CN101426793A

CN101426793A - Methods for the preparation of hcv polymerase inhibitors

Info

Publication number: CN101426793A
Application number: CNA2006800310868A
Authority: CN
Inventors: 克里斯托弗·弗雷德里克·马修斯; 罗伯特·威廉·斯科特; 约翰·礼罗德·塔克
Original assignee: Pfizer Inc
Current assignee: Pfizer Inc
Priority date: 2005-08-24
Filing date: 2006-08-16
Publication date: 2009-05-06
Also published as: ZA200800821B

Abstract

The present invention relates to methods and compounds useful in the preparation of compounds of the formula (I).

Description

Be used to prepare the method for HCV AG14361

According to 35 U.S.C. § 119 (e), the application requires the U.S. Provisional Patent Application 60/711 of submission on August 24th, 2005,042, the U.S. Provisional Patent Application 60/744 that on April 4th, 2006 submitted to, the U.S. Provisional Patent Application 60/804 that No. 273 and on June 13rd, 2006 submit to, 644 right of priority, above-mentioned patent documentation are all incorporated this paper by reference in full into.

Technical field

The present invention relates to prepare the compound and the midbody compound that can be used in its preparation process that are suitable for as hepatitis C virus (HCV) AG14361.

Background technology

Hepatitis C virus (HCV, hepatitis C virus) belongs to the hepatovirus of yellow fever virus section.It is the main pathogenic former of non-A, non-B viral hepatitis, and is the reason of the most hepatitis case of the main cause and the whole world of post-transfusion hepatitis.Though acute HCV infection is asymptomatic usually, the case near 80% is transformed into chronic hepatitis.The lasting characteristic that this HCV infects by its can by among the membrane protein E2 the hypermutability of infected zone escape host immune and inspect explained (Weiner, et al., Virology, 180:842-848 (1991); Weiner, et al., Proc.Natl.Acad.Sci.USA, 89:3468-3472 (1992)).

Because the persistent infection of HCV is relevant with chronic hepatitis, and can cause liver cancer at last, eliminates HCV regeneration and prevent one of target of hepatocellular carcinoma knurl so HCV copies as.Regrettably, at present the characteristic of the methods of treatment that HCV is infected is, effect difference and can produce disadvantageous side effect.Therefore need wholeheartedly develop a kind of molecule for the treatment of above-mentioned disease, it comprises exploitation in order to suppress the medicine that HC duplicates, and this is owing to have lasting demand for non-peptide, micromolecular compound (for having the HCV RdRp inhibitor that is suitable for required or improved physics of pharmaceutical application and chemical property).

Be suitable for being disclosed in U.S. Patent application of submitting on November 19th, 2,003 10/718,337 and the U.S. Patent application of submitting on August 15th, 2,005 11/204,269 as the compound of HCV AG14361, above-mentioned patent documentation is incorporated this paper by reference in full into.The invention provides and be applicable to that preparation is suitable for method and the midbody compound as the compound of HCV AG14361.

Summary of the invention

The invention provides the method for preparation formula (Ia) compound:

Wherein:

R ¹Be C ₁To C ₆Alkyl or C ₃To C ₆Cycloalkyl;

R ^2a, R ^2bAnd R ^2cBe selected from hydrogen, halogen, C independently of one another ₁To C ₆Alkyl, C ₃To C ₆Cycloalkyl ,-OR ^12a,-CF ₃,-CN and-NR ^12aR ^12b

R ⁴Be selected from hydrogen, C ₁To C ₆Alkyl ,-(CR ⁹R ¹⁰) _nR ¹¹,-CF ₃, halogen ,-OR ^12a,-CN and-NR ^12aR ^12b

R ⁵Be selected from hydrogen, C ₁To C ₆Alkyl ,-(CR ⁹R ¹⁰) _nR ¹¹,-CF ₃, halogen ,-OR ^12a,-CN and-NR ^12aR ^12b

R ⁶Be selected from hydrogen, C ₁To C ₆Alkyl ,-(CR ⁹R ¹⁰) _nR ¹¹,-CF ₃, halogen ,-OR ^12a,-CN and-NR ^12aR ^12b

R ⁷Be selected from hydrogen, C ₁To C ₆Alkyl ,-(CR ⁹R ¹⁰) _nR ¹¹,-CF ₃, halogen ,-OR ^12a,-CN and-NR ^12aR ^12b

Each R ⁹And R ¹⁰Be independently selected from hydrogen and C ₁To C ₆Alkyl, or R ⁹And R ¹⁰Form C with the carbon atom that they connected ₃To C ₆Cycloalkyl;

Each R ¹¹Be independently selected from hydrogen, C ₁To C ₆Alkyl, halogen ,-OR ^12a,-CN ,-CF ₃With-NR ⁹R ¹⁰

Each R ^12aAnd R ^12bBe independently selected from hydrogen and C ₁To C ₆Alkyl; And

Each n is selected for use independently, is 0 to 5 integer;

This method comprises:

A) with formula (X) compound (R wherein ¹³Be hydrogen, C ₁To C ₆Alkyl ,-Si (C ₁To C ₆Alkyl) ₃Or-CH ₂(C ₆To C ₁₀Aryl), wherein said C ₆To C ₁₀Aryl is optional by at least a halogen, the C of being selected from ₁To C ₆Alkyl ,-OH ,-OCH ₃With-N (C ₁To C ₆Alkyl) ₂Substituting group replace) anionic treatments formula V compound (R wherein ¹Definition as mentioned), to obtain formula (IV) compound;

B) the described formula of hydrolysis (IV) compound is to obtain wherein R ¹³Formula (IV) compound for hydrogen;

C) handle described formula (IV) compound to obtain formula (III) compound, wherein P with composite reagent ¹Be hydrogen or appropriate protection group, and R ¹⁴Be C ₁To C ₆Alkyl or-CH ₂(C ₆To C ₁₀Aryl), wherein said C ₆To C ₁₀Aryl is optional by at least a halogen, the C of being selected from ₁To C ₆Alkyl ,-OH ,-OCH ₃With-N (C ₁To C ₆Alkyl) ₂Substituting group replace;

D) with acid or the described formula of alkaline purification (III) compound to obtain formula (II) compound thing; And

E) with the described formula of formula (IXa) compound treatment (II) compound to obtain formula (Ia) compound

This paper further provides following method, wherein in described formula (Ia) compound:

R ¹Be C ₃To C ₆Cycloalkyl;

R ⁷System is selected from hydrogen, C ₁To C ₆Alkyl ,-(CR ⁹R ¹⁰) _nR ¹¹,-CF ₃, halogen ,-OR ^12a,-CN and-NR ^12aR ^12b

Each R ¹¹Independently be selected from hydrogen, C ₁To C ₆Alkyl, halogen ,-OR ^12a,-CN ,-CF ₃With-NR ^12aR ^12b

Each n is selected for use independently, is 0 to 5 integer.

This paper also provides following method, wherein in described formula (Ia) compound:

R ¹Be cyclopentyl;

R ^2a, R ^2bAnd R ^2cBe selected from hydrogen, halogen and C independently of one another ₁To C ₆Alkyl;

Each R ¹¹Be independently selected from hydrogen, C ₁To C ₆Alkyl, halogen ,-OR ^12a,-CN ,-CF ₃With-NR ^12aR ^12b

Each n is selected for use independently, is 0 to 5 integer.

Also comprise following method, wherein in described formula (Ia) compound:

R ¹Be cyclopentyl;

R ^2aBe C ₁To C ₆Alkyl;

R ^2bBe hydrogen;

R ^2cBe C ₁To C ₆Alkyl;

R ⁴Be hydrogen;

R ⁵Be C ₁To C ₆Alkyl;

R ⁶Be hydrogen; And

R ⁷Be C ₁To C ₆Alkyl.

