CN101039901B

CN101039901B - Process for making phenoxy benzamide compounds

Info

Publication number: CN101039901B
Application number: CN2005800349308A
Authority: CN
Inventors: P·康恩沃尔; D·S·恩尼斯; M·E·吉尔斯; S·L·詹金; J·S·帕克; B·帕特尔; J·R·J·帕金斯
Original assignee: AstraZeneca AB
Current assignee: AstraZeneca AB
Priority date: 2004-10-16
Filing date: 2005-10-11
Publication date: 2011-03-09
Anticipated expiration: 2025-10-11
Also published as: CN101039901A; ZA200702609B; GB0423042D0

Abstract

A process for making a compound of formula (I), said process comprising a) reaction of a compound of formula (II) with: i) a compound of formula (III) by nucleophilic aromatic substitution of X<sup. A process for making a compound of formula (I), said process comprising a) reaction of a compound of formula (II) with: i) a compound of formula (III) by nucleophilic aromatic substitution of X<2> andii) a compound of formula (IV) for example by nucleophilic aromatic substitution b) where necessary, conversion of X<1> to a carboxylic acid; and c) coupling of the carboxylic acid group to an appropriate heterocyclic amine; wherein all variables are as defined in the description.

Description

The method for preparing phenoxy benzamide compounds

The chemical process of the preparation compound that the present invention relates to improve, described compound are used for the treatment of or prevent the disease or the medical science symptom of glucokinase (GLK or GK) mediation, thereby have reduced the threshold glucose value that stimulates insulin secretion.Described compound estimates it is to absorb by the increase liver glucose to reduce blood-glucose.These compounds can be used for treating diabetes B and obesity.The invention still further relates to the intermediate of the chemical process that is used for described improvement.

In pancreas β cell and hepatic parenchymal cells, main plasma membrane glucose transporter is GLUT2.Under the physiology glucose concn, the speed that GLUT2 transhipment glucose passes plasma membrane is not subjected to the restriction of these cells to total speed of glucose uptake.The uptake rate of glucose is subjected to glucose phosphate to turn to the rate limiting of G-6-P ester (G-6-P), and this phosphorylation is by glucokinase (GLK) catalysis [1].GLK has high (6-10mM) Km to glucose, and is not subjected to the restriction [1] of the physiological concentrations of G-6-P.GLK expresses the restriction that is subjected to a small amount of several tissue and cell type, wherein is apparent that most to be subjected to pancreas β cell and hepatocellular restriction [1].In these cells, the active rate-constrained of GLK is in glucose utilization, so the insulin secretion and the liver glycogen synthetic degree of having regulated glucose induction.These processes are quite important to the glucose homeostasis of keeping whole machine body, and dysfunction [2] all takes place in the diabetic subject.

In a kind of hypotype diabetes, promptly in the II type maturity onset diabetes of the young (MODY-2), these diabetes are [3,4] that the GLK disappearance by function mutation causes.MODY-2 patient's hyperglycemia derives from the damaged property glucose utilization [5] in pancreas and the liver.Damaged property glucose utilization in MODY-2 patient's pancreas has caused the threshold value of glucose insulin secretion accelerating to raise.On the contrary, the activated mutant effect of rare GLK causes familial hyperinsulinemia [6,6a, 7] thereby reduced this threshold value.Except the GLK activity of observed reduction in the MODY-2 diabetes, the liver glucokinase activity in the type ii diabetes also reduces [8].Importantly, GLK comprehensively or liver optionally cross and express, stop or reversed the development [9-12] of diabetes phenotype in the diet of this disease and the genetic model.In addition, with the acute treatment of fructose, be by stimulating liver glucose to be used to improve glucose tolerance [13] to type ii diabetes.It is believed that this effect is that kytoplasm GLK activity increases and mediates in the liver cell of being brought out by fructose by following mechanism [13].

By regulating the activity that albumen (GLKRP) association can suppress liver GLK with GLK.The fructose-6-phosphate (F6P) that is attached on the GLKRP can be stablized the GLK/GLKRP mixture, and can make the mixture stabilization removal by this sugared phosphoric acid of fructose-1-phosphate (F1P) displacement.Under the phosphorylation mediation of the meals fructose that fructokinase mediates, generate F1P.So the integrity of GLK/GLKRP mixture and liver GLK activity are regulated in the mode that nutrition relies on, because F6P preponderates under postabsorptive state, and F1P preponderates under state after the dining.Form contrast with liver cell, the pancreas beta cell is expressed GLK under the non-existent condition of GLKRP.So beta cell GLK activity is subjected to the adjusting of the utilizability of its substrate glucose widely.Small molecules can be directly or by making GLK/GLKRP mixture stabilization removal, activates GLK.Last compounds expectation can promote the glucose utilization in liver and the pancreas, and then a compounds is estimated only optionally to work in liver.Yet, estimate that the compound with above-mentioned any performance all can present the treatment benefit for the treatment of type ii diabetes, this is because this disease is characterised in that: all occurred the glucose utilization of damaged property in above-mentioned two kinds of tissues.

GLK, GLKRP and K _ATPPassage is expressed in the hypothalamic neurone, and hypothalamus is the very important brain zone [14-18] of regulating energy balance and control ingestion of food.Verified, these neuron expressions improve a poor appetite neuropeptide and apocleisis neuropeptide [15,19,20], and inferred it is glucose sensing neurone in the hypothalamus, they suppress or excited [17,19,21,22] by the change of environment glucose concentration.The ability that these neurone sensation glucose levels change is in the fat model of multiple genetics and test-induced damaged [23-28].Through Intraventricular (icv) infusion glucalogue (competitive inhibitor of glucokinase just), can promote the ingestion of food [29,30] of thin and weak rat.On the contrary, suppress feed [31] through icv infusion glucose.So the small molecules activator of GLK can be by maincenter (central) the effect minimizing ingestion of food and the weight increase to GLK.So the GLK activator can be used for the treatment of to therapeutic the eating disorder (eating disorders) except that diabetes, comprises obesity.Under the adduction or synergy of these compounds, hypothalamus will be brought into play the effect that makes glucose homeostasis normalizing in liver and/or pancreas, for example treat type ii diabetes.So the GLK/GLKRP system can be described as treatment " diabetes obesity " potential target spot (acting on diabetes and obesity) (Diabesity).

GLK also expresses in specific enteroendocrine cell, it is believed that in this control incretin peptide GIP (glucose-dependent insulinotropic peptide) and GLP-1 (glucagon-like peptide-1) the sugared quick secretion from intestines K-cell and L-cell (32,33,34) respectively.Therefore, owing to can stimulate GIP and the secretion of GLP-1 from these enteroendocrine cells, the small molecules activator of GLK has additional beneficial effect to insulin secretion, b-cell function and survival and body weight.

At our common pending application (WO2005/080359, WO2005/080360, PCT/GB2005/002166, with at first to file GB0423044.7 and GB0423043.9) in, described the compound as the GLK activator, its chemical general formula (I) is:

Wherein, for example

R ¹Be methylol, methoxyl methyl or methyl; X is methyl or ethyl;

R ²Be selected from-C (O) NR ⁴R ⁵,-SO ₂NR ⁴R ⁵, S (O) _pR ⁴And HET-2;

HET-1 is 5 yuan or 6 yuan of hetero-aromatic rings that randomly substituted C connects, and contains nitrogen-atoms in the 2-position;

HET-2 is 4,5 or 6 yuan of heterocyclic rings that randomly substituted C-or N-connect, and contains 1,2,3 or heteroatoms;

R ³Be selected from halogen, methyl fluoride, difluoromethyl, trifluoromethyl, methyl, methoxyl group and cyano group;

R ⁴Be selected from hydrogen, (1-4C) alkyl [randomly substituted], (3-6C) cycloalkyl (randomly substituted) and HET-2;

R ⁵Be hydrogen or (1-4C) alkyl;

Perhaps R ⁴And R ⁵Connected nitrogen-atoms forms heterocyclic radical ring-type system together;

M is 0 or 1;

N is 0,1 or 2;

Condition is when m is 0, and n is 1 or 2

Perhaps their salt, prodrug or solvate.

Formula (I) compound is N-heterocyclic radical-arylamide, the alkyl oxide and the aryloxy substituting group 3 that are substituted of aryl rings wherein, and 5-is two to be replaced.These compounds adopt the reaction sequence of following flow process 1 and 2 examples synthetic usually:

Flow process 1

Wherein X such as its definition in formula (1), P is a for example trialkylsilkl of methyl or protecting group.

Flow process 2

The starting raw material of these two synthetic routes all is (3,5-methyl dihydroxyl) benzoic ethers.Multiple substituting group changes in proper order around the phenyl ring, but in the approach of two example explanations, is necessary to use protecting group (benzyls in flow process 1 and 2) in synthetic order, to distinguish two hydroxyls in the starting raw material.If product is a mass preparation, then introduce other synthesis step inevitably, this means the unit weight cost that will increase end product, and increase waste and the influence of environment.

Simultaneously, the compound with similar general formula also open (WO2004/076420).A kind of approach of compound that is used for is shown in flow process 3.

Flow process 3

Yet, as mentioned above, in this approach, still need use the methoxyl methyl protecting group.

Be worth in order to make this compounds have commercial exploitation, need develop one or more short, efficient synthetic routes.We find, by adopting the starting raw material that halogen replaces and randomly replacing above-mentioned used acid or ester with the carboxylic acid precursor, can overcome the problem that approach as mentioned above is correlated with.This can not only form a kind of weak point and efficient approach, and avoids using some protecting groups.

In addition, use Mitsunobu reaction conditions (PPh has been avoided in some aspect of the inventive method ₃, diethylazodicarboxylate (DEAD)), the latter can produce byproduct (P (O) ph that does not expect ₃), the inventive method also need not to use potential explosive substance (DEAD).In addition, any heavy metal catalyst is avoided using in some aspect of the inventive method, and it is minimum therefore the waste of not expecting to be reduced to, and reduces to the residue in the product minimum.

