yl) propoxy-] phenyl }-1,3-oxazole-4-yl) methyl] amine;

N-(cyclopropyl methyl)-N-[(2-{4-[3-(2-methylpyrrolidin-1-yl) propoxy-] phenyl }-1,3-oxazole-4-yl) methyl]-N-propyl group amine;

1-[(2-{4-[2-(2-methylpyrrolidin-1-yl) oxyethyl group] phenyl }-1,3-oxazole-4-yl) methyl] piperidines;

2-methyl isophthalic acid-[4-(4-{4-[(2-methylpyrrolidin-1-yl) methyl]-1,3-oxazole-2-yl } phenoxy group) butyl] piperidines;

7,8-dimethyl-1-[(2-{4-[3-(2-methylpyrrolidin-1-yl) propoxy-] phenyl }-1,3-thiazoles-4-yl) methyl]-1-azaspiro [4.4] nonane;

N-(2-furyl methyl)-N-methyl-N-[(2-{4-[3-(2-methylpyrroline-1-yl) propoxy-] phenyl }-1,3-thiazoles-4-yl) methyl] amine;

N-(sec-butyl)-N-[(2-{4-[3-(2-methylpyrrolidin-1-yl) propoxy-] phenyl }-1,3-thiazoles-4-yl) methyl]-N-propyl group amine;

1-[(2-[4-(3-(2-methylpyrrolidin-1-yl) propoxy-] phenyl }-1,3-thiazoles-4-yl) methyl] piperidines;

1-[(2-{4-[3-(2-methylpyrrolidin-1-yl) propoxy-] phenyl }-1,3-oxazole-4-base ethanoyl] piperidines;

1-[2-(2-{4-[3-(2-methylpyrrolidin-1-yl) propoxy-] phenyl }-1,3-oxazole-4-yl) ethyl] piperidines;

2-{4-[3-(2-methylpyrrolidin-1-yl) propoxy-] phenyl }-1,3-thiazoles;

4-benzyl-1-[(2-{4-[3-(2-methylpyrrolidin-1-yl) propoxy-] phenyl }-1,3-oxazole-4-yl) methyl] piperidines;

1-cyclopentyl-4-[(2-{4-[3-(2-methylpyrrolidin-1-yl) propoxy-] phenyl }-1,3-oxazole-4-yl) methylpiperazine;

4-[(2-{4-[3-(2-methylpyrrolidin-1-yl) propoxy-] phenyl }-1,3-oxazole-4-yl) carbonyl] morpholine;

1-[(2-{4-[3-(2-methylpyrrolidin-1-yl) propoxy-] phenyl }-1,3-oxazole-4-yl) carbonyl] piperidines;

1-cyclopentyl-4-[(2-{4-[3-(2-methylpyrrolidin-1-yl) propoxy-] phenyl }-1,3-oxazole-4-yl) carbonyl] piperazine;

4-[(2-methylpyrrolidin-1-yl) methyl]-2-(4-{3-[(2S)-2-(tetramethyleneimine-1-ylmethyl) tetramethyleneimine-1-yl] propoxy-} phenyl)-1, the 3-oxazole;

1-[(2-{3-fluoro-4-[3-(2-methylpyrrolidin-1-yl) propoxy-] phenyl }-1,3-oxazole-4-yl) methyl] piperidines;

1-[(4-methyl-2-{4-[3-(2-methylpyrrolidin-1-yl) propoxy-] phenyl 1-1,3 oxazoles-5-yl) carbonyl] piperidines;

N-(cyclopropyl methyl)-4-methyl-2-{4-[3-(2-methylpyrrolidin-1-yl) propoxy-]-[3-N-propyl group-1,3-oxazole-5-methane amide;

N-cyclopentyl-4-methyl-2-{4-[3-(2-methylpyrrolidin-1-yl) propoxy-] phenyl }-1,3-oxazole-5-methane amide;

The 4-[(benzylamino) methyl]-2-{4-[3-(2-methylpyrrolidin-1-yl) propoxy-] phenyl }-1,3-oxazole-5-manthanoate;

4-methyl-2-{4-[3-(2-methylpyrrolidin-1-yl) propoxy-] phenyl }-1,3-thiazoles-5-manthanoate;

2-{4-[3-(2-methylpyrrolidin-1-yl) propoxy-]-[3-4-(piperidines-1-ylmethyl)-1,3-oxazole-5-carboxylic acid;

N-(cyclopropyl methyl)-2-{4-[3-(2-methylpyrrolidin-1-yl) propoxy-]-phenyl }-N-propyl group-1,3-oxazole-4-methane amide;

N-cyclopentyl-2-{4-[3-(2-methylpyrrolidin-1-yl) propoxy-] phenyl }-1,3-oxazole-4-methane amide;

N-(4-luorobenzyl)-2-{4-[3-(2-methylpyrrolidin-1-yl) propoxy-] phenyl }-1,3-oxazole-4-methane amide;

N-benzyl-4-methyl-2-{4-[3-(2-methylpyrrolidin-1-yl) propoxy-] phenyl }-1,3-oxazole-5-methane amide;

1-cyclopentyl-4-[4-methyl-2-{4-[3-(2-methylpyrrolidin-1-yl) propoxy-] phenyl)-1,3-oxazole-5-yl) carbonyl] piperazine;