Following method is provided on the other hand, wherein in described formula (Ia) compound:

R ¹Be cyclopentyl;

R ^2aFor-CH ₃

R ^2bBe hydrogen;

R ^2cFor-CH ₃

R ⁴Be hydrogen;

R ⁵For-CH ₂CH ₃

R ⁶Be hydrogen; And

R ⁷For-CH ₂CH ₃

Following method also is provided on the other hand, and wherein said formula (Ia) compound is (Iaa),

In addition, this paper comprises following method, and wherein said formula (Ia) compound is (Iab),

This paper further provides the method for preparation formula (Ia) compound:

Wherein:

R ¹Be C ₁To C ₆Alkyl or C ₃To C ₆Cycloalkyl;

Each n is selected for use independently, is 0 to 5 integer;

Described method comprises:

A) handle formula (IV) compound (R wherein with composite reagent ¹, R ⁴, R ⁵, R ⁶And R ⁷As defined herein, P ¹Be hydrogen or appropriate protection group, and R ¹³Be hydrogen, C ₁To C ₆Alkyl ,-Si (C ₁To C ₆Alkyl) ₃Or-CH ₂(C ₆To C ₁₀Aryl), wherein said C ₆To C ₁₀Aryl is optional by at least a halogen, the C of being selected from ₁To C ₆Alkyl ,-OH ,-OCH ₃With-N (C ₁To C ₆Alkyl) ₂Substituting group replace), to obtain formula (III) compound, wherein R ¹⁴Be C ₁To C ₆Alkyl ,-Si (C ₁To C ₆Alkyl) ₃Or-CH ₂(C ₆To C ₁₀Aryl), wherein said C ₆To C ₁₀Aryl is optional by at least a halogen, the C of being selected from ₁To C ₆Alkyl ,-OH ,-OCH ₃With-N (C ₁To C ₆Alkyl) ₂Substituting group replace;

B) with acid or the described formula of alkaline purification (III) compound to obtain formula (II) compound thing; And

C) with the described formula of formula (IXa) compound treatment (II) compound to obtain formula (Ia) compound

On the other hand, provide the method for preparation formula (II) compound,

Wherein:

R ¹Be C ₁To C ₆Alkyl or C ₃To C ₆Cycloalkyl;

Each R ⁹Be independently selected from hydrogen and C with R10 ₁To C ₆Alkyl, or R ⁹And R ¹⁰Form C with the carbon atom that they connected ₃To C ₆Cycloalkyl;

Each n is selected for use independently, is 0 to 5 integer;

Described method comprises:

A) with formula (X) compound (R wherein ¹³Be hydrogen, C ₁To C ₆Alkyl ,-Si (C ₁To C ₆Alkyl) ₃Or-CH ₂(C ₆To C ₁₀Aryl), wherein said C ₆To C ₁₀Aryl is optional by at least a halogen, the C of being selected from ₁To C ₆Alkyl ,-OH ,-OCH ₃With-N (C ₁To C ₆Alkyl) ₂Substituting group replace) anionic treatments formula V compound (R wherein ¹Definition as mentioned), to obtain formula (IV) compound:

D) with acid or the described formula of alkaline purification (III) compound to obtain formula (II) compound

This paper further provides following method, and wherein said formula (II) compound is (IIa):

Or wherein said formula (II) compound is (IIb):

This paper also comprises in the aforesaid method any one, wherein in described formula (II) compound:

R ¹Be C ₃To C ₆Cycloalkyl;

Each n is selected for use independently, for from 0 to 5 integer.

And the present invention includes following aforesaid method, wherein in described formula (II) compound:

R ¹Be C ₃To C ₆Cycloalkyl;

R ⁴Be hydrogen;

R ⁵Be C ₁To C ₆Alkyl;

R ⁶Be hydrogen;

R ⁷Be C ₁To C ₆Alkyl;

R ¹¹Be independently selected from hydrogen, C ₁To C ₆Alkyl, halogen ,-OR ^12a,-CN ,-CF ₃With-NR ⁹R ¹⁰

Each n is selected for use independently, is 0 to 5 integer.

The present invention also comprises in the aforesaid method any one, wherein in described formula (II) compound:

R ¹Be cyclopentyl;

R ⁴Be hydrogen;

R ⁵For-CH ₂CH ₃

R ⁶Be hydrogen;

R ⁷For-CH ₂CH ₃

R ¹¹Be independently selected from hydrogen, C ₁To C ₆Alkyl, halogen ,-OR ^12a,-CN ,-CF ₃With-NR ^12aR ^12b

Each R ^12aAnd R ^12bBe independently selected from hydrogen and C ₁To C ₆Alkyl.

Another aspect of the present invention provides the method for formula (Ia) compound of preparation stereoisomerism enrichment,

Wherein:

R ¹Be C ₁To C ₆Alkyl or C ₃To C ₆Cycloalkyl;

Each n is selected for use independently, is 0 to 5 integer;

Described method comprises:

A) with chirality, non-racemize alkaline purification formula (IV) compound, wherein R ¹, R ⁴, R ⁵, R ⁶And R ⁷Define as mentioned and P ¹Be hydrogen or appropriate protection group, to obtain the mixture of diastereo-isomerism salt;

B) make described diastereo-isomerism salt separated from one another;

C) described isolating diastereo-isomerism salt is changed into formula (IV) compound of stereoisomerism enrichment;

D) handle formula (IV) compound (R wherein of described stereoisomerism enrichment with composite reagent ¹³Be hydrogen, C ₁To C ₆Alkyl ,-Si (C ₁To C ₆Alkyl) ₃Or-CH ₂(C ₆To C ₁₀Aryl), wherein said C ₆To C ₁₀Aryl is optional by at least a halogen, the C of being selected from ₁To C ₆Alkyl ,-OH ,-OCH ₃With-N (C ₁To C ₆Alkyl) ₂Substituting group replace), with formula (III) compound that obtains the stereoisomerism enrichment, wherein R ¹⁴Be hydrogen, C ₁To C ₆Alkyl ,-Si (C ₁To C ₆Alkyl) ₃Or-CH ₂(C ₆To C ₁₀Aryl), wherein said C ₆To C ₁₀Aryl is optional by at least a halogen, the C of being selected from ₁To C ₆Alkyl ,-OH ,-OCH ₃With-N (C ₁To C ₆Alkyl) ₂Substituting group replace;

E) with formula (III) compound of acid or the described stereoisomerism enrichment of alkaline purification, P wherein ¹Be hydrogen, with formula (II) compound that obtains the stereoisomerism enrichment; And

F) with formula (Ia) compound of formula (II) compound to obtain the stereoisomerism enrichment of the described stereoisomerism enrichment of formula (IXa) compound treatment

The present invention provides the method for formula (II) compound of preparation stereoisomerism enrichment on the other hand,

Wherein

R ¹Be C ₁To C ₆Alkyl or C ₃To C ₆Cycloalkyl;

Each n is selected for use independently, is 0 to 5 integer;

Described method comprises:

B) make described diastereo-isomerism salt separated from one another;

D) handle formula (IV) compound (P wherein of described stereoisomerism enrichment with composite reagent ¹Be hydrogen or appropriate protection group and R ¹³Be hydrogen, C ₁To C ₆Alkyl ,-Si (C ₁To C ₆Alkyl) ₃Or-CH ₂(C ₆To C ₁₀Aryl), wherein said C ₆To C ₁₀Aryl is optional by at least a halogen, the C of being selected from ₁To C ₆Alkyl ,-OH ,-OCH ₃With-N (C ₁To C ₆Alkyl) ₂Substituting group replace), with formula (III) compound that obtains the stereoisomerism enrichment, wherein R ¹⁴Be hydrogen, C ₁To C ₆Alkyl ,-Si (C ₁To C ₆Alkyl) ₃Or-CH ₂(C ₆To C ₁₀Aryl), wherein said C ₆To C ₁₀Aryl is optional by at least a halogen, the C of being selected from ₁To C ₆Alkyl ,-OH ,-OCH ₃With-N (C ₁To C ₆Alkyl) ₂Substituting group replace; And

E) with formula (III) compound of the described stereoisomerism enrichment of alkaline purification, P wherein ¹Be hydrogen, with formula (II) compound that obtains the stereoisomerism enrichment

The present invention provides formula (IV) compound of preparation stereoisomerism enrichment on the other hand,

Wherein:

R ¹Be C ₁To C ₆Alkyl or C ₃To C ₆Cycloalkyl;

Each R ^12aAnd R ^12bBe independently selected from hydrogen and C ₁To C ₆Alkyl;

P ¹Be hydrogen or appropriate protection group; And

Each n is selected for use independently, is 0 to 5 integer;

Described method comprises:

A) with chirality, non-racemize alkaline purification formula (IV) compound to form the mixture of diastereo-isomerism salt;

B) make described diastereo-isomerism salt separated from one another;

C) described diastereo-isomerism salt is changed into formula (IV) compound of stereoisomerism enrichment.