According to the bright first aspect of this law, provide the method for preparation formula (I) compound

Described method comprises:

A) formula (II) compound:

Wherein be carboxyl or its precursor, X ²Be F and X ³Be selected from F, Br and OH;

I) in The suitable solvent, adopt suitable alkali, carry out X with formula (III) compound ²The substitution reaction of nucleophilicity fragrance,

Wherein X is with its definition in formula (I), and R ¹Be selected from methyl, methoxyl methyl and methylol (or their protected pattern); With

Ii) in The suitable solvent, adopt suitable alkali, carry out the substitution reaction of nucleophilicity fragrance, perhaps work as X with formula (IV) compound ³During for Br, under the condition of suitable Ullman ether reaction,

R wherein ², R ³, the definition of m and n such as its in formula (I) definition and work as X ³X during for F or Br ⁴For OH with work as X ³X during for OH ⁴Be leavings group;

B) if needed, with X ¹Be converted into carboxylic acid; With

C) this carboxyl is coupled on the formula V compound;

Subsequently if necessary:

I) formula (I) compound is transformed another kind of formula (I) compound;

Ii) at R ¹Under the situation for the methylol of protected pattern, slough protecting group;

Iii) form prodrug; And/or

Iv) form pharmacologically acceptable salt;

Its Chinese style (I) compound:

R ¹Be methylol, methoxyl methyl or methoxy;

X is methyl or ethyl;

R ²Be selected from-C (O) NR ⁴R ⁵,-SO ₂NR ⁴R ⁵,-S (O) _pR ⁴And HET-2; HET-1 is 5 yuan or 6 yuan of hetero-aromatic rings that C-connects, and contains nitrogen in the 2-position and choose wantonly to contain 1 or 2 other ring hetero atom that is independently selected from O, N and S; Ring randomly is independently selected from R by 1 or 2 ⁶Substituting group effectively being substituted on the carbon atom, perhaps on theheterocyclic nitrogen atom, be substituted, condition is not thus by quaternized;

HET-2 is 4,5 yuan or 6 yuan of heterocyclic rings that C-or N-connect, and contains 1,2,3 or 4 heteroatoms that is independently selected from O, N and S, wherein-and CH ₂-group can be randomly-C (O)-substitute and wherein the sulphur atom on the heterocycle can randomly be oxidized to S (O) or S (O) ₂Group, ring randomly effectively are being independently selected from R by 1 or 2 on carbon or the nitrogen-atoms ⁷Substituting group replace;

R ⁴Be selected from hydrogen, (1-4C) alkyl [randomly by 1 or 2 be independently selected from HET-2 ,-OR ⁵,-SO ₂R ⁵, (3-6C) cycloalkyl (randomly is selected from R by 1 ⁷Group replace) and-C (O) NR ⁵R ⁵Group replace], (3-6C) cycloalkyl (randomly is selected from R by 1 ⁷Group replace) and HET-2;

R ⁵Be hydrogen or (1-4C) alkyl;

Or R ⁴And R ⁵Connected nitrogen-atoms forms the defined heterocyclic ring system as HET-3 together;

R ⁶Be independently selected from: (1-4C) alkyl, halogen, hydroxyl (1-4C) alkyl, (1-4C) alkoxyl group (1-4C) alkyl, (1-4C) alkyl S (O) _p(1-4C) alkyl, amino (1-4C) alkyl, (1-4C) alkylamino (1-4C) alkyl, two (1-4C) alkylamino (1-4C) alkyl and HET-4;

Perhaps, when HET-is the 2-pyridyl, R ⁶Be carboxyl;

R ⁷Be selected from-OR ⁵, (1-4C) alkyl ,-C (O) (1-4C) alkyl ,-C (O) NR ⁴R ⁵, (1-4C) alkoxyl group (1-4C) alkyl, hydroxyl (1-4C) alkyl and-S (O) _pR ⁵

HET-3 is the saturated or part unsaturated heterocycle basic ring of 4-6 unit that N-connects, and randomly comprises 1 or 2 heteroatomic other heteroatoms (except that the N atom that this is connected) that is independently selected from O, N and S; Wherein-CH ₂-group randomly by-C (O)-substitute and wherein the sulphur atom on the ring can randomly be oxidized to S (O) or S (O) ₂Group; Ring randomly effectively is being independently selected from R by 1 or 2 on carbon or the nitrogen-atoms ⁸Substituting group replace; Or

HET-3 is 7 yuan of saturated or part unsaturated heterocycle basic rings that N-connects, and randomly comprises 1 heteroatomic other heteroatoms (except that the N atom that this is connected) that is independently selected from O, N and S; Wherein-CH ₂-group randomly by-C (O)-substitute and wherein the sulphur atom on the ring can randomly be oxidized to S (O) or S (O) ₂Group; Ring randomly effectively is being independently selected from R by 1 or 2 on carbon or the nitrogen-atoms ⁸Substituting group replace; Or

HET-3 is saturated or part unsaturated heterocycle base two rings of 6-10 unit, randomly comprises 1 N (except that the N atom of this connection); Wherein-CH ₂-group is randomly by-C (O)-substitute; Wherein ring randomly effectively is being selected from hydroxyl and R by 1 ground on carbon or the nitrogen-atoms ³Substituting group replace;

R ⁸Be selected from-OR ⁵, (1-4C) alkyl-C (O) (1-4C) alkyl ,-C (O) NR ⁴R ⁵, (1-4C) alkylamino, two (1-4C) alkylamino, HET-3 (wherein said ring is unsubstituted), (1-4C) alkoxyl group (1-4C) alkyl, hydroxyl (1-4C) alkyl and-S (O) _pR ⁵

HET-4 is 5 yuan or 6 yuan of unsubstituted hetero-aromatic rings that C or N-connect, and contains 1,2 or 3 ring hetero atom that is independently selected from O, N and S; P (under different situations independently) is 0,1 or 2; M is 0 or 1; With n be 0,1 or 2; Condition is when m is 0, and n is 1 or 2.

Be understandable that step a) i) and a) ii) can carry out in proper order, and preferred order depends on substituent R ¹-R ³And X ¹-X ⁴Character, specifically referring to flow process 4:

Flow process 4

Some formula (VI), (VII) and (VIII) compound be novel, it has constituted independent aspects of the present invention separately.

Specific formula (VI) compound (X ¹Be the precursor of carboxylic acid) comprise following one or more:

3-bromo-5-isopropoxy-benzonitrile;

3-bromo-5-(2-methoxyl group-1-methyl ethoxy) benzonitrile;

3-bromo-5-(2-tert.-butoxy-1-methyl ethoxy) benzonitrile;

3-bromo-5-(2-benzyloxy-1-methyl ethoxy) benzonitrile;

3-bromo-5-(2-(trityl) Oxy-1-methyl ethoxy) benzonitrile;

3-bromo-5-(2-four hydroxyl pyranyl Oxy-1-methyl ethoxies) benzonitrile; With

3-bromo-5-(2-allyloxy-1-methyl ethoxy) benzonitrile.

Other specific formula (VI) compounds (X ¹Be the precursor of carboxylic acid) comprise following one or more:

3-bromo-5-(2-methoxyl group-1-ethyl oxyethyl group) benzonitrile;

3-bromo-5-(2-tert.-butoxy-1-ethyl oxyethyl group) benzonitrile;

3-bromo-5-(2-benzyloxy-1-ethyl oxyethyl group) benzonitrile;

3-bromo-5-(2-(t trityl) Oxy-1-ethyl oxyethyl group) benzonitrile;

3-bromo-5-(2-four hydroxyl pyranyl Oxy-1-ethyl oxyethyl groups) benzonitrile; With

3-bromo-5-(2-allyloxy-1-ethyl oxyethyl group) benzonitrile.

Specific formula (VI) compound (X ¹Be carboxylic acid) comprise following one or more:

3-bromo-5-isopropoxy-phenylformic acid;

3-bromo-5-(2-methoxyl group-1-methyl ethoxy) phenylformic acid;

3-bromo-5-(2-tert.-butoxy-1-methyl ethoxy) phenylformic acid;

3-bromo-5-(2-benzyloxy-1-methyl ethoxy) phenylformic acid;

3-bromo-5-(2-(trityl) Oxy-1-methyl ethoxy) phenylformic acid;

3-bromo-5-(2-four hydroxyl pyranyl Oxy-1-methyl ethoxies) phenylformic acid; With

3-bromo-5-(2-allyloxy-1-methyl ethoxy) phenylformic acid.

Other specific formula (VI) compounds (X ¹Be carboxylic acid) comprise following one or more:

3-bromo-5-(2-methoxyl group-1-ethyl oxyethyl group) phenylformic acid;

3-bromo-5-(2-tert.-butoxy-1-ethyl oxyethyl group) phenylformic acid;

3-bromo-5-(2-benzyloxy-1-ethyl oxyethyl group) phenylformic acid;

3-bromo-5-(2-(trityl) Oxy-1-ethyl oxyethyl group) phenylformic acid;

3-bromo-5-(2-four hydroxyl pyranyl Oxy-1-ethyl oxyethyl groups) phenylformic acid: and

3-bromo-5-(2-allyloxy-1-ethyl oxyethyl group) phenylformic acid.

Other specific formula (VI) compounds comprise the single enantiomer of above-mentioned specific compound, especially (1S) enantiomorph.

A kind of specific formula (VII) compound is 3-fluoro-5-[4-(methylsulfonyl) phenoxy group] benzonitrile.

Specific formula (VIII) compound is:

3-[(1S)-2-methoxyl group-1-methyl ethoxy]-5-[4-(first semi-annular jade pendant acyl group) phenoxy group] benzonitrile [with racemization pattern 3-(4-methylsulfonyl-phenoxy group)-5-(2-methoxyl group-1-methyl-oxyethyl group) benzonitrile];

3-[(1S)-2-methoxyl group-1-methyl ethoxy]-5-[4-(first semi-annular jade pendant acyl group) phenoxy group] phenylformic acid [with racemization pattern 3-(4-methylsulfonyl-phenoxy group)-5-(2-methoxyl group-1-methyl-oxyethyl group) phenylformic acid];

3-[(1S)-2-tert.-butoxy-1-methyl ethoxy]-5-[4-(first semi-annular jade pendant acyl group) phenoxy group] benzonitrile: and

3-[(1S)-2-tert.-butoxy-1-methyl ethoxy]-5-[4-(first semi-annular jade pendant acyl group) phenoxy group] phenylformic acid.

Specific formula (VIII) compound comprises one or more:

The 3-[isopropoxy]-5-[4-(first semi-annular jade pendant acyl group) phenoxy group] benzonitrile;

The 3-[isopropoxy]-5-[4-(first semi-annular jade pendant acyl group) phenoxy group] phenylformic acid;

3-[(1S)-2-benzyloxy-1-methyl ethoxy]-5-[4-(first semi-annular jade pendant acyl group) phenoxy group] benzonitrile;

3-[(1S)-2-benzyloxy-1-methyl ethoxy]-5-[4-(first semi-annular jade pendant acyl group) phenoxy group] phenylformic acid;

3-[(1S)-2-three benzyloxies--1-methyl ethoxy]-5-[4-(first semi-annular jade pendant acyl group) phenoxy group] benzonitrile;

3-[(1S)-2-three benzyloxies-1-methyl ethoxy]-5-[4-(first semi-annular jade pendant acyl group) phenoxy group] phenylformic acid;

3-[(1S)-2-four hydroxyl pyranyl Oxy-1-methyl ethoxies]-5-[4-(first semi-annular jade pendant acyl group) phenoxy group] benzonitrile;

3-[(1S)-2-four hydroxyl pyranyl Oxy-1-methyl ethoxies]-5-[4-(first semi-annular jade pendant acyl group) phenoxy group] phenylformic acid;

3-[(1S)-2-allyloxy-1-methyl ethoxy]-5-[4-(first semi-annular jade pendant acyl group) phenoxy group] benzonitrile: and

3-[(1S)-2-allyloxy-1-methyl ethoxy]-5-[4-(first semi-annular jade pendant acyl group) phenoxy group] phenylformic acid.