2-{4-[3-(2-methylpyrrolidin-1-yl) propoxy-]-[3-4-(tetramethyleneimine-1-base carbonyl)-1,3-oxazole;

4-{ (4-methyl-2-{4-[3-(2-methylpyrrolidin-1-yl) propoxy-] phenyl }-1,3-oxazole-5-yl) carbonyl } morpholine;

4-{[4-methyl-2-(4-{3-[(2R)-2-methylpyrrolidin-1-yl] propoxy-} phenyl)-1,3-oxazole-5-yl] carbonyl } morpholine;

4-{[4-methyl-2-(4-{3-[(2S)-2-methylpyrrolidin-1-yl] propoxy-} phenyl)-1,3-oxazole-5-yl] carbonyl } morpholine;

1-cyclopentyl-4-[(4-methyl-2-{4-[3-(2-methylpyrrolidin-1-yl) propoxy-] phenyl)-1,3-oxazole-5-yl) methyl] piperazine;

N-(cyclopropyl methyl)-N-[(4-methyl-2-{4-[3-(2-methylpyrrolidin-1-yl) propoxy-] phenyl }-1,3-oxazole-5-yl) methyl]-N-propyl group amine;

N-benzyl-N-[(4-methyl-2-{4-[3-(2-methylpyrrolidin-1-yl) propoxy-] phenyl-1,3-oxazole-5-yl) methyl] amine;

1-[(2-{3-methoxyl group-4-[3-(2-methylpyrrolidin-1-yl) propoxy-] phenyl-1,3-oxazole-4-yl) methyl] piperidines;

N-(4-benzyl chloride base)-N-[(2-{4-[3-(2-methylpyrrolidin-1-yl) propoxy-] phenyl }-1,3-oxazole-4-yl) methyl] amine;

N-{ (4-methyl-2-{4-[3-(2-methylpyrrolidin-1-yl) propoxy-] phenyl }-1,3-oxazole-5-yl) methyl] cyclopentamine;

1-[(5-bromo-2-14-[3-(2-methylpyrrolidin-1-yl) propoxy-] phenyl }-1,3-oxazole-4-yl) methyl] piperidines;

1-{[2-(4-{3-[(2R)-2-methylpyrrolidin-1-yl] propoxy-} phenyl)-1,3-oxazole-4-base-methyl } piperidines;

1-{[2-(4-{3-[(2S)-2-methylpyrrolidin-1-yl] propoxy-} phenyl)-1,3-oxazole-4-yl) methyl] piperidines;

4-[(2-{4-[3-(2-methylpyrrolidin-1-yl) propoxy-] phenyl }-1,3-oxazole-4-yl) methyl] morpholine;

1-[2-(2-{4-[2-(2-methylpyrrolidin-1-yl) oxyethyl group] phenyl }-1,3-oxazole-4-yl) ethyl] piperidines;

1-[(2-{4-[3-(2-methylpyrrolidin-1-yl) propoxy-] phenyl }-1,3-oxazole-4-yl) methyl] piperidines-2-ketone;

(5S)-and 1-[(2-{4-[3-(2-methylpyrrolidin-1-yl) propoxy-] phenyl }-1,3-oxazole-4-yl) methyl]-5-(tetramethyleneimine-1-ylmethyl) pyrrolidin-2-one;

1-[(2-{3-chloro-4-[3-(2-methylpyrrolidin-1-yl) propoxy-] phenyl }-1,3-oxazole-4-yl) methyl] piperidines;

2-{3-bromo-4-[3-(2-methylpyrrolidin-1-yl) propoxy-] phenyl-4-methyl isophthalic acid, 3-thiazole-5-manthanoate;

N-(4-fluorophenyl)-2-(2-{4-[3-(2-methylpyrrolidin-1-yl) propoxy-] phenyl }-1,3-oxazole-4-yl) ethanamide;

(4aR, 8aS)-2-[(2-{4-[3-(2-methylpyrrolidin-1-yl) propoxy-] phenyl }-1,3-oxazole-4-yl) methyl] Decahydroisoquinolinpreparation;

2-{4-[3-(2-methylpyrrolidin-1-yl) propoxy-] phenyl }-4-{[(2S)-and 2-(tetramethyleneimine-1-ylmethyl) tetramethyleneimine-1-yl] carbonyl }-1, the 3-oxazole;

4-[(2-{4-[3-(2-methylpyrrolidin-1-yl) propoxy-] phenyl }-1,3-oxazole-4-yl) ethanoyl] morpholine;

N-cyclopentyl-2-(2-{4-[3-(2-methylpyrrolidin-1-yl) propoxy-] phenyl }-1,3-oxazole-4-yl) ethanamide;

N-(cyclopropyl methyl)-2-(2-(4-[3-(2-methylpyrrolidin-1-yl) propoxy-] phenyl }-1,3-oxazole-4-yl)-the N-propyl acetamide;

1-[(2-{4-[3-(2-methylpyrrolidin-1-yl) propoxy-] phenyl }-1,3-oxazole-4-yl)-ethanoyl] azepan;

(5S)-and 1-[(2-{4-[3-(2-methylpyrrolidin-1-yl) propoxy-] phenyl)-1,3-oxazole-4-yl) methyl]-5-(morpholine-4-ylmethyl) pyrrolidin-2-one;