This paper also comprises in the aforesaid method any one, and wherein said chirality, non-racemize alkali are chirality, non-racemic amines; And wherein said chirality, non-racemic amines are selected from cis-1-amino-2-indanol, Xin Keniting (cinchonidine), 1-aminoidan, uncle-bright amine alcohol (leucinol), 2-amino-1,2-phenylbenzene ethanol, α-Jia Jibianji amine and 2-amino-1-(4-nitrophenyl)-1, ammediol; And wherein said chirality, non-racemic amines are selected from (1R, 2S)-(+)-cis-1-amino-2-indanol, (-)-Xin Keniting, (R)-1-aminoidan, (S)-uncle-bright amine alcohol, (1R, 2S)-2-amino-1,2-phenylbenzene ethanol, (S)-α-Jia Jibianji amine and (1R, 2R)-(-)-and 2-amino-1-(4-nitrophenyl)-1, ammediol; And wherein said chirality, non-racemic amines be (1R, 2R)-(-)-2-amino-1-(4-nitrophenyl)-1, ammediol.

The present invention provides formula (IV) compound on the other hand,

Wherein:

R ¹³Be hydrogen, C ₁To C ₆Alkyl ,-Si (C ₁To C ₆Alkyl) ₃Or-CH ₂(C ₆To C ₁₀Aryl), wherein said C ₆To C ₁₀Aryl is optional by at least a halogen, the C of being selected from ₁To C ₆Alkyl ,-OH ,-OCH ₃With-N (C ₁To C ₆Alkyl) ₂Substituting group replace;

P ¹Be hydrogen or suitable blocking group; And

Each n is selected for use independently, is 0 to 5 integer.

This paper further comprises this following compounds, wherein P ¹For-Si (C ₁To C ₆Alkyl) ₃Or-CH ₂(C ₆To C ₁₀Aryl), wherein said C ₆To C ₁₀Aryl is optional by at least a halogen, the C of being selected from ₁To C ₆Alkyl ,-OH ,-OCH ₃With-N (C ₁To C ₆Alkyl) ₂Substituting group replace.

This paper also comprises following this compounds, wherein:

R ¹¹For-CN;

P ¹Be hydrogen or suitable blocking group; And

Each n is selected for use independently, is 0 to 5 integer.

Another aspect of the present invention is following this compounds, wherein:

R ⁴Be hydrogen;

R ⁵Be C ₁To C ₆Alkyl;

R ⁶Be hydrogen; And

R ⁷Be C ₁To C ₆Alkyl;

This paper further provides following this compounds, wherein:

R ⁴Be hydrogen;

R ⁵For-CH ₂CH ₃

R ⁶Be hydrogen;

R ⁷For-CH ₂CH ₃And

R ¹³Be hydrogen or C ₁To C ₆Alkyl.

The present invention provides following formula: compound on the other hand:

This paper also comprises following compound, wherein P ¹For-Si (C ₁To C ₆Alkyl) ₃Or-CH ₂(C ₆To C ₁₀Aryl), wherein said C ₆To C ₁₀Aryl is optional by at least a halogen, the C of being selected from ₁To C ₆Alkyl ,-OH ,-OCH ₃With-N (C ₁To C ₆Alkyl) ₂Substituting group replace.

Another aspect of the present invention is following formula: compound:

The present invention provides following formula: compound on the other hand:

Wherein:

P ¹Be hydrogen or suitable blocking group;

R ¹¹For-CN;

Each n is selected for use independently, is 0 to 5 integer; And

A ⁺Be suitable gegenion.

This paper also comprises following this compounds, wherein P ¹For-Si (C ₁To C ₆Alkyl) ₃Or-CH ₂(C ₆To C ₁₀Aryl), wherein said C ₆To C ₁₀Aryl is optional by at least a halogen, the C of being selected from ₁To C ₆Alkyl ,-OH ,-OCH ₃With-N (C ₁To C ₆Alkyl) ₂Substituting group replace.

This paper also comprises following this compounds, wherein:

P ¹Be hydrogen;

R ⁴Be hydrogen;

R ⁵Be C ₁To C ₆Alkyl;

R ⁶Be hydrogen;

R ⁷Be C ₁To C ₆Alkyl; And

A ⁺Be suitable gegenion.

This paper further comprises in the above-claimed cpd any one, and wherein said suitable gegenion is derived from amine alkali; And wherein said amine alkali is dicyclohexyl amine; Or wherein said amine alkali is chirality, non-racemic amines alkali.This paper further comprises following compound, wherein said chirality, non-racemic amines are selected from a kind of enantiomer of following compound: cis-1-amino-2-indanol, Xin Keniting, 1-aminoidan, uncle-bright amine alcohol, 2-amino-1,2-phenylbenzene ethanol, α-Jia Jibianji amine and 2-amino-1-(4-nitrophenyl)-1, ammediol; Or wherein said chirality, non-racemic amines alkali are selected from (1R, 2S)-(+)-cis-1-amino-2-indanol, (-)-Xin Keniting, (R)-1-aminoidan, (S)-uncle-bright amine alcohol, (1R, 2S)-2-amino-1,2-phenylbenzene ethanol, α-Jia Jibianji amine and (1R, 2R)-(-)-and 2-amino-1-(4-nitrophenyl)-1, ammediol; Or wherein said chirality, non-racemic amines alkali be (1R, 2R)-(-)-2-amino-1-(4-nitrophenyl)-1, ammediol.

The present invention provides formula (IIIa) compound on the other hand

P ¹Be hydrogen or suitable blocking group;

R ¹⁴Be C ₁To C ₆Alkyl or-CH ₂(C ₆To C ₁₀Aryl), wherein said C ₆To C ₁₀Aryl is optional by at least a halogen, the C of being selected from ₁To C ₆Alkyl ,-OH ,-OCH ₃With-N (C ₁To C ₆Alkyl) ₂Substituting group replace; And

Each n is selected for use independently, is 0 to 5 integer.

This paper also comprises following this compounds, wherein:

R ⁴Be hydrogen;

R ⁵Be C ₁To C ₆Alkyl;

R ⁶Be hydrogen;

R ⁷Be C ₁To C ₆Alkyl;

P ¹Be hydrogen; And

R ¹⁴Be hydrogen or C ₁To C ₆Alkyl.

This paper also comprises following this compounds, wherein:

R ⁴Be hydrogen;

R ⁵For-CH ₂CH ₃

R ⁶Be hydrogen;

R ⁷For-CH ₂CH ₃

P ¹Be hydrogen; And

R ¹⁴Be hydrogen or C ₁To C ₆Alkyl.

The present invention provides formula (IIIb) compound on the other hand:

Wherein:

P ¹Be hydrogen or suitable blocking group;

Each n is selected for use independently, is 0 to 5 integer.

This paper also comprises following compound, wherein:

R ⁴Be hydrogen;

R ⁵Be C ₁To C ₆Alkyl;

R ⁶Be hydrogen;

R ⁷Be C ₁To C ₆Alkyl;

P ¹Be hydrogen; And

R ¹⁴Be hydrogen or C ₁To C ₆Alkyl.

This paper also comprises following compound, wherein:

R ⁴Be hydrogen;

R ⁵For-CH ₂CH ₃

R ⁶Be hydrogen;

R ⁷For-CH ₂CH ₃

P ¹Be hydrogen; And

R ¹⁴Be hydrogen or C ₁To C ₆Alkyl.

The present invention provides following formula: compound on the other hand:

Wherein:

R ¹⁴Be hydrogen or C ₁To C ₆Alkyl; And

Each n is selected for use independently, is 0 to 5 integer.

This paper also comprises following this compounds, wherein:

R ⁴Be hydrogen;

R ⁵Be C ₁To C ₆Alkyl;

R ⁶Be hydrogen; And

R ⁷Be C ₁To C ₆Alkyl.

This paper also comprises following this compounds, wherein:

R ⁴Be hydrogen;

R ⁵For-CH ₂CH ₃

R ⁶Be hydrogen; And

R ⁷For-CH ₂CH ₃

The present invention provides following formula: compound on the other hand:

Wherein:

R ¹¹Each independently is selected from hydrogen, C ₁To C ₆Alkyl, halogen ,-OR ^12a,-CN ,-CF ₃With-NR ⁹R ¹⁰

R ^12aAnd R ^12bSystem independently is selected from hydrogen, C ₁To C ₆Alkyl;

R ¹⁴Be hydrogen or C ₁To C ₆Alkyl; And

Each n is independently selected for use, is 0 to 5 integer.

This paper also comprises following this compounds, wherein:

R ⁴Be hydrogen;

R ⁵Be C ₁To C ₆Alkyl;

R ⁶Be hydrogen; And

R ⁷Be C ₁To C ₆Alkyl.