Another kind of specific formula (VIII) compound is the 3-[hydroxyl]-5-[4-(first semi-annular jade pendant acyl group) phenoxy group] phenylformic acid.

A kind of specific formula (I) compound (protected pattern) is 3-[(1S)-2-tert.-butoxy-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl)-5-[4-(first semi-annular jade pendant acyl group) phenoxy group] benzamide.

Be suitable for protecting R ¹In the protecting group of methylol, be those protecting groups that are used to protect primary alconol known in the art (referring to for example " Protective groups in Organic Chemistry ", the 2nd edition, TW Greene and PGM Wuts, 1991).By methods known in the art, by commercially available propylene glycol starting raw material, preparation contains formula (II) compound of this class protecting group, for example when X is methyl:

Be used to protect R ¹Other suitable protecting groups of middle methylol are the tertiary butyl, benzyl, trityl (trityl) and tetrahydropyrans-2-base; So preferred formula (III) compound is:

Another kind of suitable protecting group is an allyl ethers.

On the one hand, tertbutyl ether

It is preferred protecting group.

In building-up process, can adopt methods known in the art, take off protecting group constantly easily.For example, can take off benzyl by hydrogenization.Can take off trityl or tertiary butyl groups by acid treatment.The suitable acid or the acidic conditions that are used to remove tertiary butyl groups are for example to handle with hydrogenchloride in methyl alcohol, or use the Amberlyst plastic resin treatment, or handle with formic acid.

Suitable X as the carboxylic acid precursor ¹Be-CO ₂(1-4C) alkyl ,-CHO ,-CH ₂OP (is under the situation of suitable protecting group at P), cyano group, trifluoromethyl, methyl and halogen.

What other were suitable is-CO ₂Et, cyano group and trifluoromethyl.

Preferred cyano group and trifluoromethyl, especially cyano group.

Being suitable for operation steps condition a)-C) is:

Operation steps is i a))

The solvent that is suitable for the substitution reaction of nucleophilicity fragrance be known in the art (referring to for example Advanced Organic Chemistry, M B Smith ﹠amp; J March (editor), 2001 the 5th editions, 13 chapters, 850 pages); Usually, polar aprotic solvent suits, for example dimethyl formamide (DMF), N-Methyl pyrrolidone (NMP), dimethyl sulfoxide (DMSO) (DMSO) or N,N-DIMETHYLACETAMIDE (DMA).The alkali that is suitable for the reaction of this class be known in the art those, for example comprise: mineral alkali is salt of wormwood, yellow soda ash, sodium hydride and organic bases hexamethyl two silica-based amido lithiums for example for example.Ground preferably, solvent is that DMF and alkali are salt of wormwood.

Operation steps a) ii)

Usually, be suitable for this reaction and (work as X ³Be F and X ⁴When being OH) condition, as step a) i) as described in.Ground preferably, solvent is that DMF and alkali are hexamethyl two silica-based amido lithiums.

Work as X ³During=Br, this reaction is the Ullman reaction; Reaction of this class and required condition be well known in the art (referring to for example K Kunz, U Scholz, D Ganzer, Synlett, 2003,2428-2439, G Mann, C Incarvito, A L Rheingold ﹠amp; J Hartwig, J.Am.Chem.Soc, 1999,121,3224-3225 and A Aranyos, D W Old, AKiyomori, J P Wolfe, J P Sadighi ﹠amp; S L Buckwald, J.Am.Chem.Soc, 1999,121,4369-4378.

Usually, suitable condition is to use high boiling solvent (toluene for example, 1,4-diox or DMSO), use copper or palladium catalyst, copper for example, copper (I) muriate, copper (I) bromide, copper (I) iodide, copper (II) muriate, copper (II) bromide, copper (II) iodide, copper (II) oxide compound, palladium (II) acetate or dibenzalacetone two palladiums (0), the part (ligand) that is used for catalyzer for example 1,10-phenanthronine, new Tong Shiji, 1, the 3-diketone, racemization-2-(two-t-butylphsophino)-1,1 '-dinaphthalene, 2-(two-t-butylphosphino) biphenyl or 1, two (two-t-butylphosphino) ferrocene of 1`-, and alkali, mineral alkali salt of wormwood for example for example, cesium carbonate and organic bases for example sodium tert-butoxide with Pyrogentisinic Acid's deprotonation.

For example, reaction can be carried out in NMP, uses copper (I) muriate as catalyzer, 2,2,6,6-tetramethyl--3,5-heptadione as part and cesium carbonate as alkali.

Work as X ³=OH and X ⁴When being leavings group, similarly, for example among DMF, NMP, DMSO or the DMA, carry out the substitution reaction of nucleophilicity fragrance in The suitable solvent (being generally aprotic, polar), wherein adopt alkali for example salt of wormwood, yellow soda ash or sodium hydride that phenol is removed is protonated.Suitable X as leavings group ⁴, for example be halogen, methanesulfonates and tosylate.Ground preferably, X ⁴Be halogen, be preferably F.

Operation steps b)

Under the situation of needs, be used for X ¹The suitable condition that is converted into carboxylic acid is:

X ¹Be-CO ₂(1-4C) alkyl: hydrolysis in aqueous acid or alkali;

X ¹Be-CHO: for example adopting, silver (I) oxide compound, sodium wolframate/hydrogen peroxide carry out oxidation;

X ¹Be-CH ₂OP: deprotection (changing condition) and for example adopt that manganese (IV) oxide compound, sodium wolframate/hydrogen peroxide carry out oxidation according to used protecting group and this area general knowledge,

X ¹Be CN: adopt the aqueous solution or the organic solution (for example aqueous hydrochloric acid or aqueous sodium hydroxide solution) of acid or alkali to be hydrolyzed,

X ¹Be trifluoromethyl: strong acid is the vitriol oil for example

X ¹Be methyl: for example adopting, potassium permanganate carries out oxidation

X ¹Be halogen: adopt highly basic (for example n-Butyl Lithium) and carbonic acid gas to carry out carboxylation usually.

Be understandable that can adopt the alternative of above-mentioned exemplary condition well known in the art, selective is.In particular, be those skilled in the art recognize that can be according to compound in substituent characteristic come under the situation of preferred alternative.

Preferably, X ¹=CN and adopt ethanol as solvent makes 10% sodium hydroxide in the water as alkali, reacts.

Be understandable that, can the acid that produce be separated with the form of free acid or with this tart salt form according to used condition.Salt can be directly for this next step use of this method, or adopts condition well known in the art that its conversion (for example transforming on the spot) is become free acid.

Specific salts (the X of formula compound (VIII) ¹Be carboxylic acid), be an alkali metal salt, alkaline earth salt or with the organic bases salt that for example amine became.Specific example is 3-[(1S)-2-tert.-butoxy-1-methyl ethoxy]-5-[4-(methylsulfonyl) phenoxy group] benzoic morpholine and tert-butylamine salt, the tert-butylamine salt of more specifically saying so.

Operation steps C)

Being suitable for carboxylic acid derivative is coupled to the condition of formula V heterocyclic amine derivative, is well known in the art, for example,

(i) adopt suitable coupled reaction, for example, in the presence of Dimethylamino pyridine (4-DMAP) (in The suitable solvent for example among DCM chloroform or the DMF), (3-dimethylamino-propyl-3-ethyl-carbodiimide hydrochloride (EDAC) carries out coupled reaction for carbodiimide and 1-under the room temperature; Perhaps under the room temperature The suitable solvent for example among the THF with N,N'-carbonyldiimidazole (CDI) coupled reaction; Perhaps

(II) The suitable solvent for example DCM in the presence of, add the DMF of catalytic amount where necessary, by with the oxalyl chloride reaction, carboxyl is activated into chloride of acid.Then, in the presence of alkali triethylamine or pyridine, in The suitable solvent for example in DCM or the pyridine, this chloride of acid between 0 ℃-80 ℃ with formula (v) compound reaction.

Be preferred for method C) condition be, at room temperature, the N,N'-carbonyldiimidazole in suitable solvent (CDI).

Protecting group example known in the art (and formation method and last deprotection), referring to T.W.Greene and P.G.M.Wuts, " Protective Groups in OrganicSynthesis ", the third edition, John Wiley ﹠amp; Sons, New York, 1999.

In others of the present invention, provide each step of aforesaid method; Be formula compound (II) to (VI), (II) to (VTI), (VI) to (VIII) and, all provided as an independent aspects of the present invention (VII) to each conversion of (VIII).

In another aspect of this invention, work as X ¹When being CN, step B) comprises that the CN partial hydrolysis is to-CONH ₂Comprise and the halogen-Hete rocyclic derivatives coupling of formula (IX) that and step C then) wherein halogen is suitably chlorine, bromine or iodine; Adopt palladium or nickel catalysis.

In another aspect of this invention, X ²Being hydroxyl and step a) i) employing formula (X) compound carries out:

Wherein, under the situation of X such as its definition in formula (III) compound above and LG be for example halogen, methanesulfonates or tosylate of leavings group.Be understandable that nucleophilic substitution reaction has produced the stereochemistry counter-rotating at the chiral centre of formula (X) compound.Be applicable to the condition of this class reaction, comprise and use for example DMF, NMP, DMSO or DMA and alkali for example salt of wormwood, yellow soda ash or sodium hydride of mineral alkali for example of aprotic, polar inert solvent.About this class SN ₂The general information of reaction can be referring to for example Advanced Organic Chemistry, M B Smith ﹠amp; J March (editor), 2001, the five editions, 10 chapters, the 389th page.

In one aspect of the invention, X ³Be selected from F and OH.On the other hand, X ³Be F.

In one aspect of the invention, formula (II) compound is 3-hydroxyl-5-trifluoromethyl-fluorobenzene.

On the other hand, formula (II) compound is 3-fluoro-5-cyano group-bromobenzene.

On the other hand, formula (II) compound is 3,5-difluoro benzonitrile.

Step a) i on the other hand) a) carrying out before ii); Promptly order as shown in Scheme 4 is (II) → (VI) → (VIII), and is as follows,

On the other hand, step a) is ii) at a) i) carry out before; Promptly order as shown in Scheme 4 is (II) → (VII) → (VIII), and is as follows,

Of the present invention preferred aspect, formula (II) compound is 3,5-difluoro benzonitrile and step a) are ii) at a) i) carry out before.

In others of the present invention, provide the method (shown in the flow process 5) of preparation formula (Ib) compound, described method:

I) difluoro benzonitrile (IIa) obtains formula (VIla) compound with the reaction of 4-methylsulfonyl phenol;

(ii) formula (VIla) compound and formula (IIIa) compound reaction, (R wherein ^1aBe methoxyl methyl, methylol or their protection pattern), obtain formula (VIIIa) compound;

(iii) the hydrolysis nitrile obtains formula (VIIIb); Obtain formula (Ib) compound with the heterocyclic amine reaction;

After this if necessary, then

I) formula (Ib) compound is converted into another kind of formula (Ib) compound;

Ii) at R ^1aBe under the methylol situation of protection pattern, slough protecting group;

Iii) form prodrug; And/or

Iv) form pharmacologically acceptable salt;

Flow process 5

At this respect of the present invention, R ^1aBe methoxyl methyl or tert.-butoxy methyl (for the protection pattern of methylol);

HET-1 is a pyrazolyl, is randomly replaced by (1-4C) alkyl; And/or

Compound (VIIIb) is separated with the form of salt;

In others of the present invention, provide method as shown in Scheme 5, wherein R ^1aBe formula (Ib) compound of methoxyl methyl or tert.-butoxy methyl, subsequent transformation is formula R ^1aIt is (Ib) compound of methylol.