2-methyl-N-[(2-{4-[3-(2-methylpyrrolidin-1-yl) propoxy-] phenyl }-1,3-oxazole-4-yl) methyl]-2H-tetrazolium-5-amine;

N-(3-p-methoxy-phenyl)-N-[(2-{4-[3-(2-methylpyrrolidin-1-yl) propoxy-] phenyl }-1,3-oxazole-4-yl) methyl] amine;

N-(4-fluorophenyl)-N-[(2-{4-[3-(2-methylpyrrolidin-1-yl) propoxy-] phenyl }-1,3-oxazole-4-yl) methyl] amine;

N-[(2-{4-[3-(2-methylpyrrolidin-1-yl) propoxy-] phenyl }-1,3-oxazole-4-yl) picoline-3-amine;

4-[(4-methyl-2-{4-[3-(2-methylpyrrolidin-1-yl) propoxy-] phenyl }-1,3-oxazole-5-yl) methyl] morpholine;

4-((2S)-and 1-[(2-{4-[3-(2-methylpyrrolidin-1-yl) propoxy-] phenyl }-1,3-oxazole-4-yl) methyl] tetramethyleneimine-2-yl } methyl) morpholine;

1-[(2-{2-fluoro-4-{3-(2-methylpyrrolidin-1-yl) propoxy-] phenyl }-1,3-oxazole-4-yl) methyl] piperidines;

4,4-two fluoro-1-[(2-{4-[3-(2-methylpyrrolidin-1-yl) propoxy-] phenyl }-1,3-oxazole-4-yl) methyl] piperidines;

4-[(4-methyl-2-{6-[3-(2-methylpyrrolidin-1-yl) propoxy-] pyridin-3-yl }-1,3-thiazoles-5-yl) carbonyl } morpholine;

1-(2-{3,5-two fluoro-4-[3-(2-methylpyrrolidin-1-yl) propoxy-] phenyl-1,3-oxazole-4-yl) methyl] piperidines;

4,4-two fluoro-1-{ (4-methyl-2-{4-[3-(2-methylpyrrolidin-1-yl) propoxy-] phenyl }-1,3-thiazoles-5-yl) carbonyl] piperidines;

4,4-two fluoro-1-{{4-methyl-2-(4-{3-[(2R)-2-methylpyrrolidin-1-yl] propoxy-} phenyl)-1,3-thiazoles-5-base carbonyl] piperidines;

4,4-two fluoro-1-{[4-methyl-2-(4-{3-[(2S)-2-methylpyrrolidin-1-yl] propoxy-] phenyl)-1,3-thiazoles-5-yl } carbonyl) piperidines;

4-[(4-methyl-2-{4-[3-(2-methylpyrrolidin-1-yl) propoxy-] phenyl }-1,3-thiazoles-5-yl) carbonyl] morpholine;

4-{[4-methyl-2-(4-{3-[(2R)-2-methylpyrrolidin-1-yl] propoxy-} phenyl)-1,3-thiazoles-5-yl] carbonyl } morpholine;

4-{[methyl-2-(4-{3-[(2S)-2-methylpyrrolidin-1-yl] propoxy-} phenyl)-1,3-thiazoles-5-yl] carbonyl } morpholine;

1-[(2-{2-methyl-4-[3-(2-methylpyrrolidin-1-yl) propoxy-] phenyl }-1,3-oxazole-4-yl) methyl] piperidines; With

1-[(4-methyl-2-{4-[3-(2-methylpyrrolidin-1-yl) propoxy-] phenyl }-1,3-thiazoles-5-yl) methyl] pyrrolidin-2-one.

Formula XVIII described in WO 2008/005338 and the compound of XIX and pharmacologically acceptable salts thereof also can use method of the present invention more easily to be prepared:

Wherein

R ¹And R ²Be selected from independently of one another: H, C _1-6Acyl group, C _1-8Alkyl, C _2-8Thiazolinyl, C _2-8Alkynyl, C _3-7Cycloalkyl, aryl, heterocyclic radical, heteroaryl, aryl-C _1-4-thiazolinyl, aryloxy-C _1-4-thiazolinyl, heteroaryl-C _1-4-thiazolinyl and heteroaryl oxygen base-C _1-4-thiazolinyl, and each R ¹And R ²Choose wantonly by 1,2,3,4 or 5 and be independently selected from following substituting group replacement: C _1-6Acyl group, C _1-6Acyloxy, C _2-8Thiazolinyl, C _1-6Alkoxyl group, C _1-8Alkyl, C _1-8Alkyl formamides, C _2-8Alkynyl, C _1-8Alkyl sulfonamide, C _1-8Alkyl sulphinyl, C _1-8Alkyl sulphonyl, C _1-8The alkyl sulfenyl, C _1-8The alkyl urea groups, amino, aryl, C _1-8Alkylamino, C _2-8Dialkyl amido, carbon-C _1-6-alkoxyl group, methane amide, carboxyl, cyano group, C _3-7Cycloalkyl, C _2-8Dialkylformamide, C _2-8The dialkyl group sulphonamide, halogen, C _1-6Halogenated alkoxy, C _1-6Haloalkyl, C _1-6The haloalkyl sulfinyl, C _1-6Halogenated alkyl sulfonyl, C _1-6The haloalkyl sulfenyl, heterocyclic radical, hydroxyl, mercaptan, nitro and sulphonamide; Each C wherein _1-8Alkyl also can further be replaced by hydroxyl;