This paper also comprises following this compounds, wherein:

R ⁴Be hydrogen;

R ⁵For-CH ₂CH ₃

R ⁶Be hydrogen; And

R ⁷For-CH ₂CH ₃

The present invention provides the method for preparation formula (Ie) compound on the other hand:

Wherein:

Each n is selected for use independently, is 0 to 5 integer;

Described method comprises with formula (IXa) compound treatment formula (IIa) compound, wherein R ⁴, R ⁵, R ⁶And R ⁷Definition as mentioned,

To obtain formula (Ie) compound.

This paper also comprises following these class methods, wherein:

R ⁴Be hydrogen;

R ⁵Be C ₁To C ₆Alkyl;

R ⁶Be hydrogen;

R ⁷Be C ₁To C ₆Alkyl; And

This paper also comprises following these class methods, wherein:

R ⁴Be hydrogen;

R ⁵For-CH ₂CH ₃

R ⁶Be hydrogen; And

R ⁷For-CH ₂CH ₃

The present invention provides the method for preparation formula (If) compound on the other hand:

Wherein:

Each n is independently selected for use, is 0 to 5 integer;

To obtain formula (If) compound.

This paper also comprises following these class methods, wherein:

R ⁴Be hydrogen;

R ⁵Be C ₁To C ₆Alkyl;

R ⁶Be hydrogen;

R ⁷Be C ₁To C ₆Alkyl; And

This paper also comprises following these class methods, wherein:

R ⁴Be hydrogen;

R ⁵For-CH ₂CH ₃

R ⁶Be hydrogen; And

R ⁷For-CH ₂CH ₃

This paper further provides a kind of (R)-6-cyclopentyl-6-(2-(2,6-parvoline-4-yl) ethyl)-3-((5,7-dimethyl-[1,2,4] triazolo [1,5-a] pyrimidine-2-base) methyl)-4-hydroxyl-5, the crystal formation of 6-dihydropyrane-2-ketone.Described crystal formation has in x-ray diffractogram of powder and is selected from about 7.1; Or about 12.1; Or about 16.1; Or about 17.5; Or any one of about 23.5 the characteristic peak of representing with the 2 θ number of degrees.

The present invention provides a kind of (R)-6-cyclopentyl-6 on the other hand, and (2-(2,6-parvoline-4-yl) ethyl)-3-((5,7-dimethyl-[1,2,4] triazolo [1,5-a] pyrimidine-2-base) methyl)-4-hydroxyl-5, the crystal formation of 6-dihydropyrane-2-ketone, described crystal formation have in x-ray diffractogram of powder and are selected from about 7.1 and about 12.1; Or about 7.1 and about 16.1; Or about 7.1 and about 17.5; Or about 7.1 and about 23.5; Or about 12.1 and about 16.1; Or about 12.1 and about 17.5; Or about 12.1 and about 23.5; Or about 16.1 and about 17.5; Or about 16.1 and about 23.5; Or about 17.5 and about 23.5 with 2 θ number of degrees representation feature peaks.

The present invention provides a kind of (R)-6-cyclopentyl-6-on the other hand, and (2-(2,6-parvoline-4-yl) ethyl)-3-((5,7-dimethyl-[1,2,4] triazolo [1,5-a] pyrimidine-2-base) methyl)-4-hydroxyl-5, the crystal formation of 6-dihydropyrane-2-ketone, described crystal formation have in x-ray diffractogram of powder and are selected from about 7.1, about 12.1 and about 16.1; Or about 7.1, about 12.1 and about 17.5; Or about 7.1, about 12.1 and about 23.5; About 12.1, about 16.1 and about 17.5; Or about 12.1, about 16.1 and about 23.5; Or about 16.1, about 17.5 and about 23.5; Or about 7.1, about 17.5 and about 23.5; Or about 7.1, about 12.1 and about 23.5; Or about 7.1, about 16.1 and about 23.5 the characteristic peak of representing with the 2 θ number of degrees.

The present invention provides a kind of (R)-6-cyclopentyl-6-on the other hand, and (2-(2,6-parvoline-4-yl) ethyl)-3-((5,7-dimethyl-[1,2,4] triazolo [1,5-a] pyrimidine-2-base) methyl)-4-hydroxyl-5, the crystal formation of 6-dihydropyrane-2-ketone, described crystal formation have about 7.1, about 12.1, about 16.1, about 17.5 and about 23.5 characteristic peaks of representing with the 2 θ number of degrees in x-ray diffractogram of powder.

This paper also provides a kind of (R)-6-cyclopentyl-6-, and (2-(2,6-parvoline-4-yl) ethyl)-3-((5,7-dimethyl-[1,2,4] triazolo [1,5-a] pyrimidine-2-base) methyl)-4-hydroxyl-5, the crystal formation of 6-dihydropyrane-2-ketone, described crystal formation have about 154.6, about 153.0, about 151.2, about 146.4, about 146.0, about 121.6, about 120.4, about 119.7, about 118.8, about 110.2, about 100.7 and about 100.3 characteristic peaks of representing with ppm in solid state NMR spectrum.

In another embodiment, a kind of (R)-6-cyclopentyl-6-is provided, and (2-(2,6-parvoline-4-yl) ethyl)-3-((5,7-dimethyl-[1,2,4] methyl triazolo [1,5-a] pyrimidine-2-base))-4-hydroxyl-5, the crystal formation of 6-dihydropyrane-2-ketone, described crystal formation have in about 162 ℃ of melt temperatures to about 165 ℃ of scopes.

This paper also provides a kind of (R)-6-cyclopentyl-6-, and (2-(2,6-parvoline-4-yl) ethyl)-3-((5,7-dimethyl-[1,2,4] triazolo [1,5-a] pyrimidine-2-base) methyl)-4-hydroxyl-5, the crystal formation of 6-dihydropyrane-2-ketone, described crystal formation have the arbitrary combination at the arbitrary characteristics peak in above-mentioned solid phase NMR spectrum of the arbitrary characteristics peak in above-mentioned x-ray diffractogram of powder of any amount and any amount.For example in one embodiment, a kind of (R)-6-cyclopentyl-6-is provided, and (2-(2,6-parvoline-4-yl) ethyl)-3-((5,7-dimethyl-[1,2,4] methyl triazolo [1,5-d] pyrimidine-2-base))-4-hydroxyl-5, the crystal formation of 6-dihydropyrane-2-ketone, described crystal formation have about 7.1 characteristic peaks of representing with the 2 θ number of degrees and have about 154.6 peaks of representing with ppm in solid phase NMR spectrum in x-ray diffractogram of powder.

In another embodiment, a kind of (R)-6-cyclopentyl-6-is provided, and (2-(2,6-parvoline-4-yl) ethyl)-3-((5,7-dimethyl-[1,2,4] methyl triazolo [1,5-a] pyrimidine-2-base))-4-hydroxyl-5, the crystal formation of 6-dihydropyrane-2-ketone, described crystal formation have about 7.1 characteristic peaks of representing with the 2 θ number of degrees in x-ray diffractogram of powder, have about 154.6 peaks of representing with ppm and have in about 162 ℃ of melt temperatures to about 165 ℃ of scopes in solid phase NMR spectrum.

The invention still further relates to the method for a kind of treatment through the hepatitis C virus (HCV) of the Mammals (such as the people) of HCV infection, described method comprises to be bestowed a certain amount of (R)-6-cyclopentyl-6-that can effectively treat HCV to described Mammals (2-(2,6-parvoline-4-yl) ethyl)-3-((5,7-dimethyl-[1,2,4] methyl triazolo [1,5-a] pyrimidine-2-base))-and 4-hydroxyl-5, the crystal formation of 6-dihydropyrane-2-ketone or its pharmaceutically-acceptable salts.In other embodiments, following method is provided, (2-(2 for wherein said (R)-6-cyclopentyl-6-, 6-parvoline-4-yl) ethyl)-3-((5,7-dimethyl-[1,2,4] triazolo [1,5-a] pyrimidine-2-base) methyl)-4-hydroxyl-5, the crystal formation of 6-dihydropyrane-2-ketone has in the x-ray diffractogram of powder case and is selected from about 7.1; Or about 12.1; Or about 16.1; Or about 17.5; Or about 23.5 in the characteristic peak of representing with the 2 θ number of degrees any one.