In the embodiment in this respect, (VIIIb) changes into R with the formula compound ^1aBe formula (Ib) compound of methylol, the latter does not isolate wherein R ^1aIt is formula (Ib) midbody compound of methoxyl methyl or tert.-butoxy methyl.

Formula (I) compound is converted into the exemplary method of another kind of formula (I) compound, be well-known to those skilled in the art, comprise: functional group transforms for example hydrolysis, oxidation or reduction reaction mutually, and/or by standard reaction for example acid amides or metal catalytic coupling are further functionalized, perhaps nucleophilic substitution reaction.

Be understandable that, with formula (I) or (Ib) compound be converted into another kind of formula (I) or (Ib) under some condition of compound, perhaps removing the formula of protected pattern (I) or (Ib) in the chemical combination species under the condition of protecting group, can form salt.This salt can be used as final desired compounds, perhaps can pass through methods known in the art as required, is converted into the formula (I) of free form or (Ib) compound, perhaps is converted into the form of another kind of salt.Shown in the following attached embodiment of these class methods.

Be understandable that some intermediate of Miao Shuing itself promptly has the activity of GLK activator herein, constituted another aspect independently of the present invention thus.Will also be appreciated that herein the intermediate of describing may also be to warm-blooded animal people's metabolite of using formula (I) or (Ib) forming in vivo behind the compound for example.

The compounds of this invention can prodrug form use.But being a kind of degradation in vivo, prodrug produces the bioprecursor of The compounds of this invention or pharmaceutically acceptable compound (for example ester of The compounds of this invention or acid amides, especially can at interior hydrolyzable ester).The technology that forms prodrug is known in the art.The example of this class prodrug derivant, referring to:

A) Design of Prodrugs H.Bundgaard edits, (Elsevier, 1985) and Methods in Enzymology, 42 volumes, 309-396 page or leaf, editors such as K.Widder, (Academic Press, 1985;

B) A Textbook of Drug Design and Development, Krogsgaard-Larsen edits;

C) H.Bundgaard, 5 chapters " Design and Application of Prodrugs ', H.Bundgaard edits, 113-191 page or leaf (1991);

d)H.Bundgaard，Advanced?Drug?Delivery?Reviews，8，1-38(1992)；

E) H.Bundgaard etc., Journal of Pharmaceutical Sciences, 77,285 (1988); With

F) N.Kakeya etc., Chem Pharm Bull, 32,692 (1984).

The content of above citing document is hereby incorporated by.

The example of prodrug is as follows.The interior hydrolyzable ester of body that contains the The compounds of this invention of carboxyl or hydroxyl is that for example hydrolysis produces parent acid or pure pharmaceutically acceptable ester in people or animal body.Hydrolyzable becomes the suitable pharmaceutically acceptable ester of carboxyl to comprise: C ₁-C ₆The alkoxy methyl ester is methoxyl methyl for example, C ₁-C ₆Alkyloyl oxygen methyl ester is the pivalyl yloxymethyl for example, phthalidyl ester, C ₃-C ₈Cycloalkyloxy carbonyl oxygen base C ₁-C ₆Alkyl ester is 1-cyclohexyl carbonyl oxygen base ethyl for example; 1,3-dioxole-2-ketone group methyl ester, 5-methyl isophthalic acid for example, 3-dioxole-2-ketone group methyl (onylmethyl); And C _1-6Alkoxyl group carbonyl oxygen base ethyl ester.

Contain hydrolyzable ester in the body of The compounds of this invention of hydroxyl, comprise inorganic ester for example phosphoric acid ester (comprising amino phosphono cyclic ester) and alpha-acyloxy alkyl oxide and related compound, it is ester mirror hydrolysis and decompose the hydroxyl that obtains parent in vivo.The example of alpha-acyloxy alkyl oxide comprises acetoxyl group methoxyl group and 2,2-dimethyl propylene acyloxy-methoxyl group.The ester of hydrolysis formation hydroxyl is selected from vivo: the benzoyl of alkyloyl, benzoyl, phenylacetyl and replacement and phenylacetyl, carbalkoxy (obtaining the alkyl carbonate ester), dialkyl amido formyl and N-(dialkyl amido ethyl)-N-alkyl carbamoyl (obtaining carbamate), dialkyl amido ethanoyl and carboxyl ethanoyl.

The suitable pharmacologically acceptable salt of The compounds of this invention is, acid-the additive salt of basic cpd of the present invention for example, for example with for example inorganic or organic acid, for example spirit of salt, Hydrogen bromide, sulfuric acid, phosphoric acid, trifluoracetic acid, citric acid or toxilic acid, the acid-additive salt of formation.In addition, the suitable pharmacologically acceptable salt of acid benzoxazinone (benzoxazinone) derivative salt of the present invention is an an alkali metal salt, for example sodium or sylvite, alkaline earth salt is calcium or magnesium salts for example, ammonium salt, the perhaps salt that becomes with organic bases (it provides physiology acceptable positively charged ion) is for example with methylamine, dimethylamine, Trimethylamine 99, piperidines, salt that morpholine or three-(2-hydroxyethyl) amine becomes.

In this manual, generic term " alkyl " comprises straight chain and branched-chain alkyl.Yet, consider concrete alkyl for example " propyl group ", only refer in particular to the straight chain pattern; With the concrete branched-chain alkyl tertiary butyl for example, then refer in particular to the side chain pattern.For example, " (1-4C) alkyl " draw together methyl, ethyl, propyl group, sec.-propyl and-butyl.Above-mentioned agreement also is applicable to other generic terms.For fear of causing doubt, contain the group HET-1 of nitrogen in the 2-position, its 2-position is meant for the position of amide nitrogen atom on the group.

The hetero-aromatic ring type HET-1 of the C-of the 5-6 of definition unit connection comprises hereinbefore: thiazolyl, isothiazolyl, thiadiazolyl group, pyridyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, pyrimidyl, oxazolyl, isoxazolyl, oxadiazole base and triazolyl.

Be understandable that HET-2 can be saturated or partly or completely unsaturated ring.

The suitable example of HET-2 comprises: azetidine (azetidinyl), furyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl group, pyridyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, pyrimidyl oxazolyl isoxazolyl oxadiazole base, morpholino, morpholinyl, piperidyl, piperazinyl, morpholinyl, thio-morpholinyl, pyrryl, pyrrolidyl, pyrrolidone-base (pyrrolidonyl), 2,5-dioxy pyrrolidyl, 1,1-dioxy tetrahydro-thienyl, 2-oxygen imidazolidyl (oxoimidazolidinyl), 2,4-dioxy imidazolidyl, 2-oxo-1,3,4-(4-triazoline base), 2-oxazolidine ketone group 2-oxo-tetrahydrofuran, tetrahydrofuran base, THP trtrahydropyranyl, sulphur dioxide is for morpholino (dioxothiomorpholino), 1,3-dioxolane base, 1,2,4 triazolyls 1,2, the 3-triazolyl, pyranyl and 4-pyriconyl.

Be understandable that HET-2 connects by any suitable available C or N atom, therefore for example, HET-2 " imidazolyl " comprises 1-, 2-, 4-and 5-imidazolyl.

The HET-3 saturated or part unsaturated heterocycle type of 4-6 unit is morpholino, piperidyl, piperazinyl, pyrrolidyl and azetidine.

7-unit HET-3 example saturated or part unsaturated heterocycle type is high piperazinyl, high morpholino, (and wherein sulphur is oxidized to SO or S (O) to high-sulfur for morpholino ₂The pattern of group) and homopiperidinyl.

The HET-3 example of 6-10 unit bicyclic heterocycle type is the saturated or part unsaturated heterocycle basic ring of bicyclic, for example the ring of structure as follows (wherein dotted line is represented the tie point with the surplus portion of molecule).

Suitable HET-4 example is furyl, pyrryl, thienyl thiazolyl isothiazolyl, thiadiazolyl group (thiadiazolyl), piperazine base, piperazine base, azoles base, azoles base, pyridine Ji, oxazolyl, isoxazolyl and triazolyl.

Be understandable that under the definition of heterocyclic radical HET-1 to HET-4 comprised that its nitrogen can the situation of substituted hetero-aromatic ring, this class replaces can not produce the lotus quaternary nitrogen atoms.Be understandable that the definition of HET-1 to HET-4 does not comprise any O-O, O-S or S-S key.Be understandable that the definition of HET-1 to HET-4 does not comprise unsettled structure.

(1-4C) example of alkyl comprises methyl, ethyl, propyl group, sec.-propyl butyl and the tertiary butyl; (3-6C) example of cycloalkyl comprises cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; The example of halogen comprises fluorine, chlorine, bromine and iodine; The example of hydroxyl (1-4C) alkyl comprises methylol, 1 hydroxyethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-hydroxyl sec.-propyl and 4-hydroxybutyl; (1-4C) example of alkoxyl group (1-4C) alkyl comprises methoxyl methyl, ethoxymethyl, uncle's fourth oxygen methyl, 2-methoxyethyl, 2-ethoxyethyl, methoxycarbonyl propyl, 2-methoxycarbonyl propyl and methoxy butyl; (1-4C) alkyl S (O) _p(1-4C) example of alkyl comprises methyl sulfinyl methyl, ethyl sulfinyl methyl, ethyl sulfinyl ethyl, methyl sulfinyl propyl group, methyl sulfinyl butyl, sulfonyloxy methyl methyl, ethyl sulfonymethyl, ethyl sulphonyl ethyl, sulfonyloxy methyl propyl group, sulfonyloxy methyl butyl, ethyl thiomethyl, ethyl sulphur ethyl, methyl thiopropyl and methyl sulphur butyl; The example of amino (1-4C) alkyl comprise aminomethyl, aminoethyl, 2-aminopropyl, 3-aminopropyl, the amino sec.-propyl of 1-and 4-ammonia butyl; (1-4C) example of alkylamino (1-4C) alkyl comprise (N-methyl) aminomethyl, (N-ethyl) aminomethyl, 1-((N-methyl) amino) ethyl, 2-((N-methyl) amino) ethyl, (N-ethyl) aminoethyl, (N-methyl) aminopropyl and 4 ((N-methyl) amino) butyl; The example of two (1-4C) alkylamino (1-4C) alkyl comprise dimethylamino methyl methyl (ethyl) aminomethyl, methyl (ethyl) aminoethyl, (N, N-diethyl) aminoethyl, (N, N-dimethyl) aminopropyl and (N, N-dimethyl) ammonia butyl; (1-4C) example of alkylamino comprises methylamino-, ethylamino, Propylamino, isopropylamine base, butylamine base and TERTIARY BUTYL AMINE base; The example of two (1-4C) alkylamino comprises dimethylamino, methyl (ethyl) amino, diethylin, isopropylamine base, diisopropylamino and dibutyl amino;-C (O) (1-4C) alkyl example comprises methyl carbonyl, ethyl carbonyl, propyl group carbonyl and tertiary butyl carbonyl.