Replaced by hydroxyl;

J is-CH ₂CH ₂-or 1,2-C _3-7-cycloalkylidene is chosen wantonly separately by 1,2,3 or 4 and is independently selected from following substituting group replacement: C _1-3Alkyl, C _1-4Alkoxyl group, carboxyl, cyano group, C _1-3Haloalkyl, halogen, hydroxyl and oxygen base;

R ³, R ⁴, R ⁵, R ⁶, R ⁷, R ¹⁰, R ¹¹And R ¹²Be selected from independently of one another: H, C _1-6Acyl group, C _1-6Acyloxy, C _2-8Thiazolinyl, C _1-6Alkoxyl group, C _1-8Alkyl, C _1-8Alkyl formamides, C _2-8Alkynyl, C _1-8Alkyl sulfonamide, C _1-8Alkyl sulphinyl, C _1-8Alkyl sulphonyl, C _1-8The alkyl sulfenyl, C _1-8The alkyl urea groups, amino, C _1-8Alkylamino, C _2-8Dialkyl amido, carbon-C _1-6-alkoxyl group, methane amide, carboxyl, cyano group, C _3-7Cycloalkyl, C2-8 dialkylformamide, C _2-8The dialkyl group sulphonamide, halogen, C _1-6Halogenated alkoxy, C _1-6Haloalkyl, C _1-6The haloalkyl sulfinyl, C _1-6Halogenated alkyl sulfonyl, C _1-6The haloalkyl sulfenyl, hydroxyl, mercaptan, nitro and sulphonamide;

With

R ⁸And R ⁹Be selected from independently of one another: H, C _1-8Alkyl, C _2-8Thiazolinyl, C _2-8Alkynyl, C _3-7Cycloalkyl, aryl, heterocyclic radical, heteroaryl, aryl-C _1-4-alkylidene group, aryloxy-C _1-4Alkylidene group, heteroaryl-C _1-4-alkylidene group and heteroaryl oxygen base-C _1-4-alkylidene group and each R ⁸And R ⁹Choose wantonly by 1,2,3,4 or 5 and be independently selected from following substituting group replacement: C _1-6Acyl group, C _1-6Acyloxy, C _2-8Thiazolinyl, C _1-6Alkoxyl group, C _1-8Alkyl, C _1-8Alkyl formamides, C _2-8Alkynyl, C _1-8Alkyl sulfonamide, C _1-8Alkyl sulphinyl, C _1-8Alkyl sulphonyl, C _1-8The alkyl sulfenyl, C _1-8The alkyl urea groups, amino, C _1-8Alkylamino, C _2-8Dialkyl amido, carbon-C _1-6-alkoxyl group, methane amide, carboxyl, cyano group, C _3-7Cycloalkyl, C _2-8Dialkylformamide, C _2-8The dialkyl group sulphonamide, halogen, C _1-6Halogenated alkoxy, C _1-6Haloalkyl, C _1-6The haloalkyl sulfinyl, C _1-6Halogenated alkyl sulfonyl, C _1-6Haloalkyl sulfenyl, hydroxyl, mercaptan, nitro and sulphonamide.

Preparation of the present invention (R) and (S) method of 2-crassitude can be used for more easily preparing above-mentioned compound.(R)-or (S)-the 2-crassitude can and make (R)-2-crassitude L-tartrate and alkali reaction (R)-2-crassitude to be provided or (S)-2-crassitude D-tartrate and alkali reaction are made so that (S)-2-crassitude to be provided according to the present invention.Following reaction scheme has illustrated the use of the 2-crassitude of preparation like this.

Reaction scheme 23

LG wherein ¹, LG ², X and Y are leavings group independently of one another, for example, and halogen, triflate etc., and R ¹⁵Be C _1-8Alkyl.

Reaction scheme 24

Reaction scheme 25

Wherein X is a leavings group, halogen for example, triflate etc.

Reaction scheme 26

Wherein X is leavings group, for example halogen, triflate etc.

Reaction scheme 27

LG wherein ³For leavings group such as sulphonate, triflate, halogen etc. and Z are halogen.

Reaction scheme 28

LG wherein ³For leavings group such as sulphonate, triflate, halogen etc. and Z are halogen 2

Therefore, another embodiment of the invention comprises the method for preparation formula XVIII and XIX compound:

Each variable as mentioned above, described method comprises:

(1b) optionally remove hydrogenation catalyst from mixture;

(1c) L-tartrate or D-tartrate are dissolved in mixture to form solution;

(3a) (R)-or (S)-2-crassitude is converted into the compound of formula XVIII or formula XIX.

This method also can be chosen wantonly and may further comprise the steps:

(1h) optional repeating step (f) and (g).