The present invention provides the method for the treatment of the Mammals (such as the people) that is infected by hepatitis C virus on the other hand, described method comprises to be bestowed (R)-6-cyclopentyl-6 of hepatitis C virus amount of suppression to described Mammals (2-(2,6-parvoline-4-yl) ethyl)-3-((5,7-dimethyl-[1,2,4] methyl triazolo [1,5-a] pyrimidine-2-base))-and 4-hydroxyl-5, the crystal formation of 6-dihydropyrane-2-ketone or its pharmaceutically-acceptable salts.In other embodiments, following method is provided, (2-(2 for wherein said (R)-6-cyclopentyl-6-, 6-parvoline-4-yl) ethyl)-3-((5,7-dimethyl-[1,2,4] triazolo [1,5-a] pyrimidine-2-base) methyl)-4-hydroxyl-5, the crystal formation of 6-dihydropyrane-2-ketone has in x-ray diffractogram of powder and is selected from about 7.1; Or about 12.1; Or about 16.1; Or about 17.5; Or about 23.5 in the characteristic peak of representing with the 2 θ number of degrees any one.。

This paper also provides and has contained (R)-6-cyclopentyl-6-(2-(2,6-parvoline-4-yl) ethyl)-3-((5,7-dimethyl-[1,2,4] triazolo [1,5-a] pyrimidine-2-base) methyl)-4-hydroxyl-5, the crystal formation of 6-dihydropyrane-2-ketone or the pharmaceutical compositions of its pharmaceutically-acceptable salts and pharmaceutically acceptable supporting agent.In other embodiments, following pharmaceutical compositions is provided, (2-(2 for wherein said (R)-6-cyclopentyl-6-, 6-parvoline-4-yl) ethyl)-3-((5,7-dimethyl-[1,2,4] triazolo [1,5-a] pyrimidine-2-base) methyl)-4-hydroxyl-5, the crystal formation of 6-dihydropyrane-2-ketone presents to have in x-ray diffractogram of powder and is selected from about 7.1; Or about 12.1; Or about 16.1; Or about 17.5; Or about 23.5 in the characteristic peak of representing with the 2 θ number of degrees any one.

This paper further provides the pharmaceutical compositions that is used for the treatment of hepatitis C virus (HCV) in the Mammals (such as the people), described composition comprises a certain amount ofly can effectively treat (R)-6-cyclopentyl-6-through infecting mammiferous hepatitis C virus (2-(2,6-parvoline-4-yl) ethyl)-3-((5,7-dimethyl-[1,2,4] triazolo [1,5-a] pyrimidine-2-base) methyl)-4-hydroxyl-5, the crystal formation of 6-dihydropyrane-2-ketone or its pharmaceutically-acceptable salts and pharmaceutically acceptable supporting agent.In other embodiments, following pharmaceutical compositions is provided, (2-(2 for wherein said (R)-6-cyclopentyl-6-, 6-parvoline-4-yl) ethyl)-3-((5,7-dimethyl-[1,2,4] triazolo [1,5-a] pyrimidine-2-base) methyl)-4-hydroxyl-5, the crystal formation of 6-dihydropyrane-2-ketone has in x-ray diffractogram of powder and is selected from about 7.1; Or about 12.1; Or about 16.1; Or about 17.5; Or about 23.5 in the characteristic peak of representing with the 2 θ number of degrees any one.

The invention still further relates to the inhibition method that hepatitis C virus duplicates in the Mammals (such as the people) that HCV infects, described method comprises that described Mammals is bestowed hepatitis C virus duplicates (R)-6-cyclopentyl-6-of amount of suppression (2-(2,6-parvoline-4-yl) ethyl)-3-((5,7-dimethyl-[1,2,4] methyl triazolo [1,5-a] pyrimidine-2-base))-and 4-hydroxyl-5, the crystal formation of 6-dihydropyrane-2-ketone or its pharmaceutically-acceptable salts.In other embodiments, following method is provided, (2-(2 for wherein said (R)-6-cyclopentyl-6-, 6-parvoline-4-yl) ethyl)-3-((5,7-dimethyl-[1,2,4] triazolo [1,5-a] pyrimidine-2-base) methyl)-4-hydroxyl-5, the crystal formation of 6-dihydropyrane-2-ketone has in x-ray diffractogram of powder and is selected from about 7.1; Or about 12.1; Or about 16.1; Or about 17.5; Or about 23.5 in the characteristic peak of representing with the 2 θ number of degrees any one.

(2-(2 to the invention still further relates to (R)-6-cyclopentyl-6-, 6-parvoline-4-yl) ethyl)-3-((5,7-dimethyl-[1,2,4] triazolo [1,5-a] pyrimidine-2-base) methyl)-4-hydroxyl-5, the crystal formation of 6-dihydropyrane-2-ketone or its pharmaceutically-acceptable salts are used for the treatment of the purposes of the mammiferous medicine that is infected by hepatitis C virus in preparation.Described medicine can comprise hepatitis C virus amount of suppression (R)-6-cyclopentyl-6-, and (2-(2,6-parvoline-4-yl) ethyl)-3-((5,7-dimethyl-[1,2,4] triazolo [1,5-a] pyrimidine-2-base) methyl)-4-hydroxyl-5, the crystal formation of 6-dihydropyrane-2-ketone or its pharmaceutically-acceptable salts and pharmaceutically acceptable supporting agent or multiple supporting agent.In other embodiments, following medicine is provided, (2-(2 for wherein said (R)-6-cyclopentyl-6-, 6-parvoline-4-yl) ethyl)-3-((5,7-dimethyl-[1,2,4] triazolo [1,5-a] pyrimidine-2-base) methyl)-4-hydroxyl-5, the crystal formation of 6-dihydropyrane-2-ketone has in x-ray diffractogram of powder and is selected from about 7.1; Or about 12.1; Or about 16.1; Or about 17.5; Or about 23.5 in the characteristic peak of representing with the 2 θ number of degrees any one.

Term used herein " comprises " and " comprising " uses with opening mode, there is no limitation.

Term used herein " hydrogen " refers to substituting group " H ".

Term " C used herein ₁To C ₆Alkyl " refer to the saturated univalence hydrocarbyl that has the straight or branched fragment and contain 1 to 6 carbon atom.Described examples of groups include, but not limited to methyl, ethyl, propyl group, sec.-propyl, just-butyl, different-butyl, tert-butyl etc.

This term " C used herein ₃To C ₈Cycloalkyl " refer to have the saturated of 3 to 8 carboatomic ring atoms (but not having heteroatoms) altogether or partly saturated, monocycle or condensed ring or volution polynuclear plane.The example of cycloalkyl comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, suberyl, Ldamantin and similar group.Term used herein " cyclopentyl " refers to by 5 carbon atoms and 9 cycloalkyl that hydrogen atom is formed, and can be by chemistry

The formula representative.

Term " C used herein ₆To C ₁₀Aryl " refer to derive by aromatic hydrocarbons by removing a hydrogen and contain the group of 6 to 10 carbon atoms altogether.Term used herein " phenyl " and symbol " Ph " refer to C ₆H ₅Group.

Term used herein " halogen " refers to fluorine, chlorine, bromine or iodine.Described term " fluoro " refers to fluorine, and " chloro " refers to chlorine, and " bromo " refers to that bromine and " iodo " refer to iodine.

Term " cyano group " refers to-C ≡ N group wherein between carbon atom and nitrogen-atoms triple bond is arranged.Cyano group is also write as " CN " in this article.

Term " trifluoromethyl " refers to-CF ₃Group.

Refer to chemical process about chemical conversion or the employed term of a series of chemical conversion " processing " herein, 2 kinds or multiple reactant are contacted with each other to realize chemical reaction, change or conversion.For example contact with each other when obtaining new chemical compound C when reactant A and reactant B, it is said that A is obtained C by B " processing ".

Term used herein " protection " refers to a kind of method, and in the described method, thereby the functional group in the chemical compound is covered in the generation selective reaction of the other places of described chemical compound with selection mode by non-reacted functional group.Described non-reacted functional group is called as " blocking group " in this article.For example, term used herein " hydroxy-protective group " refers to optionally cover hydroxyl (reactive group OH).Term used herein " appropriate protection group " refers to be applicable to the blocking group of preparation The compounds of this invention.The common use of this class group can not disturbed other segmental mild reaction conditions of host compound and be imported and remove by selectivity.The blocking group that is applicable to process of the present invention and method is well known to a person skilled in the art.(OH) blocking group of group includes, but not limited to trialkylsilyl ethers (such as-Si (CH for example to be suitable for Ldamanti ₃) ₃), alkyl oxide is (such as-CH ₃), the benzyl oxide that is unsubstituted and is substituted is (such as-CH ₂C ₆H ₅With right-methoxy-benzyl ether).The chemical property of these blocking groups, introduction method and its removal method can be at for example T.Greene and P.Wuts, Protective Groups in Organic Synthesis(the 3rd edition), John Wiley ﹠amp; Sons, NY finds in (1999).Term used herein " removes provide protection ", " through removing provide protection " or " removing provide protection " means the process of being removed blocking group by compound.