In others of the present invention, formula defined above (I) compound is provided, wherein:

R ¹It is methylol; X is methyl or ethyl, preferable methyl;

HET-1 is that pyrazolyl, thiazolyl or thiadiazolyl group and HET-1 are randomly replaced by methyl or ethyl;

R ³Be fluorine or chlorine;

M be 1 and n be 0 or 1;

R ²Be selected from methyl sulphonyl, azetidin alkyl carbonyl, dimethylamino carbonyl, ethylsulfonyl, dimethylamino alkylsulfonyl and pyrrolidyl carbonyl;

Perhaps their salt, prodrug or solvate.

R ¹It is methylol;

X is methyl or ethyl;

R ³Fluorine or chlorine;

M be 1 and n be 0 or 1;

R ²Be selected from azetidin alkyl carbonyl and pyrrolidyl carbonyl;

Perhaps their salt, prodrug or solvate.

In others of the present invention, be provided at formula defined above (I) compound, wherein:

R ¹It is methylol;

X is methyl or ethyl, preferable methyl;

R ³Fluorine or chlorine;

M be 1 and n be 0 or 1;

R ²It is methylsulfonyl;

Perhaps their salt, prodrug or solvate.

In others of the present invention, the compound of formula (I) compound formula (Ia) expression.

Formula (Ia)

Wherein:

R ³Be selected from fluorine, chlorine, C _1-3Alkyl and C _1-3Alkoxyl group;

R ¹Be selected from methyl and methoxyl methyl;

N is 0,1 or 2;

X is a methyl;

Perhaps their salt, prodrug or solvate.

In others of the present invention, provide by the inventive method obtain formula (I) compound.In the specific embodiments in this respect, described formula (I) compound is formula (Ib) compound and is: 3-[(1S)-and 2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl)-5-[4-(methylsulfonyl) phenoxy group] benzamide.In another specific embodiments in this respect, described formula (I) compound is formula (Ib) compound and is: 3-[(1S)-and 2-methoxyl group-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl)-5-[4-(methylsulfonyl) phenoxy group] benzamide.In another specific embodiments in this respect, described formula (I) compound is formula (Ib) compound and is: 3-[(1S)-and 2-tert.-butoxy-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl)-5-[4-(methylsulfonyl) phenoxy group] benzamide.

Be used as the activator of glucokinase (GLK) by the compound of the inventive method preparation.By this activity of test method susceptible of proof known in the art, described method is for example described at our patent application WO03/015774 WO2005/080359 and WO2005/080360.Also referring to Brocklehurst etc., Diabetes 2004,53, the 535-541 page or leaf.

Be understandable that, the method in following examples, the purification process of compound among for example following embodiment only is example explanation and alternative, but not to the qualification of the application's scope.

In following indefiniteness embodiment, unless otherwise stated, otherwise:

(i) evaporate by the rotary evaporation in vacuo method, remove residual solids (for example remove and filter siccative) and carry out aftertreatment afterwards;

(ii) operate in room temperature, promptly in 18-25 ℃ of scope and under rare gas element such as argon gas or nitrogen, carry out;

(iii) the yield of giving only for the usefulness of example explanation, maximum yield not necessarily;

(iv) the structure of end product confirms through nuclear magnetic resonance nmr (being generally H NMR) and mass-spectrometric technique; The chemical displacement value of proton NMR spectrum is that unit measures with δ, adopts the multiplicity at following abbreviation expression peak: s, and is unimodal; D, doublet; T, triplet; M, multiplet; Br, broad peak; Q, quartet; Quin, quintet;

(v) generally without identifying fully, its purity adopts thin-layer chromatography (TLC), high performance liquid chromatography (HPLC), infrared (IR) or NMR to analyze and measures intermediate;

(vi) the Biotage post refers to the pre-silicagel column of loading (40g is to reaching as high as 400g), adopts Biotage pump and flow point collection system wash-out; Biotage UK Ltd, Hertford, Herts, UK.

Shortenings

The DCM methylene dichloride

The DMSO dimethyl sulfoxide (DMSO)

The DMF dimethyl formamide

The HPLC high pressure liquid chromatography

The LCMS liquid chromatography/mass spectrometry

NMR mr (spectroscopy)

CDCl ₃Deuteriochloroform

NaHMDS hexamethyl two silica-based azane sodium

The MTBE methyl tert-butyl ether

The THF tetrahydrofuran (THF)

The TMSI Iodotrimethylsilane

The NMP N-Methyl pyrrolidone

The TFA trifluoroacetic acid

HATU O-(7-azepine benzo triazol-1-yl)-N, N, N`, N`-tetramethyl-ammonium hexafluorophosphate

Embodiment 1: initial by the difluoro benzonitrile

Preparation 3-{[(1S)-1-(methylol) ethyl oxygen base }-N-(1-methyl isophthalic acid H-pyrazole-3-yl)-5-[4-(first Sulphonyl) phenoxy group] benzamide

3-fluoro-5-[4-(methylsulfonyl) phenoxy group] benzonitrile

With 4-methylsulfonyl-phenol (7.6g 44mmol) places dry DMF (61ml) to stir, add Anhydrous potassium carbonate (9.1g, 66mmol), and with mixture heating up to 130 ℃ 1 hour.Add 3, (6.1g 44mmol), stirs and with mixture heating up to 130 ℃ 18 hours 5-two fluoro-benzonitriles.Reaction mixture is cooled to room temperature, adds entry (183ml), isolates the throw out (3.0g) of gained after filtration.(3x122ml) extracts moisture DMF with toluene, and toluene extract water (4x122ml) washing, and solvent removed in vacuo obtain the 5.0g solid matter.This material and previous isolated throw out are merged, and, obtain white solid title product (7.1g, 56% yield) with flash column chromatography purifying (elutriant is 60%n-hexane 40% ethyl acetate).

¹H?NMR(400MHz，CDCl ₃)δ：3.09(s，3H)，7.04(d，1H)，7.13(s，1H)，7.20(m，3H)，8.00(d，2H)

Alternative method:

With 3,5-difluoro benzonitrile (23.23mmol; 3.23g) add in the 100ml round-bottomed flask, (17.42mmol 2.43g), adds extremely dried (extra dry) NMP (15.5ml) and extremely dried DMF (2ml) more then to add Anhydrous potassium carbonate.Temperature rises to 130 ℃, and stirred solution is to the reaction mixture overstrike.With 4-methylsulfonyl phenol (11.61mmol; 2.0g) be dissolved among the NMP (2.5ml), adding through 1 hour syringe pump time spent then, mixture stirred 3 hours in 130 ℃.Reaction mixture is cooled to 60 ℃, adds toluene (20ml), then adds entry (20ml).With two layers of separation, water-based/NMP/DMF layer extracts (20ml) again with toluene.The combining methylbenzene extract washes (3x20ml) with water.4 hours times spent were reduced to 20 ℃ with organic layer by 60 ℃ then, removed precipitation after filtration, toluene distillation filtrate (to about 10ml), 50 ℃ of heating of residual white soup compound.Add isohexane (40ml), 4 hours times spent made temperature reduce to 20 ℃.Isolate product (2.81g after filtration; 82.7% yield)

3-(4-methylsulfonyl-phenoxy group)-5-(2-methoxyl group-1-methyl-oxyethyl group) benzonitrile

(0.63g 3.4mmol) places 50ml round-bottomed flask (through nitrogen purge), adds dry DMF (5ml), and mixture is cooled to 0-5 ℃ with NaHMDS.(mixture slowly is heated to room temperature for 0.31g, 3.4mmol) (heat release), and stirs 30 minutes in this temperature to add 1-methoxy propan-2-ol.With 3-fluoro-5-(4-methylsulfonyl-phenoxy group) benzonitrile (1.0g 3.4mmol) is dissolved in the dry DMF (5ml), and adds in the reaction mixture, then stir the mixture and be heated to 70 ℃ 18 hours.Reaction mixture is cooled to room temperature, adds entry (30ml), uses toluene (3x30ml) extraction mixture then.The combining methylbenzene extract, water (4x30ml) washing, vacuum-evaporation removes and desolvates, obtain the clear and bright oily matter of 1.0g, through flash column chromatography purifying (elutriant is 60%n-hexane 40% ethyl acetate), obtain clear and bright oily title product (0.74g, 60% yield) again.

¹HNMR(400MHz，CDCl ₃)δ：7.95(d，2H)，7.14(d，2H)，7.04(m，1H)，6.90(m，1H)，6.87(m，1H)，4.54(m，1H)，3.53(m，2H)，3.39(s，3H)，3.08(s，3H)，1.32(d，3H)

3-[(1S)-and 2-methoxyl group-1-methyl ethoxy-5-[4-(first semi-annular jade pendant acyl group) phenoxy group] benzonitrile

With NaHMDS (24.5mmol; 4.74g) place the 50ml round-bottomed flask, add dry DMF (32.5ml).Use the nitrogen purging flask, mixture is cooled to 0-5 ℃.Keep temperature to be lower than 6 ℃, 5 minutes times spent added S-1-methoxy propan-2-ol (22.31mmol; 2.01g).Mixture remain on 0-5 ℃ 25 minutes, 35 minutes times spent slowly were heated to room temperature then.

With 3-fluoro-5-(4-methylsulfonyl-phenoxy group)-benzonitrile (22.31mmol; 6.50g) be dissolved in the dry DMF (32.5ml), add to then in the anionic flask that contains S-1-methoxy propan-2-ol.Mixture heating up to 70 ℃, and remain on 70 ℃ 18 hours.Add entry (20ml), add the solid that capacity toluene is separated out with dissolving then.(3x100ml) further extracts mixture with toluene, and the toluene extract of merging washes (3x200ml) with water.The vacuum distilling toluene layer adds isohexane (50ml).Leach the throw out of required product, with isohexane washing (2x25ml), and in vacuum drying oven 40 ℃ of dried overnight (6.0g, 74.4% yield).

3-(4-methylsulfonyl-phenoxy group)-5-(2-methoxyl group-1-methyl-oxyethyl group) phenylformic acid

(0.1g 0.27mmol) is dissolved in the ethanol (1.0ml), then adds in the 5ml round-bottomed flask of being furnished with condenser with 3-(4-methylsulfonyl-phenoxy group)-5-(2-methoxyl group-1-methyl-oxyethyl group) benzonitrile.Add entry (0.2ml, 11.1mmol), then add sodium hydroxide (in the 18.9M water, 0.2ml, 3.78mmol).Reaction mixture was heated to reflux temperature 18 hours.Reaction mixture is cooled to room temperature, and vacuum evaporating solvent is dispensed among water (10ml) and the MTBE (10ml) through residue, and separating layer.(2.5ml 5mmol) is acidified to pH=1 to the HCl of water usefulness 2M, adds MTBE (10ml) extraction product.The MTBE extract is through MgSO ₄Drying, vacuum-evaporation obtains the title compound (0.1g, 100% yield) of white solid then.