4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-xenyl-4-sulfonic acid (tetrahydropyran-4-base)-acid amides;

2-{4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-xenyl-4-alkylsulfonyl }-2,3-dihydro-1H-isoindole;

4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-xenyl-4-sulfonic acid (pyridine-2-ylmethyl)-acid amides;

4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-xenyl-4-sulfonic acid 4-methyl-benzyl acid amides;

4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-xenyl-4-sulfonic acid (2-oxyethyl group-ethyl)-acid amides;

4-{4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-xenyl-4-alkylsulfonyl }-thiomorpholine 1, the 1-dioxide;

4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-xenyl-4-sulfonic acid (2-isopropoxy-ethyl)-acid amides;

4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl] xenyl-4-sulfonic acid (2-phenoxy group-ethyl)-acid amides;

4 '-[2-(2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-xenyl-4-sulfonic acid 4-methoxyl group-benzyl acid amides;

4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-xenyl-4-sulfonic acid cyclohexyl amide;

The 2-methyl isophthalic acid-2-[4 '-(tetramethyleneimine-1-alkylsulfonyl)-xenyl-4-yl]-ethyl }-tetramethyleneimine;

2-{4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-xenyl-4-alkylsulfonyl)-1,2,3,4-tetrahydrochysene-isoquinoline 99.9;

4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-xenyl-4-sulfonic acid benzyl-ethyl-acid amides;

4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-xenyl-4-sulfonic acid 4-trifluoromethyl-benzyl acid amides;

1-{2-[4 '-(azetidine-1-alkylsulfonyl)-xenyl-4-yl]-ethyl }-2-methyl-tetramethyleneimine;

4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-xenyl-4-azochlorosulfonate acid ring butyl amide;

4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-xenyl-4-sulfonic acid tert-butylamides;

4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-xenyl-4-sulfonic acid propyl amides;

4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-xenyl-4-sulfonic acid sec.-propyl acid amides;

4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-xenyl-4-sulfonic acid methyl acid amides;

4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-xenyl-4-sulfonic acid (2-methoxyl group-ethyl)-acid amides;

4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-xenyl-4-sulfonic acid (4-fluoro-phenyl)-acid amides;

4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-xenyl-4-sulfonic acid 4-fluoro-benzyl acid amides;

4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-xenyl-4-sulfonic acid 4-chloro-benzyl acid amides;

4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-xenyl-4-sulfonic acid (2-hydroxyl-ethyl)-acid amides;

4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-xenyl-4-sulfonic acid diethylamide;

4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-xenyl-4-sulfonic acid (1-propyl group-butyl)-acid amides;

4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-xenyl-4-azochlorosulfonate acid ring hexyl methyl-acid amides;

4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-xenyl-4-sulfonic acid benzyl acid amides;

4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-xenyl-4-sulphenyl acid amides;

4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-xenyl-4-azochlorosulfonate acid ring propyl group methyl-acid amides;

4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-xenyl-4-sulfonic acid cyclopentyl amide;

4-{4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-xenyl-4-alkylsulfonyl }-morpholine;

1-{4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-xenyl-4-alkylsulfonyl }-piperidines;

4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-xenyl-4-sulfonic acid amides;

4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-xenyl-4-azochlorosulfonate acid ring propyl amides;

4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-xenyl-4-sulfonic acid buserelin;

4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-xenyl-4-sulfonic acid (2-methoxyl group-1-methyl-ethyl)-acid amides;

1-{4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-xenyl-4-alkylsulfonyl }-tetramethyleneimine-3-alcohol;

(1-{4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-xenyl-4-alkylsulfonyl }-piperidines-3-yl)-methyl alcohol;

1-{2-[4 '-(aziridine-1-alkylsulfonyl)-xenyl-4-yl]-ethyl }-2-methyl-tetramethyleneimine;

2-(methoxymethyl)-1-(4 '-(2-(2-methylpyrrolidin-1-3,1) ethyl) xenyl-4-base alkylsulfonyl) tetramethyleneimine;

4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-xenyl-4-sulfonic acid (2-methoxyl group-ethyl)-methyl-acid amides;

1-{4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-xenyl-4-alkylsulfonyl }-piperidines-3-alcohol;

Propionic acid 1-{4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-xenyl-4-alkylsulfonyl }-the piperidin-4-yl ester;

4 '-(2-tetramethyleneimine-1-base-ethyl)-xenyl-4-sulfonic acid buserelin;

(1-{4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-xenyl-4-alkylsulfonyl }-tetramethyleneimine-2-yl)-methyl alcohol;

4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-xenyl-4-sulfonic acid benzyl-(2-hydroxyl-ethyl)-acid amides;

4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-xenyl-4-sulfonic acid 3,5-dichloro benzyl acid amides;

4 '-2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-xenyl-4-sulfonic acid ethanoyl-(2-hydroxyl-ethyl)-acid amides;

4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-xenyl-4-sulfonic acid 3,4-dichloro benzyl acid amides;

4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-xenyl-4-sulfonic acid (2-hydroxyl-1-methyl-ethyl)-acid amides;

Propionic acid 2-(1-(4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-xenyl-4-alkylsulfonyl }-piperidin-4-yl)-ethyl ester;

1-{4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-xenyl-4-alkylsulfonyl }-piperidines-4-benzyl carboxylate;

Acetate 2-(ethanoyl-{ 4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-xenyl-4-alkylsulfonyl }-amino)-ethyl ester;

4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-xenyl-4-sulfonic acid [2-(4-fluoro-phenyl)-ethyl]-acid amides;