Term used herein " hydrolysis ", " hydrolysis ", " hydrolytic action " reach " through hydrolysis " and all mean a kind of chemical reaction, and in this reaction, ester, acid amides or both all can be by such as the proton (H that can be present in acidity or the alkaline aqueous solution ⁺) or (effect OH) and change into corresponding carboxylic acid derivative of hydroxyl negatively charged ion.

Term used herein " leavings group " refers to can take place at the atom place that is connected with it usually the chemical functional group of nucleophilic substitution reaction.For example in formula Cl-C (O) R acyl chlorides (wherein R is alkyl, aryl or heterocycle), described-Cl base is commonly referred to leavings group, because it can nucleophilic substitution reaction take place at the carbonyl carbon place that is connected with it.Suitable leavings group is well known to a person skilled in the art, and can comprise halogen, heteroaromatic, cyano group, amino (usually under acidic conditions), ammonium, alkoxyl group, carbonate group, Ldamant base and by with such as the reaction of the compound of carbonization imide and activatory Ldamanti base.For example suitable leavings group can comprise, but be not limited to chlorine, bromine, iodine, cyano group, imidazoles and the Ldamanti base that has reacted with carbonization imide (such as dicyclohexyl carbonization imide) (can be selected under the existence such as the hydroxybenzotriazole additive) or carbonization diimide derivative.

Term " composite reagent " refers to can be used for influencing the chemical reagent of required chemical reaction or more than one reagent in case of necessity the time.Factor well known to those skilled in the art is depended in the selection of particular agent or agent combination, it is drawn together, but is not limited to: other functional group that exists in the characteristic of reactant, the reactant, be used in the method for solvent, the temperature of carrying out chemical reaction and the required chemical reaction product of purifying in the particular chemical reaction.React being chosen in the scope that those skilled in the art can understand of required reagent or agent combination to influencing particular chemical, and do not need a large amount of experiments just can carry out this selection.In the present invention, formula (IV) compound for example can adopt the negatively charged ion of malonate derivative (such as malonic ester) to handle.For example formula (IV) compound can adopt malonic ester magnesium (such as malonic ester magnesium) to handle to obtain formula (III) compound.In this case, this malonic ester magnesium can be described as " reagent ".If malonic ester magnesium in-situ preparing and using without separating or being further purified down, then it can be described as " composite reagent ".

Term used herein " alkali " refers to so-called Bronsted-Lowry alkali.Bronsted-Lowry alkali is for accepting to be present in the proton (H of the acid in the reaction mixture ⁺) reagent.The example of Bronsted-Lowry alkali includes, but not limited to mineral alkali, such as yellow soda ash, sodium bicarbonate, sodium hydroxide, salt of wormwood, saleratus, potassium hydroxide and cesium carbonate; Organic bases, such as triethylamine, diisopropyl ethyl amine, diisopropylamine, dicyclohexylamine, morpholine, pyrrolidone, piperidines, pyridine, 4-N, N-Dimethylamino pyridine (DMAP) and imidazoles.

This term used herein " acid " refer to suitable Bronsted-Lowry acid and Lewis acid the two.Bronsted-Lowry acid is for providing proton (H for the alkali that is present in the reaction mixture ⁺) compound or reagent.Bronsted-Lowry acid comprises mineral acid and organic acid.Mineral acid includes, but not limited to spirit of salt, Hydrogen bromide, hydroiodic acid HI, sulfuric acid and nitric acid.Organic acid includes, but not limited to sulfonic acid (such as methylsulfonic acid, trifluoromethanesulfonic acid and right-toluenesulphonic acids) and carboxylic acid (formic acid, acetate and phenylformic acid).Lewis acid is for forming the chemical compound of so-called Lewis affixture by the electron pair that coordination reaction accepts to derive from corresponding Lewis alkali.Lewis alkali is for providing the chemical compound of electron pair for corresponding Lewis acid.Suitable Lewis acid includes, but not limited to aluminum chloride (III), titanium chloride (II), titanium chloride (IV), tin chloride (II) and tin chloride (IV).

Term used herein " chirality, non-racemize alkali " refers to and can exist but the basic cpd that do not exist with the form of the reverse enantiomer equivalent corresponding with it with enantiomeric forms.For example the sweet amine alcohol of compound 2-phenyl exists with two kinds of enantiomeric forms of reverse configuration, and promptly so-called (R)-and (S)-enantiomer.If (R)-and (S)-enantiomer equivalent exists, then this mixture is called as and has " racemism ".Yet, if a kind of amount of enantiomer greater than another kind of enantiomer, this mixture is called as and has " non-racemism ".

Term " steric isomer " refers to have identical chemical constitution, but the different compound of the spatial disposition of its atom or group.In more detail, term " enantiomer " refers to two kinds of steric isomers that mirror images of each other can not the eclipsed compound.Term used herein " racemize " or " racemic mixture " refer to the 1:1 mixture of the enantiomer of specific compound.On the other hand, term " diastereomer " relates to two or more center of asymmetries and the relation between a pair of steric isomer of mirror image each other not each other of comprising.

Term used herein " the stereochemistry enrichment " product refers to a kind of reaction product, and wherein the amount of particular stereoisomer is statistically obviously greater than the possible stereoisomerism product of another kind.For example wherein a kind of content of enantiomer product of being higher than another kind of enantiomer has constituted the product of stereochemistry enrichment.Similarly, wherein a kind of content of diastereoisomer product of being higher than all the other diastereomers has also constituted the product of stereochemistry enrichment.Method that this paper comprised and process it is said and can obtain " the stereochemistry enrichment " product.In this case, method that this paper comprised and process begin to carry out from the mixture of Stereoisomeric compounds, during beginning, the approximate equivalent of all possible steric isomer exists, and can obtain product, in the described product, the amount of at least a steric isomer is statistically obviously greater than all the other steric isomers.

Term used herein " diastereo-isomerism " refer to comprise two or more center of asymmetries and each other each other can a pair of steric isomer of overlapping mirror image between relation.Phrase used herein " diastereo-isomerism salt " or " diastereo-isomerism salt " refer to the salt of diastereo-isomerism compound, and wherein " diastereomer " as defined herein.

Term used herein " racemize " refers to contain the composition of 1:1 enantiomer.Term used herein " does not wait (scalemic) " and refers to contain the composition of inequality enantiomer.The composition that for example contains the 1:1 mixture of The compounds of this invention (R)-and (S)-enantiomer is called as racemize composition or mixture.As additional example, the composition that contains the 2:1 mixture of The compounds of this invention (R)-and (S)-enantiomer is called as and does not wait composition or mixture.Anticipate that clearly method of the present invention can be advantageously used in by racemic compound of the present invention and prepare the compound that do not wait of the present invention.

Term " fractionation effect " and " fractionation " refer to the method by the mixture of steric isomer (such as the racemic mixture of two kinds of enantiomers that contain specific compound) physical sepn Stereoisomeric compounds." fractionation effect " used herein and " fractionation " mean the part fractionation or split the two fully.

Term used herein " separation " or " through separating " are instigated at least two kinds of different chemical compounds isolating method of physics each other.If for example carry out chemical reaction and produce at least two kinds of products, (A) and (B), then make the isolating each other method of (A) and (B) be called as " separation " (A) with (B).Anticipate that clearly these centrifugations of the present invention can be that part is separated or separated fully, this measures by analytical technology well known by persons skilled in the art and described herein those.

Term used herein " conversion " refers to use raw material to carry out chemical reaction to produce the different chemical product.If for example make chemical reactant (A) and (B) react each other to produce product (C), then raw material (A) and (B) it is said and become product (C) by " conversions " or it is said that (A) is by " conversion " one-tenth (C) or (B) quilt " conversion " one-tenth (C).