¹HNMR(400MHz，CDCl ₃)δ：7.92(d，2H)，7.51(m，1H)，7.35(m，1H)，7.12(d，2H)，6.90(m，1H)，4.63(m，1H)，3.57(m，2H)，3.42(s，3H)，3.08(s，3H)，1.33(d，3H)。

3-[(1S)-2-methoxyl group-1-methyl ethoxy]-5-[4-(first semi-annular jade pendant acyl group) phenoxy group] phenylformic acid

With 3-[(1S)-2-methoxyl group-1-methyl ethoxy]-5-[4-(first semi-annular jade pendant acyl group) phenoxy group] (0.1g 0.27mmol) is dissolved in the ethanol (1.0ml) benzonitrile, then adds in the 5ml round-bottomed flask of being furnished with condenser and magnetic stirring apparatus.Add entry (0.2ml, 11.1mmol), then add 18.9M sodium hydroxide (in the water, 0.2ml, 3.78mmol).Reaction mixture was heated to reflux temperature 18 hours.Reaction mixture is cooled to room temperature, and vacuum evaporating solvent is dispensed among water (10ml) and the MTBE (10ml) through residue, and separating layer.(2.5ml 5mmol) is acidified to pH=1 to the HCl of water usefulness 2M, adds MTBE (10ml) extraction product.The MTBE extract is through MgSO ₄Drying, vacuum-evaporation obtains faint yellow oily thing (0.1g, 100% yield) then.

3-[(1S)-2-methoxyl group-1-methyl ethoxy-N-(1-methyl isophthalic acid H-pyrazole-3-yl)-5-[4-(methylsulfonyl) Phenoxy group] benzamide

With diisopropylethylamine (2.5 equivalent); be incorporated in 3-{ (1S)-2-methoxyl group-(1-methylethyl) the oxygen base among the DMF (20ml) }-5-{[4-(first semi-annular jade pendant acyl group) phenyl] the oxygen base } phenylformic acid (2.0g; 5.25mmol), O-(7-azepine benzo triazol-1-yl)-N; N; N`, N`-tetramethyl-ammonium hexafluorophosphate (HATU, 2.5g; 6.6mmol) and 1-methyl isophthalic acid H-pyrazoles-3-amine (0.64g is in suspension 6.6mmol).Initial suspension is dissolved into dark orange solution.The gained mixture stirred 2 hours in envrionment temperature.Vacuum is removed DMF, residue and methylbenzene azeotropic.Add entry, use the ethyl acetate extraction mixture.Merge extract, with 1M hydrochloric acid, saturated sodium bicarbonate solution and the washing of salt solution (brine) order.Solution drying (MgSO ₄), filtration, vacuum-evaporation, obtain crude product, obtain required product (25% yield) through chromatographic separation (50% ethyl acetate in the isohexane) again, and reclaim initiator.

¹H?NMR(300MHz，d ₆-DMSO)δ：1.2(d，3H)，3.2(s，3H)，3.25(s，3H)，3.5(m，2H)，3.8(s，3H)，4.75(m，1H)，6.55(s，1H)，6.9(s，1H)，7.2(d，2H)，7.3(s，1H)，7.45(s，1H)，7.6(s，1H)，7.9(d，2H)，10.85(br?s，1H)

m/z：460(M+H) ⁺

3-[(1S)-2-hydroxyl-1-methyl ethoxy-N-(1-methyl isophthalic acid H-pyrazole-3-yl)-5-[4-(methylsulfonyl) benzene The oxygen base] benzamide

Under nitrogen atmosphere, with Iodotrimethylsilane (11.06ml, 76.25mmol) add 3-[(1S)-2-methoxyl group-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl)-5-[4-(methylsulfonyl) phenoxy group] benzamide (7.00g, in anhydrous acetonitrile 15.25mmol) (100ml) solution 21 hours.Add (40ml) cancellation reaction, vacuum is removed acetonitrile.Residue separates organic layer with ethyl acetate (200ml) and the dilution of 1M water-based hydrochloric acid, further washs to remove residual iodine with 10%w/v water-based five water Sulfothiorine.Organic layer drying (MgSO ₄), filtration, vacuum-evaporation, separate (3%-5% methyl alcohol: the methylene dichloride wash-out), obtain the title compound (5.70g, 84%) of white foam shape through column chromatography again.Through hot ethanol (125mg/ml) recrystallization, obtain colourless acicular title compound (87% rate of recovery);

¹HNMR(300MHz，CDCl ₃)δ：1.33(d，3H)，2.10(t，1H)，3.08(s，3H)，3.78(m，2H)，3.82(s，3H)，4.57(m，1H)，6.80(m，2H)，7.15(m，3H)，7.25(m，2H)，7.93(d，2H)，8.43(s，1H)；m/z?444(M-H) ^-

Embodiment 2:

This embodiment example has illustrated the preparation of formula (VIII) compound.

3-(3,5-two fluorophenoxies)-5-(2-methoxyl group-1-methyl ethoxy) phenylformic acid

With 3-(3,5-two fluorophenoxies)-5-(2-methoxyl group-1-methyl ethoxy) benzonitrile (1.00 equivalents; 9.40mmol; 3.00g) insert and contain ethanol (515mmol; 30.0ml; 23.7g) the low flask of 100ml circle in (being furnished with 1 neck, condenser, magnetic stirring apparatus).Add entry (138mmol; 2.49ml; 2.49g), then add sodium hydroxide (in water, 18.9M, 47.0mmol; 2.49ml; 3.75g), with mixture heating up to refluxing (90 ℃ of bath temperatures) 4 hours.Cooling mixture, solvent removed in vacuo obtains colourless solution (do not eliminate and anhydrate).Mixture is dispensed among water (50ml) and the MTBE (50ml), and separating layer (water layer pH=14).Water is with HCl solution (2M, aq, 50ml) acidifying, and extract with MTBE (50ml).Organic layer drying (MgSO ₄), filter, and vacuum-evaporation falls volatile matter, obtains 3-(3,5-two fluorophenoxies)-5-(2-methoxyl group-1-methyl ethoxy) phenylformic acid (3.15g, 99%) of colorless oil.

¹HNMR(400MHz，CDCl ₃)δ：7.49(m，1H)，7.34(m，1H)，6.87(m，1H)，6.54(m，3H)，4.62(m，1H)，3.57(m，2H)，3.42(s，3H)，1.34(d，3H)。

3-(3,5-two fluorophenoxies)-5-(2-methoxyl group-1-methyl ethoxy) benzonitrile

With 3,5-difluorophenol (2.00 equivalents; 51.8mmol; 6.74g) insert in the low flask of 100ml circle (being furnished with 3 necks, 2 valves, the atmospheric condenser that has the argon inlet mouth, magnetic stirring apparatus, oven dry), then add NMP (471mmol; 45.3ml; 46.7g) and cesium carbonate (51.8mmol; 16.9g).Mixture is used argon purge 10 minutes, and order adds cuprous chloride (6.48mmol then; 641mg), 2,2,6,6 tetramethyl-s-3,5-heptadione (1.30mmol; 271 μ l; 239mg) with 3-bromo-5-(2-methoxyl group-1-methyl ethoxy) benzonitrile (1.00 equivalents; 25.9mmol; 7.00g).Mixture is with argon purge 5 minutes, is heated to 120 ℃ and stirred 24 hours then.Reaction mixture, and (1M, water-based is 200ml) and among the MTBE (200ml) to be allocated in HCl solution.And separating layer, organic layer with NaOH solution (1M, aq, 200ml), water (200ml) and salt solution (200ml) washs.The organic layer that obtains is through MgSO ₄Dry, filter, and vacuum-evaporation falls solvent, obtains brown oil.Separate through flash column chromatography again, obtain 3-(3,5-two fluorophenoxies)-5-(2-methoxyl group-1-methyl ethoxy) benzonitrile (5.17g, 63%) of faint yellow oily.

¹HNMR(400MHz，CDCl ₃)δ：7.01(s，1H)，6.86(m，2H)，6.62(m，1H)，6.53(m，2H)，4.54(m，1H)，3.53(m，2H)，3.39(s，3H)，1.32(d，3H)。

3-bromo-5-(2-methoxyl group-1-methyl ethoxy) benzonitrile

With NaHMDS (148mmol; 27.2g) insert in the low flask of 100ml circle (be furnished with 4 necks, thermometer, all press dropping funnel, valve, nitrogen inlet mouth, magnetic stirring apparatus, oven dry, nitrogen to purge), then add DMF (300ml).Mixture stirred 5 minutes, and 10 minutes times spent dripped 1-methoxyl group-2-propyl alcohol (1.50 equivalents then; 148mmol; 14.3ml; 13.4g).Temperature of reaction is increased to 25 ℃.With cooling bath mixture is cooled to 23 ℃, 5 minutes times spent were added in the 3-bromo-5-fluorobenzonitrile (1.00equiv among the DMF (90ml) then; 99.0mmol; 20.0g) (maintenance cooling bath).Between charge period, mixture heating up to 27 ℃, color becomes brown by redness.Add DMF (10ml) and do linear washing (line wash).Mixture stirred 30 minutes in envrionment temperature, add then HCl solution (2M, water-based, 200ml) cancellation, dun reaction mixture becomes faint yellow.With in the mixture impouring water (400ml), and extract with EtOAC (3x400ml).Merge organic extract, with (3x400ml) water washing, through MgSO ₄Dry, filter, and vacuum-evaporation falls solvent, obtains orange buttery 3-bromo-5-(2-methoxyl group-1-methyl ethoxy) benzonitrile (25.38g, 95%).

¹HNMR(400MHz，CDCl ₃)δ：7.32(s，1H)，7.26(s，1H)，7.11(s，1H)，4.58-4.55(m，1H)，3.59-3.48(m，2H)，3.41(s，3H)，1.33-1.31(d，3H)。

Embodiment 3:

Synthetic route

3-[(1S)-uncle 2--butoxy-1-methyl ethoxy]-5-[4-(methylsulfonyl) phenoxy group] benzonitrile

In the low flask (100ml is furnished with condenser, partition, thermometer and magnetic probe) of 3-neck circle, and the adding sodium hydride (32.96mmol, 1.32g).Flask places under the inert atmosphere, and is added with anhydrous NMP (80ml).In the suspension of gained, add (S)-1-tert.-butoxy-2-propyl alcohol (30.21mmol, 3.99g; Five equilibrium with 0.2ml adds, and controlled temperature is with control H ₂Generation).In case gas stops, then with 3-fluoro-5-(4-sulfonyloxy methyl-phenoxy group] (referring to embodiment 1,27.46mmol 8.0g) once adds benzonitrile.Reaction mixture be heated to 70 ℃ 3 hours.Reaction is cooled to room temperature, adds toluene (240ml), then adds entry (240ml).Content moves in the separating funnel then in stirring at room 30 minutes.Isolate 2 layers, water layer is further used toluene (240ml) extraction.Merge organic extract, (160mmol, 160ml) washing once then washes (4x160ml) with water with sodium hydroxide.Vacuum is removed toluene, obtains slow solidified oily matter (9.20g; 83.02% yield).