4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-xenyl-4-sulfonic acid (tetrahydrochysene-pyrans-4-ylmethyl)-acid amides;

Propionic acid 1-{4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-xenyl-4-alkylsulfonyl }-the piperidin-4-yl methyl esters;

Propionic acid 2-(methyl-{ 4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-xenyl-4-alkylsulfonyl }-amino)-ethyl ester;

4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-xenyl-4-sulfonic acid (2-methoxy ethyl)-(tetrahydrochysene-pyrans-4-ylmethyl)-acid amides;

4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-xenyl-4-sulfonic acid diphenyl-methyl acid amides;

2-methyl-7-{4-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl)-and phenyl }-3,4-dihydro-2H benzo [b] [1,4,5] oxygen thia

1, the 1-dioxide;

4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-xenyl-4-sulfonic acid (2-hydroxyl-1,1-dimethyl-ethyl)-acid amides;

Propionic acid 1-{4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-xenyl-4-alkylsulfonyl }-tetramethyleneimine-2-base methyl esters;

4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-xenyl-4-sulfonic acid isobutyl--(2-methoxyl group-ethyl)-acid amides;

7-{4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl] phenyl)-3,4-dihydro-2H-benzo [b] [1,4,5] oxygen thia 1, the 1-dioxide;

4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-xenyl]-sulfonic acid (2-hydroxyl-ethyl)-methyl-acid amides;

4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-xenyl-4-sulfonic acid two-(2-hydroxyethyl)-acid amides;

4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-xenyl-4-sulfonic acid sec.-propyl-(2-methoxyl group-ethyl)-acid amides;

4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-xenyl-4-sulfonic acid (2-hydroxyethyl)-sec.-propyl-acid amides;

4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-xenyl-4-sulfonic acid (3-phenyl propyl)-acid amides;

4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-xenyl-4-sulfonic acid [2-(2-oxo-imidazolidine-1-yl)-ethyl]-acid amides;

4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-xenyl-4-sulfonic acid [3-(2-oxo-tetramethyleneimine-1-yl)-propyl group]-acid amides;

4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-xenyl-4-sulfonic acid benzyl-(2-methoxyl group-ethyl)-acid amides;

3-methoxymethyl-1-{4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-xenyl-4-alkylsulfonyl }-piperidines;

4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-xenyl-4-sulfonic acid styroyl acid amides;

(1-{4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-xenyl-4-alkylsulfonyl }-piperidin-4-yl)-methyl alcohol;

1-{4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-xenyl-4-alkylsulfonyl }-piperidines-4-carboxylic acid, ethyl ester;

4-(2-oxyethyl group-ethyl)-1-{4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-xenyl-4-alkylsulfonyl }-piperidines;

1-(4-{4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-xenyl-4-alkylsulfonyl }-piperazine-1-yl)-propane-1-ketone;

4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl)-xenyl-4-sulfonic acid (pyridin-4-yl methyl)-acid amides;

3-{4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-xenyl-4-sulfuryl amino-methyl propionate;

4-ethoxyl methyl-1-{4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-xenyl-4-alkylsulfonyl }-piperidines;

(1-{4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-xenyl-4-alkylsulfonyl)-piperidines-3-yl)-methyl alcohol;

3-methoxyl group-1-{4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-xenyl-4-alkylsulfonyl }-piperidines;

4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-xenyl-4-sulfonic acid (pyridin-3-yl methyl)-acid amides;

2-(1-{4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-xenyl-4-alkylsulfonyl }-piperidin-4-yl)-ethanol;

2-{4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-xenyl-4-sulfuryl amino }-methyl propionate;

4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-xenyl-4-sulfonic acid (1-hydroxymethyl-cyclopentyl)-acid amides;

(1-{4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-xenyl-4-alkylsulfonyl }-piperidines-2-yl)-methyl alcohol;

4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-xenyl-4-sulfonic acid 4-trifluoromethoxy-benzyl acid amides;

4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-xenyl-4-sulfonic acid two-(2-methoxyl group-ethyl)-acid amides;

4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-xenyl-4-sulfuryl amino)-methyl acetate;

2-{4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-xenyl-4-sulfuryl amino }-isopropyl propionate;

1-{4 '-2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-xenyl-4-alkylsulfonyl }-tetramethyleneimine-2-carboxylic acid;

6,7-dimethoxy-2-{4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-xenyl-4-alkylsulfonyl }-1,2,3,4-tetrahydrochysene-isoquinoline 99.9;

4-methoxyl group-1-{ " 2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-xenyl-4-alkylsulfonyl }-piperidines;

4-{4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-xenyl-4-alkylsulfonyl)-piperazine-2-ketone;

{ 4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-xenyl-4-sulfuryl amino }-isopropyl acetate;

1-{4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-xenyl-4-alkylsulfonyl 1-tetramethyleneimine-2-carboxylic acid methane amide;

3,5-dimethyl-4-{4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-xenyl-4-alkylsulfonyl)-morpholine;

Propionic acid 1-{4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-xenyl-4-alkylsulfonyl-tetramethyleneimine-3-base ester;

1-{4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl)-xenyl-4-alkylsulfonyl }-piperidines-4-alcohol;

Propionic acid 2-methyl-2-{4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-xenyl-4-sulfuryl amino }-propyl ester;

2-{4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-xenyl-4-sulfuryl amino)-the propionic acid tert-butyl ester;

1-{4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-xenyl-4-alkylsulfonyl }-piperidines-4-carboxylic acid;

{ 4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-xenyl-4-sulfuryl amino }-tert.-butyl acetate;

4-hydroxyl-1-{4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-xenyl-4-alkylsulfonyl }-tetramethyleneimine-2-carboxylate methyl ester;

4-(2-methoxyl group-ethyl)-1-{4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-xenyl-4-alkylsulfonyl }-piperidines; With

4-methoxymethyl-1-{4 '-[2-(2-methyl-tetramethyleneimine-1-yl)-ethyl]-xenyl-4-alkylsulfonyl }-piperidines.