Term used herein " suitable gegenion " refers to and the ion that is present in the ionic opposite charge in the The compounds of this invention that total mixture of result or salt are electric neutrality.Add up to negative 1 (1) electric charge if compound for example of the present invention contains, then suitable counter can be to have to add up to positive 1 (+1) electric charge, thereby can make this mixture or salt obtain ading up to the ion of neutral charge.The example of suitable just (+) gegenion includes, but not limited to sodium ion (Na ⁺), potassium ion (K ⁺), cesium ion (Cs ⁺) and protonated amines (such as protonated triethylamine, protonated dicyclohexyl amine, protonated morpholine or protonated pyridine).Perhaps, add up to positive 1 (+1) electric charge if compound of the present invention contains, then suitable gegenion can be to have to add up to negative 1 (1) electric charge, thereby can make this mixture or salt obtain ading up to the ion of neutral charge.The example of suitable negative (-) gegenion includes, but not limited to fluorion (F ^-), chlorion (Cl ^-), bromide anion (Br ^-), iodide ion (I ^-), hydroxide radical ( ^-OH) and acetate moiety ( ^-O-C (O) CH ₃).Suitable counter in the compound of the present invention (comprise with in the methods of the invention compound) also can have more than one the relevant single electric charge of compound therewith.If compound for example of the present invention contains negative 1 (1) electric charge, and suitable gegenion can contain positive 2 (+2) electric charge, then two The compounds of this invention and suitable gegenion associated with negative 1 electric charge.Example with suitable counter of an above positive charge includes, but not limited to calcium (Ca ²⁺).At last, anticipate also that compound of the present invention can contain an above electric charge, thereby the result needs an above suitable counter to make the neutrality that adds up to of mixture or salt.Compound for example of the present invention can contain more than one negative 1 (1) electric charge, and the result needs two suitable counter (tool positive 1 (+1) electric charge separately) thereby makes the neutrality that adds up to of mixture or salt.

Term " is substituted " and refers to that special groups or fragment have one or more substituting groups.Term " is unsubstituted " and refers to that special groups does not have substituting group.Term " optional replacement " refers to that special groups is unsubstituted or replaces through one or more substituting groups.

The solution of each Stereoisomeric compounds of the present invention can make the plane polarized light rotation.Known to the symbol " (+) " that uses in the The compounds of this invention name or " (-) " expression as the use technical measurement well known by persons skilled in the art, the solution of particular stereoisomer can make the plane polarized light rotation along (+) or (-) direction.

Term used herein " HCV " refers to hepatitis C virus (hepatitis C virus).

Term " inhibition hepatitis C virus " and " suppress hepatitis C virus duplicate " refer to contact with hepatitis C virus and suppress hepatitis C virus and duplicate in the external or body such as Mammals (such as the people) by making HCV duplicate the The compounds of this invention of amount of suppression or its pharmaceutically-acceptable salts or solvate.Can in such as Mammals (such as the people's) body, carry out above-mentioned restraining effect by Mammals is bestowed the The compounds of this invention of hepatitis C virus amount of suppression.Can use method known to those skilled in the art to measure inhibition HCV virus and in or body external, duplicate required The compounds of this invention amount such as Mammals (such as the people).For example can bestow a certain amount of The compounds of this invention to Mammals separately or as the some of pharmaceutically acceptable preparation.Can take a blood sample by Mammals then, and use method known to those skilled in the art that the content of hepatitis C virus in the sample is carried out quantitatively.With bestow before the The compounds of this invention in the blood content of hepatitis C virus relatively, the restraining effect that the minimizing of hepatitis C virus quantity representative is duplicated hepatitis C virus in the Mammals in the sample.Mammals is bestowed compound of the present invention can or be a series of dosage forms of continuous a couple of days for the single dose form.

Term used herein " HCV suppresses medicament " refers to (R)-6-cyclopentyl-6-, and (2-(2,6-parvoline-4-yl) ethyl)-3-((5,7-dimethyl-[1,2,4] triazolo [1,5-a] pyrimidine-2-base) methyl)-4-hydroxyl-5, the crystal formation of 6-dihydropyrane-2-ketone or its pharmaceutically-acceptable salts.

Term described herein " HCV amount of suppression " refers to when to Mammals (such as the people) when bestowing, and is enough to suppress the consumption of the The compounds of this invention that hepatitis C virus duplicates.

Term used herein " HCV polysaccharase amount of suppression " refers to when compound is contacted with enzyme, is enough to suppress the consumption of the The compounds of this invention of hepatitis C virus polysaccharase effect.

Unless otherwise stated, used herein with the relevant term " treatment " of the mammiferous treatment that infected by HCV is instigated this term suitable deficiency disorder or the evolution process of illness or one or more symptom of described deficiency disorder or illness reverse, alleviate, suppress, or prevent one or more symptom of described deficiency disorder or illness or described deficiency disorder or illness.Unless otherwise stated, term used herein " treatment " refers to treatment behavior, as directly in above defined " treatment ".

Unless otherwise stated, term used herein " pharmaceutically-acceptable salts " comprises the acidity that can be present in the The compounds of this invention or the acid of basic group.This The compounds of this invention as alkalescence can form various salt with various mineral acids and organic acid.The acid that can be used for preparing the pharmaceutical acceptable acid additive salt of basic cpd of the present invention is, can form the acid of following non-toxic acid addition salt: promptly contain on the pharmacology and can accept anionic salt, such as acetate, benzene sulfonate, benzoate, supercarbonate, hydrosulfate, bitartrate, borate, bromide, calcium Ldamanti, camsilate, carbonate, muriate, Clavulanate (clavulanate), Citrate trianion, dihydrochloride, Ldamanti, own stilbene-4,4'-bis-(1-azo-3, 4-dihydroxy-benzene)-2,2'-disulfonate, lauryl sulfate, esilate, ethylsuccinate, fumarate, gluceptate, gluconate, glutaminate, to hydroxyl kharophen phenylarsonic acid (glycollylarsanilate) salt, hexylresorcin salt, Hai Bamin (hydrabamine), hydrobromate, hydrochloride, iodide, different sulphur hydrochlorate, lactic acid salt, Lactobionate, lauroleate, malate, maleic acid salt, mandelate, mesylate, Methylsulfate, the mucus hydrochlorate, naphthalenesulfonate, nitrate, oleate, oxalate, palmoxiric acid salt (embonate (embonate)), palmitate, pantothenate, the Ldamantin/ diphosphate, Polygalacturonate, salicylate, stearate, inferior acetate, succinate, tannate, tartrate, chloro theophylline salt (teoclate), tosylate, triethiodide (triethiodode) and valerate.

Phrase " significant quantity in the treatment ", " significant quantity " and " HCV-amount of suppression " mean, when the Mammals of needs treatment is bestowed, be enough to strengthen anti-cancer therapies or cause the neurotoxicity of apoplexy, head trauma and neurodegenerative disease to alleviate injury or illness such as being used to, to reach the pharmaceutical quantities of the present invention of therapeutic purpose by inhibition by suppressing the HCV rna replicon.Significant quantity can be according to following factor and difference in the treatment of used in the methods of the invention specific HCV inhibitor: such as specific HCV inhibitor, illness and seriousness thereof, need the mammal species and the feature of treatment, this consumption can be by technician's conventional determining.

Description of drawings

Fig. 1 is crystal formation (R)-6-cyclopentyl-6-(2-(2,6-parvoline-4-yl) ethyl)-3-((5,7-dimethyl-[1,2,4] triazolo [1,5-a] pyrimidine-2-base) methyl)-4-hydroxyl-5, the illustrative x-ray diffractogram of powder of 6-dihydropyrane-2-ketone.

Fig. 2 is crystal formation (R)-6-cyclopentyl-6-(2-(2,6-parvoline-4-yl) ethyl)-3-((5,7-dimethyl-[1,2,4] triazolo [1,5-a] pyrimidine-2-base) methyl)-4-hydroxyl-5, the illustrative solid state NMR spectrogram of 6-dihydropyrane-2-ketone.

Fig. 3 is crystal formation (R)-6-cyclopentyl-6-(2-(2,6-parvoline-4-yl) ethyl)-3-((5,7-dimethyl-[1,2,4] triazolo [1,5-a] pyrimidine-2-base) methyl)-4-hydroxyl-5, the illustrative differential scanning calorimetric figure of 6-dihydropyrane-2-ketone.

Embodiment

According to this area routine, the symbol in this paper structural formula

The key of fragment or substituting group and nuclear structure or backbone structure tie point is described.According to another routine, in some structural formulas of this paper, carbon atom and its bonded hydrogen atom clearly do not illustrate, for example Represent methylidene, Represent ethyl,

Represent cyclopentyl etc.