¹HNMR(400MHz，d-6DMSO)δ：7.92(d，2H)7.33(s，1H)；7.23(d，2H)；7.19(s，1H)；7.07(t，1H)；4.62(m，1H)；3.44(m，2H)；3.19(s，3H)；1.21(d，3H)；1.07(s，9H)。

3-[(1S)-uncle 2--butoxy-1-methyl ethoxy]-5-[4-(methylsulfonyl) phenoxy group] benzyl formic acid

With 3-[(1S)-uncle 2--butoxy-1-methyl ethoxy-5-[4-(methylsulfonyl) phenoxy group] benzonitrile (23.7mmol; 9.56g) be dissolved in the ethanol (95.60ml), and move in the 250ml round-bottomed flask, (5ml) washes out the residual solids in the flask with ethanol.Add entry (6.25ml) and sodium hydroxide (118.5mmol; 6.30ml), say that then reaction is heated to backflow 18 hours.Vacuum is removed ethanol.Residual yellow suspension is dissolved in MTBE (162.5ml) and the water (162.5ml).Separate two layers, discard the MTBE layer, water layer 2M HCl (100ml) acidifying.Water layer extracts 2 times with MTBE (162.5ml).Merge organic extract, through MgSO ₄Drying, vacuum is removed MTBE, obtains required product (7.0g, 69.9% yield).

¹HNMR(400MHz，d-6DMSO)δ：7.92(d，2H)，7.32(s，1H)，7.21(d，2H)，7.10(s，1H)，7.00(t，1H)，4.53(m，1H)，3.42(m，2H)，3.19(s，3H)，1.22(d，3H)，1.09(s，9H)。

(3-[(1S)-uncle 2--butoxy-1-methyl ethoxy]-5-[4-(methylsulfonyl) phenoxy group] benzoyl } oxygen Base) (tert-butyl) ammonium

(0.31L 2.94mol) is added in the reactor that contains MTBE (2.27L), preparation TERTIARY BUTYL AMINE solution with TERTIARY BUTYL AMINE.Solution stirs in envrionment temperature, and be added to contain 3-[(1S)-uncle 2--butoxy-1-methyl ethoxy]-5-[4-(methylsulfonyl) phenoxy group] (1.13Kg is 267mol) and in another reactor of MTBE (2.54L) for benzyl formic acid.It is 20-30 ℃ that reinforced process keeps temperature, with the TERTIARY BUTYL AMINE of MTBE (0.57L) wash residual.Under nitrogen environment, with reaction mixture be heated to 38-40 ℃ 3 hours.Last 1-2 hour reaction mixture is cooled to 18-25 ℃, and keep this temperature to crystallization to take place.Filter to isolate product, with MTBE (2.28L) washing 2 times, vacuum drying oven 38-40 ℃ drying.Obtain title compound (1.32Kg, 100% yield).

¹HNMR (400MHz, d-6DMSO) δ: 7.86 (d, 2H), 7.47 (s, 1H), 7.26 (s, 1H), 7.08 (d, 2H), 6.74 (t, 1H), 4.45 (sextet, 1H), 3.56 (dd, 1H), 3.37 (dd, 1H), 3.04 (s, 3H), 1.30 (d, 3H), 1.25 (s, 9H), 1.16 (s, 9H).

(7.35g 38.25mmol) in water-soluble (100mL), obtains citric acid solution with citric acid.Aqueous citric acid solution be added to contain ({ 3-[(1S)-uncle 2--butoxy-1-methyl ethoxy]-5-[4-(methylsulfonyl) phenoxy group] benzoyl } the oxygen base) (10g, 94.6%w/w is 19.13mmol) and in the reactor of MTBE (80mL) for (tert-butyl) ammonium.This biphasic mixture stirred 30 minutes in envrionment temperature.Separate two-phase, water extracts with MTBE (80mL).Merge two organic phases, with salt solution (3x80mL) washing 3 times, then water (2x80mL) washing.Merge the MTBE extract, be distilled to small volume, add fresh MTBE (80mL), then with mixture distillation to small volume.Add acetonitrile (120mL), then mixture is distilled to small volume in 50 ℃, 209mbar.The repetition azeotropic is operated, and obtains the anhydrous acetonitrile of title compound, and it directly uses for next step.

¹HNMR (400MHz, CDCl ₃) δ: 7.91 (d, 2H), 7.54 (s, 1H), 7.33 (s, 1H), 7.12 (d, 2H), 6.91 (t, 1H), 4.53 (sextet, 1H), 3.58 (dd, 1H), 3.43 (dd, 1H), 3.07 (s, 3H), 1.34 (d, 3H), 1.19 (s, 9H)

3-[(1S)-uncle 2--butoxy-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl]-5-[4-(first Sulphonyl) phenoxy group] benzamide

In the low flask (being furnished with condenser, nitrogen pipeline, magnetic stirrer, thermometer and partition) of the 25ml of 3-neck circle, add 1,1`-N,N'-carbonyldiimidazole (CDI) (7.44mmol, 1.21g).Flask places under the inert atmosphere, and be added with THF (160.9mmol, 13.1ml).With 3-[(1S)-uncle 2--butoxy-1-methyl ethoxy]-5-[4-(methylsulfonyl) phenoxy group] (6.20mmol 2.62g) is dissolved among the THF (10.48ml) benzyl formic acid, lasts 5 minutes then and adds in the flask with branches such as 2ml, then with THF (5ml) flushing.Solution was in stirring at room 1 hour.Temperature of reaction rises to 60 ℃, will be dissolved in the amino 1-methylpyrazole of the 3-(6.82mmol in the toluene (13.1ml); 662.2ml) once add in the reaction, and then wash with toluene (4ml).React on 60 ℃ of heating 18 hours.Solvent removed in vacuo stays thick yellow oil, and (1M 50ml), separates two layers, and (1M, 20ml) washing is then with HCl (2M, 30ml) washing with sodium hydroxide for organic layer to add MTBE (100ml) and sodium hydroxide.Organic collection layer is through MgSO ₄Drying, solvent removed in vacuo obtains thick yellow oil.Take a morsel and separate (elutriant 80% Iso Butyl Acetate: 20% isohexane), obtain required product through flash column chromatography.

¹HNMR(400MHz，d-6DMSO)δ：10.89(s，1H)，7.96-7.92(m，2H)，7.60(d，1H)，7.50(s，1H)，7.29(s，1H)，7.27-7.21(m，2H)，6.91(t，1H)，6.56(d，1H)，4.64-4.54(m，1H)，3.78(s，3H)，3.60-3.46(m，2H)，3.21(s，3H)，1.24(d，3H)。

Alternative method:

Add acetonitrile (250mL) in the 1L-exsiccant jacketed vessel under nitrogen atmosphere.Carry out overhead stirring, disease is heated to 25 ℃ with reaction.In case the reaction reach required temperature, promptly in reactor, add CDI (149.11mmol, 24.18g).Then, 90 minutes times spent, constant speed is added in 3-[(1S in the acetonitrile in reaction)-uncle 2--butoxy-1-methyl ethoxy]-5-[4-(methylsulfonyl) phenoxy group] the 39.8%w/w solution of benzyl formic acid.Behind the liquid feeding, then add acetonitrile (50mL) and carry out linear washing.Gained solution in 25 ℃ stir 30/.

Then, temperature of reaction is risen to 60 ℃, (117.51mmol 17.24g) once adds in the reaction, and then carries out linear washing with acetonitrile (504ml) will to be dissolved in the amino 1-methylpyrazole of 3-in the acetonitrile (50ml).React on 60 ℃ of heating 18 hours.This solution of HPLC analysis revealed contains the enamine product of 11.71%w/w.The yield of this expression title compound is 91% (53.78g; 100.72mmol).Need not separated product, this solution can directly use for following reaction.

¹HNMR(400MHz，d-6DMSO)10.89(s，1H，NH)，7.96-7.92(m，2H)，7.60(d，1H)，7.50(m，1H)，7.30(m，1H)，7.26-7.22(m，2H)，6.91(t，1H)，6.56(d，1H)，4.70-4.62(m，1H)，3.78(s，3H)，3.60-3.46(m，2H)，3.21(s，3H)，1.25(d，3H)。

3-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl]-5-[4-(methylsulfonyl) Phenoxy group] benzamide

In the 25ml round-bottomed flask, once add the 3-[(1S that is dissolved in methyl alcohol (4ml) and HCl (4ml))-uncle 2--butoxy-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl]-5-[4-(methylsulfonyl) phenoxy group] and benzamide (498.4 μ mol, 250.0mg).React 50 ℃ of heating 1.5 hours.Solvent removed in vacuo obtains colorless solid (becoming liquid in the placement fast).This liquid is dissolved in ¹PrOAC (10ml) and (10ml) in the water.Water layer is used again ¹PrOAC (10ml) extraction.Merge organic layer, through MgSO ₄Drying, solvent removed in vacuo obtains the title product crude product (142mg of white foam; 63.95% yield).

Sampling (110mg) is dissolved in the ethanol (0.5ml), and reflux.Solution is cooled to room temperature, adds one little spoon of product so that the seed of recrystallization to be provided in 45-50 ℃.Stir after several days, filter to isolate the recrystallization solid, obtain the required product (50mg, 45% yield) of crystalline solid shape.

¹HNMR(400MHz，d-6DMSO)δ：10.89(s，1H)，7.97-7.92(m，2H)，7.60(d，1H)，7.50(s，1H)，7.30(s，1H)，7.27-7.22(m，2H)，6.91(t，1H)，6.57(d，1H)，4.88(t，1H)，4.63-4.55(m，1H)，3.77(s，3H)，3.60-3.52(m，1H)，3.21(s，3H)31.24(d，3H)。

Alternative method:

3-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl]-5-[4-(methylsulfonyl) Phenoxy group] the benzamide hydrochloride

In jacketed vessel, add 3-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl]-5-[4-(methylsulfonyl) phenoxy group] benzamide solution (456.32g, the 11.41%w/w solution in acetonitrile; 103.80mmol).Stirred mixture is heated to 93 ℃-101 ℃ (bushing temperatures), and normal atmosphere distills down to remove and desolvates, to collecting the 370mL overhead product.Then, cooling mixture (30 ℃ of bushing temperatures) adds MTBE (500mL) and forms muddy mixture.Bushing temperature is made as 20 ℃, adds water-based spirit of salt (the 2.10M solution of 250mL) when mixture temperature reaches 23.6 ℃.Mixture stirred 10 minutes, separated then.Organic layer above water (250mL) washing separates layer.Heating organic layer (bushing temperature is 68 ℃), normal atmosphere distill down to remove and desolvate, to collecting the 440mL overhead product.Then, add Virahol (300mL) in the compound in reactor.Bushing temperature is made as 95 ℃, and normal atmosphere distills down to remove and desolvates, to collecting the 250mL overhead product.Mixture is cooled to 20-21 ℃, and the adding hydrogen chloride solution (in Virahol, 5.52M, 616mL).40 minutes times spent are with mixture heating up to 50 ℃.Mixture kept 70 minutes in 50 ℃ again, added 3-[(1S then)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl]-5-[4-(methylsulfonyl) phenoxy group] seed of benzamide (66mg).Mixture restir 15 minutes, and then seed addition (53mg).According to default cooling curve (ramp), 400 minutes times spent were cooled to 15 ℃ with mixture.After initial 40 minutes, product begins crystallization about cooling curve.At the initial back of cooling curve stir about hour, filter then and collect the crystalline product.The solid of collecting washs with MTBE (150mL).Blot product with filter paper, and then, obtain title compound (40.52g in about 18 hours of 45 ℃ of vacuum-dryings; The HPLC purity assay is 94.22%w/w (being 73.4% yield after calibrated)).