Embodiment

Method and scheme

Determine the chiral purity of (R)-2-crassitude by vapor-phase chromatography (GC)

Post Chiraldex B-DA, 30m * 0.25mm,

0.25μm?df(mfr：Astec-Advanced

Separation Technologies, Inc.) or equivalent

150 ℃ of injector temperature

Splitting ratio 40: 1

Carrier gas He, constant voltage 8psi

Volume injected 2 μ L

Detect FID, at 250 ℃

Flow velocity hydrogen, 30mL/min

Air, 400mL/min

Replenish the gas helium, 30mL/min

110 ℃ of isothermals of heating chamber program last 25 minutes

Specimen preparation is in the methylene dichloride that contains sample (10mg) (1mL)

Add trifluoroacetic anhydride (200 μ L).60 ℃ of reactions

15 minutes.Under the nitrogen gas stream of gentleness, remove and desolvate,

And in resistates, add methylene dichloride (1mL).

Resolving power between system's suitability enantiomorph should 〉=1.2

Retention time (R)-2-crassitude=11 minute

(S)-2-crassitude=11.5 minute

Embodiment 1 Use synthetic (the R)-2-crassitude L-tartrate of 5%Pt-C

(2.50g, 30.12mmol) under 55psi, under the envrionment temperature, hydrogenation is 16 hours in the mixture of 5%Pt-C (250mg, catalytic), dehydrated alcohol (62mL) and methyl alcohol (26mL) around to make the 2-methylpyrroline.Gas chromatographic analysis shows that 93.7% of parent material is converted into product.The mixture filtration is passed through

(4g), and with filtrate and L-tartrate (3.80g 25.32mmol) places single neck round-bottomed flask of the 250mL that is furnished with stirring rod together.With mixture heating up to 25 ℃ up to obtaining solution.Add believable (R)-2-crassitude L-tartrate (10.0mg) as crystal seed, and with mixture around envrionment temperature stirred 16 hours.Use ice bath that mixture is cooled to 0 ℃ and other the stirring 2 hours.Cross filter solid, and carried out dry air then 1 hour, (R)-2-crassitude L-tartrate (3.55g, 15.09mmol, 50.1%) is provided.The chirality gas chromatographic analysis shows 55%ee, total purity of 93%.

Embodiment 2 Use synthetic (the R)-2-crassitude L-tartrate of oxidation Pt (IV)

(2.50g, 30.12mmol) under 55psi, under the envrionment temperature, hydrogenation is 5 hours in the mixture of platinum oxide (IV) (250mg, catalytic), dehydrated alcohol (62mL) and methyl alcohol (26mL) around to make the 2-methylpyrroline.Gas chromatographic analysis shows that 98.3% of parent material is converted into product.The mixture filtration is passed through

(4g), and with filtrate and L-tartrate (3.80g 25.32mmol) places the single neck round-bottomed flask of the 250mL that is furnished with stirring rod together.With mixture heating up to 25 ℃ up to obtaining solution.Add believable (R)-2-crassitude L-tartrate (100.0mg) as crystal seed, and mixture was stirred 8 hours at 25 ℃.Mixture is cooled to ambient temperature and other the stirring 16 hours.Use ice bath that mixture is cooled to 0 ℃ and other the stirring 2 hours.Cross filter solid,, carried out dry air then 1 hour, so that (R)-2-crassitude L-tartrate (2.85g, 12.12mmol, 40.3%) to be provided with methyl alcohol (5mL) washing.The chirality gas chromatographic analysis shows 49.2%ee, total purity of 75%.

Embodiment 3 (R)-recrystallization of 2-crassitude L-tartrate

General recrystallization process: a part of product (2.71g) that will obtain in embodiment 1 places the single neck round-bottomed flask of the 100mL that is furnished with stirring rod with dehydrated alcohol (38mL) and methyl alcohol (16mL).To form solution, make it be cooled to ambient temperature then mixture heating up to 60 ℃.Add believable (R)-2-crassitude L-tartrate (2.50mg) as crystal seed, and with mixture around envrionment temperature stirred 16 hours, then 0 ℃ of (ice bath) restir 2 hours.Cross filter solid, and in vacuum chamber, use dry 1 mouse of nitrogen gas stream of 29in.Hg under 60 ℃, (R)-2-crassitude L-tartrate (1.80g, 66.4% same yield) is provided.The chirality gas chromatographic analysis shows 84.9%ee, total purity of 93%.

Use the dehydrated alcohol of 25mL and the methyl alcohol of 11mL, the solid (1.79g) that obtains is further split according to general recrystallization process, so that (R)-2-crassitude L-tartrate (1.70g, 95.5% rate of recovery) to be provided.The chirality gas chromatographic analysis shows 93.4%ee, total purity of 97%.

Use the dehydrated alcohol of 24mL and the methyl alcohol of 10mL, the solid (1.69g) that obtains is further split according to general recrystallization process, so that (R)-2-crassitude L-tartrate (1.58g, 93.5% rate of recovery) to be provided.The chirality gas chromatographic analysis shows 96.7%ee, total purity of 98%.

Use the dehydrated alcohol of 22.5mL and the methyl alcohol of 9.5mL, the solid (1.57g) that obtains is further split according to general recrystallization process, difference is not carry out inoculating, and with dry 4 hours of the crystal that obtains, (R)-2-crassitude L-tartrate (1.49g is provided, 94.9% rate of recovery, 6.334mmol is 21.0% from the total recovery of 2-methylpyrroline).The chirality gas chromatographic analysis shows 98.4%ee, total purity of 99%.

Those skilled in the art can understand, and according to above-mentioned instruction, might carry out many changes and modification to the present invention.Therefore, will be understood that in the scope of claims, practice of the present invention can be specifically described different with this paper, and scope of the present invention has been intended to contain these all variants.

Claims

1. prepare the method for (R)-2-crassitude L-tartrate, may further comprise the steps:

(b) optionally remove hydrogenation catalyst from mixture;

(c) L-tartrate is dissolved in the mixture to form solution;

(d) make (R)-2-crassitude L-tartrate from solution crystallization; With

(e) fractional crystallization (R)-2-crassitude L-tartrate.

2. the process of claim 1 wherein that hydrogenation catalyst is a platinum catalyst.

3. the method for claim 2, wherein platinum catalyst is 5%Pt-C.

4. the method for claim 2, wherein platinum catalyst is platinum oxide (IV).

5. each method among the claim 1-4, wherein alcoholic solvent is ethanol and methanol mixture.

6. the method for claim 5, wherein the alcoholic solvent mixture that to be ethanol and methyl alcohol exist with about 2: 1 to about 3: 1 (v/v) ratios.

7. each method among the claim 1-6, wherein step (a) is carried out under the envrionment temperature around.

8. each method among the claim 2-4, wherein platinum catalyst is filtered in step (b) and removes.

9. each method among the claim 1-8, wherein separated (R)-2-crassitude L-tartrate has the optical purity of 50%ee at least.

10. each method among the claim 1-9, further comprising the steps of:

(f) make isolating (R)-2-crassitude L-tartrate recrystallization;

(g) (R)-2-crassitude L-tartrate of separation recrystallization; With

(h) optional repeating step (f) and step (g).

11. the method for claim 10 comprises that also (the R)-2-crassitude L-tartrate that makes isolating recrystallization and alkali reaction are to provide (R)-2-the step of crassitude.

12. each method among the claim 1-9 comprises that also (the R)-2-crassitude L-tartrate with preparation is converted into H ₃The step of receptors ligand.

13. the method for claim 10 or 11 comprises that also (the R)-2-crassitude L-tartrate with preparation is converted into H ₃The step of receptors ligand.

14. the method for claim 12 or 13, wherein H ₃Receptors ligand is 6-{4-[3-((R)-2-methyl-tetramethyleneimine-1-yl)-propoxy-]-phenyl }-the 2H-pyridazin-3-one:

15. prepare 6-{4-[3-((R)-2-methyl-tetramethyleneimine-1-yl)-propoxy-]-phenyl }-method of 2H-pyridazin-3-one:

May further comprise the steps:

(1b) optionally remove hydrogenation catalyst from mixture;

(1c) L-tartrate is dissolved in the mixture to form solution;

(1d) make (R)-2-crassitude L-tartrate from solution crystallization;

(1e) fractional crystallization (R)-2-crassitude L-tartrate; With

16. the method for claim 15, wherein 6-[4-(3-halogen-propoxy-)-phenyl]-the 2H-pyridazin-3-one is produced by following steps:

(b) make 1-[4-(3-halogen-propoxy-)-phenyl]-ethyl ketone and oxoethanoic acid to be to be enough to generate 6-[4-(3-halogen-propoxy-)-phenyl]-contact under time of 2H-pyridazin-3-one and the condition.

17. the method for claim 15 is further comprising the steps of:

(f) make isolating (R)-2-crassitude L-tartrate recrystallization;

(g) (R)-2-crassitude L-tartrate of separation recrystallization; With

(h) optional repeating step (f) and step (g).

18. the method for preparation (S)-2-crassitude D-tartrate may further comprise the steps:

(b) optionally remove hydrogenation catalyst from mixture;

(c) D-tartrate is dissolved in the mixture to form solution;

(d) make (S)-2-crassitude D-tartrate from solution crystallization; With

(e) fractional crystallization (S)-2-crassitude D-tartrate.

19. the method for claim 18, wherein hydrogenation catalyst is a platinum catalyst.

20. the method for claim 19, wherein platinum catalyst is 5%Pt-C.

21. the method for claim 20, wherein platinum catalyst is platinum oxide (IV).

22. each method among the claim 18-21, wherein alcoholic solvent is ethanol and methanol mixture.