¹HNMR(400MHz，d-6DMSO)δ10.90(s，1H)，7.97-7.91(m，2H)，7.60(d，1H)，7.50(s，1H)，7.30(s，1H)，7.27-7.22(m，2H)，6.91(t，1H)，6.56(d，1H)，5.52(br?s)，4.64-4.55(m，1H)，3.77(s，3H)，3.61-3.45(m，2H)，3.21(s，3H)，1.24(d，3H)。

With 3-[(1S)-2-hydroxyl-1-methyl ethoxy]-N-(1-methyl isophthalic acid H-pyrazole-3-yl]-5-[4-(methylsulfonyl) phenoxy group] the benzamide hydrochloride (2907.8g, 6.03mol) and ethyl acetate (30L) add in the reactor, obtain thick emulsus slurry.Add saturated sodium bicarbonate water solution (7.3L) in reaction, 15 minutes times spent took place with pilot-gas at least.Mixture stirred 30 minutes at least, obtained clear and bright solution up to the solid dissolving.Discard water, organic phase water (14.6L) washing, and filter (screen) in crystallisation vessel.Reaction mixture is through the distillation azeotropic drying; Ethyl acetate solution is distilled to 14.5L by 31.0L, adds fresh ethyl (14.5L) distillation again again, in reactor, stay the 14.5L ethyl acetate.With-0.4 ℃/minute speed, reaction mixture is cooled to 45 ℃, keep then 45 ℃ 18 hours.The reaction mixture knot is planted, and about 1 hour of time spent added MTBE (29L) in reaction mixture, and keeping temperature of reaction is 45 ℃; Then, mixture stirred 3 hours in this temperature, and the speed of following with-0.4 ℃/minute is cooled to 20 ℃.Mixture was in 20 ℃ of maintenances 18 hours, and the filtering separation product is used MTBE (6.0L) washing then, and in 40 ℃ of dryings of vacuum drying oven.Promptly obtain 2216g title product (82% yield).

¹HNMR (400MHz, d-6DMSO) δ 10.86 (s, 1H), 7.91 (d, 2H), 7.56 (d, 1H), 7.47 (s, 1H), 7.26 (s, 1H), 7.20 (d, 2H), 6.88 (t, 1H), 6.53 (d, 1H), 4.85 (t, 1H), 4.55 (sextets, 1H), 3.73 (s, 3H), 3.57-3.42 (m, 2H), 3.17 (s, 3H), 1.20 (d, 3H)

¹³C?NMR(100MHz，d-6DMSO)δ162.98，160.80，159.46，155.85，146.78，136.76，135.15，130.89，129.59，118.19，111.07，110.91，110.79，97.41，75.09，64.08，43.74，38.29，16.38。

Reference:

1.Printz, R.L., Magnuson, M.A. and Granner, D.K. (1993) AnnualReview of Nutrition 13,463-96

2.DeFronzo，R.A.(1988)Diabetes?37，667-87

3.Froguel, P., Zouali, H., Vionnet, N., Velho, G., Vaxillaire, M., Sun, F., Lesage, S., Stoffel, M., Takeda, J. and Passa, P. (1993) NewEngland Journal of Medicine 328,697-702

4.Bell, G.I., Pilkis, S.J., Weber, I.T. and Polonsky, K.S. (1996) Annual Review of Physiology 58,171-86

5.Velho, G., Petersen, K.F., Perseghin, G., Hwang, J.H., Rothman, D.L., Pueyo, M.E., Cline, G.W., Froguel, P. and Shulman, G.I. (1996) Journal of Clinical Investigation 98,1755-61

6.Christesen, H.B., Jacobsen, B.B., Odili, S., Buettger, C, Cuesta-Munoz, A., Hansen, T., Brasgaard, K., Massa, O., Magnuson, M.A., Shiota, C, Matschinsky, F.[0288] M. and Barbetti, F. (2002) Diabetes 51,1240-6

6a.Gloyn, A.L., Noordam, K., Willemsen, M.A.A.P., Ellard, S., Lam, W.W.K., Campbell, I.W., Midgley, P., Shiota, C, Buettger, C, Magnuson, M.A., Matschinsky, F.M., and Hattersley, A.T.; Diabetes52:2433-2440

7.Glaser, B., Kesavan, P., Heyman, M., Davis, E., Cuesta, A., Buchs, A., Stanley, C.A., Thornton, P.S., Permutt, M.A., Matschinsky, F.M. and Herold, K.C. (1998) New England Journal ofMedicine 338,226-30

8.Caro, J.F., Triester, S., Patel, V.K., Tapscott, E.B., Frazier, N.L. and Dohm, G.L. (1995) Hormone ﹠amp; Metabolic Research 27,19-22

9Desai, U.J., Slosberg, E.D., Boettcher, B.R., Caplan, S.L., Fanelli, B., Stephan, Z., Gunther, V.J., Kaleko, M. and Connelly, S. (2001) Diabetes 50,2287-95

10.Shiota, M., Postic, C, Fujimoto, Y., Jetton, T.L., Dixon, K., Pan, D., Grimsby, J., Grippo, J.F., Magnuson, M.A. and Cherrington, A.D. (2001) Diabetes 50,622-9

11.Ferre, T., Pujol, A., Riu, E., Bosch, F. and Valera, A. (1996) Proceedings of the National Academy of Sciences of the United Statesof America 93,7225-30

12.Seoane, J., Barbera, A., Telemaque-Potts, S., Newgard, C.B. and Guinovart, J.J. (1999) Journal of Biological Chemistry 274,31833-8

13.Moore, M.C, Davis, S.N., Mann, S.L. and Cherrington, A.D. (2001) Diabetes Care 24,1882-7

14.Alvarez, E., Roncero, L, Chowen, J.A., Vazquez, P. and Blazquez, E. (2002) Journal of Neurochemistry 80,45-53

15.Lynch, R.M., Tompkins, L.S., Brooks, H.L., Dunn-Meynell, A.A. and Levin, B.E. (2000) Diabetes 49,693-700

16.Roncero, L, Alvarez, E., Vazquez, P. and Blazquez, E. (2000) Journal of Neurochemistry 74,1848-57

17.Yang, X.J., Kow, L.M., Funabashi, T. and Mobbs, C.V. (1999) Diabetes 48,1763-1772

18.Schuit, F.C, Huypens, P., Heimberg, H. and Pipeleers, D.G. (2001) Diabetes 50,1-11

19.Levin, B.E. (2001) International Journal of Obesity 25, supplementary issue 5, S68-S72.

20.Alvarez, E., Roncero, L, Chowen, J.A., Thorens, B. and Blazquez, E. (1996) Journal of Neurochemistry 66,920-7

21.Mobbs, C.V., Kow, L.M. and Yang, X.J. (2001) AmericanJournal of Physiology-Endocrinology ﹠amp; Metabolism 281, E649-54

22.Levin, B.E., Dunn-Meynell, A.A. and Routh, V.H. (1999) American Journal of Physiology 276, Rl223-31

23.Spanswic k, D., Smith, M.A., Groppi, V.E., Logan, S.D. and Ashford, M.L. (1997) Nature 390,521-5

24.Spanswick, D., Smith, M.A., Mirshamsi, S., Routh, V.H. and Ashford, M.L. (2000) Nature Neuroscience 3,757-8

25.Levin, B.E. and Dunn-Meynell, A.A. (1997) Brain Research776,146-53

26.Levin, B.E., Gove k, E.K. and Dunn-Meynell, A.A. (1998) BrainResearch 808,317-9

27.Levin, B.E., Brown, K.L. and Dunn-Meynell, A.A. (1996) BrainResearch 739,293-300

28.Rowe, I.C, Boden, P.R. and Ashford, M.L. (1996) Journal ofPhysiology 497,365-77

29.Fujimoto, K., Sakata, T., Arase, K., Kurata, K., Okabe, Y. and Shiraishi, T. (1985) Life Sciences 37,2475-82

30.Kurata, K., Fujimoto, K. and Sakata, T. (1989) Metabolism:Clinical ﹠amp; Experimental 38,46-51

31.Kurata, K., Fujimoto, K., Sakata, T., Etou, H. and Fukagawa, K. (1986) Physiology ﹠amp; Behavior 37,615-20

32.Jetton T.L., Liang Y., Pettepher CC, Zimmerman E.C, CoxF.G., Horvath K., Matschinsky F.M. and Magnuson M.A., J.Biol.Chem., Feb 1994; 269:3641-3654.

33.Reimann F. and Gribble F.M., Diabetes 2002 51:2757-2763

34.Cheung A.T., Dayanandan B., Lewis J.T., Korbutt G.S., Rajotte R.V., Bryer-Ash M., Boylan M.O., Wolfe M.M., Kieffer T.J., Science, the 290th volume, 5498 phases, 1959-1962,8.12 months 2000.

Claims

1. the method that is used for preparation formula (Ib) compound or pharmaceutically acceptable salt thereof, wherein R ^1aBe methylol, HET-1 is a pyrazolyl, is randomly replaced by (1-4C) alkyl, and described method comprises:

(i) difluoro benzonitrile (IIa) and 4-methylsulfonyl phenol reactant obtain formula (VIIa) compound;

(ii) formula (VIIa) compound and formula (IIIa) compound reaction, wherein R ^1aBe methylol or its shielded form, obtain formula (VIIIa) compound;

(iii) the described nitrile of hydrolysis obtains formula (VIIIb) compound; Obtain formula (Ib) compound with the heterocyclic amine reaction;

(iv) at R ^1aBe under the situation of methylol of protected form, slough protecting group; And randomly

(v) form pharmacologically acceptable salt;

2. the described method of claim 1, the R in its Chinese style (VIIIa) ^1aBe methoxyl methyl or tert.-butoxy methyl.

3. the described method of claim 1, wherein compound (VIIIb) is separated with the form of salt.

4. the described method of claim 2 changes into wherein R with formula (VIIIb) compound ^1aBe formula (Ib) compound of methylol, need not separate wherein R ^1aIt is formula (Ib) midbody compound of methoxyl methyl or tert.-butoxy methyl.