Compound of the present invention can exist with the form of several tautomers.For example, shown in following (A), compound of the present invention can exist with the form that two ketone groups are present on the ring of compound.Perhaps, following compound (B) and (C) shown in, compound of the present invention can exist with the form of two kinds of different enols at least.These 3 kinds of forms are in equilibrium state, and compound of the present invention can exist with more than one these forms simultaneously.For example, in specific compound of the present invention, specific percentile molecule may reside in the form (A), and rest part be present in form (B) and (C) in.Any form accounts for to dominate and depends on several factors in specific compound of the present invention, and whether it includes, but not limited to compound is solid, liquid or crystallized form, and whether compound is dissolved in the solvent, solvent types, envrionment temperature and relative humidity.Anticipate clearly, when compound of the present invention with particular form, form (A) for example during expression, also comprises all tautomers simultaneously, for example form (B) and (C).

Compound of the present invention can have asymmetric c atom.Can use solid line (---), real wedge shape line herein

Or empty wedge shape line

The C-C of The compounds of this invention is described.Represent with the solid line description and the associative key of asymmetric c atom, on this carbon atom, comprise all possible steric isomer.State with the associative key of asymmetric c atom with real or empty wedge shape line drawing and to represent, only comprise unique shown in steric isomer.Compound of the present invention can contain an above asymmetric c atom.In these compounds, represent with the solid line description and the associative key of asymmetric c atom, comprise all possible steric isomer.Mean with realizing being described in the compound of the present invention, have the mixture of diastereomer with the associative key of one or more asymmetric c atom and the associative key that is described in the same compound with other asymmetric c atom with reality or empty wedge shape line.

Can pass through method known to those skilled in the art, for example chromatography or fractional crystallizaton method are separated into independent diastereomer with the diastereo-isomerism mixture according to the difference of its physical chemistry.Separating enantiomer can be as follows; By the enantiomerism mixture being changed into the diastereo-isomerism mixture with suitable optically active compounds (for example chirality, non-racemize alkali) reaction, diastereomeric separation is come out, and independent diastereomer is transformed the pure enantiomer that (for example hydrolysis) becomes correspondence.All these isomer comprise diastereo-isomerism mixture and pure to isomer, are considered to some of the present invention.

Perhaps, can make the of the present invention independent Stereoisomeric compounds of enantiomerism enriched form by asymmetric synthesis method.It is asymmetric synthetic to use technology well known by persons skilled in the art to carry out, such as the asymmetric prepared using method known to those skilled in the art of using commercially available or easy preparation, use can maybe can use enzyme catalysis to carry out the fractionation of midbody compound by removed asymmetric adjuvant when synthetic method is finished.Selection to these methods can be depending on following factor, and it includes, but not limited to the operability of raw material, whether relative efficiency and this method of method is applicable to the compound of the present invention that contains the particular functional group.This selection is included in the scope of those skilled in the art's understanding.

And " three-dimensional chosen process " is the method for a kind of particular stereoisomer of reaction product than the preferential generation of other possible steric isomer of this product.Enantioselectivity quantitatively be usually following defined " enantiomerism is excessive " (ee): [the excessive A of enantiomerism (ee) %=(enantiomer A%) (enantiomer B%)], wherein A and B are the enantiomerism product that is formed by raw material.

When compound of the present invention contained asymmetric c atom, its derivative salt, prodrug and solvate can exist with the form of single stereoisomers, racemic modification and/or enantiomer and/or non-enantiomer mixture.All these single steric isomers, racemic modification and composition thereof are included in the present invention's the scope.

As usually known to those skilled in the art, optically pure compound is the compound of enantiomer-pure.According to the present invention, optically pure compound preferably comprises at least 90% (80% enantiomerism is excessive), more preferably contain at least 95% (90%e.e.), even more preferably contain at least 97.5% (95%e.e.), most preferably contain the single stereoisomers of at least 99% (98%e.e.).

Used powder X-ray diffractometry (PXRD), solid state NMR (ssNMR) and dsc (DSC) to characterize the contained crystal formation of the present invention.Those skilled in the art recognize that X-ray diffractogram, solid state NMR spectrum and differential scanning calorimetric scanning have measuring error, it depends on employed condition determination.In more detail, the intensity in the common known X-ray diffractogram can fluctuate according to employed condition determination.Should recognize further that relative intensity also changes according to experiment condition, therefore, should not consider the definite order of magnitude of intensity.In addition, the measuring error of the angle of diffraction of conventional X-ray diffractogram is generally about 0.1 (representing with the 2 θ number of degrees), and should consider above-mentioned measuring error degree is applicable to above-mentioned diffraction angle.And the ppm measuring error in solid state NMR spectrum is generally about 0.2ppm, and should consider above-mentioned measuring error degree is applicable to above-mentioned diffraction angle.In addition, all " ppms " relevant with peak in the solid state NMR spectrum are relevant with the external standard of crystal Ldamantine, and its High-Field resonance is set to 29.5ppm.Therefore, should recognize that X-ray diffractogram, ssNMR spectrum or the DSC stitching and the described X-ray diffractogram of this paper accompanying drawing, ssNMR spectrum or the identical crystal formation of DSC stitching that are provided is provided crystal formation of the present invention.The X-ray diffractogram that is provided, ssNMR spectrum or DSC stitching all belong to the scope of the invention with the described substantially the same any crystal formation of accompanying drawing.The ability of determining the fundamental characteristics of X-ray diffractogram, ssNMR spectrum or DSC stitching is that those skilled in the art should possess.

If with derivative in the methods of the invention is alkali, then required salt can be made by any appropriate method known in the art, and described method comprises uses following acid treatment free alkali: mineral acid, all example hydrochloric acids, Hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid etc.; Or organic acid, such as acetate, toxilic acid, succsinic acid, amygdalic acid, fumaric acid, propanedioic acid, pyruvic acid, oxalic acid, oxyacetic acid, Whitfield's ointment, pyrans glycosyl acid (such as glucuronic acid or galacturonic acid), alpha hydroxy acid (such as citric acid or tartrate), amino acid (such as aspartic acid or L-glutamic acid), aromatic acid (such as phenylformic acid or styracin), sulfonic acid (such as right-toluenesulphonic acids or ethyl sulfonic acid) etc.

Be acid if be used in the derivative of the inventive method, then required salt can be made by any appropriate method known in the art, described method comprises uses inorganic or organic bases, such as amine (primary, the second month in a season or uncle), basic metal or alkaline earth metal hydroxides etc., to handle free acid.The illustrative example of acceptable acid addition salts comprises organic salt, and it is derived from amino acid (such as glycine and arginine), ammoniacal liquor, primary, the second month in a season and tertiary amine and cyclic amine (such as piperidines, morpholine and piperazine); And inorganic salt, it is derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminium and lithium.

The preparation method of compound of the present invention is as follows.Be to be understood that the details of methods described herein only can be used for preparing the representative of The compounds of this invention method for those skilled in the art.In the others of invention required for protection, suitable alternative and equivalent comprise interchangeable reagent, solvent and temperature, can be expected immediately and are used to prepare compound of the present invention by those skilled in the art, and not need a large amount of experiments.Therefore, below explanation can't and should not be considered as the scope of the present invention for required protection is limited in any way.

As shown in the formula (Ia) but compound through type (II) compound (R wherein ¹And R ²As defined herein) react and prepare with formula (IXa) compound,

Wherein:

R ¹Be C ₁To C ₆Alkyl or C ₃To C ₆Cycloalkyl;

R ^2a, R ^2bAnd R ^2cIndependently be selected from hydrogen, halogen, C separately ₁To C ₆Alkyl, C ₃To C ₆Cycloalkyl ,-OR ^12a,-CF ₃,-CN and-NR ^12aR ^12b

R ⁹And R ¹⁰Be selected from hydrogen and C independently of one another ₁To C ₆Alkyl, or R ⁹And R ¹⁰Connect the ground atom with them and form C ₃To C ₆Cycloalkyl;

Each R ¹¹Be independently selected from hydrogen, C ₁To C ₆Alkyl, halogen ,-OR ¹²,-CN ,-CF ₃With-NR ^12aR ^12b

Each n is independently selected for use, is 0 to 5 integer;

These reactions are carried out in the presence of reductive agent (such as the borine source or at the hydrogen in the presence of the suitable catalyst) usually.Suitable borine source includes, but not limited to diboron hexahydride, borine-THF, borine-methyl-sulfide, borine-Trimethylamine 99 title complex, borine-dimethylamine title complex, borine tert-butylamine title complex and borine-pyridine complex.The catalyzer that is suitable in the presence of reductive agent (such as hydrogen) comprises, but is not limited to nickel, palladium, platinum, rhodium and ruthenium.And this is reflected in the solvent that can not disturb required chemical reaction or in the solvent mixture and carries out.And, suitable solvent comprise those skilled in the art known can with the solvent of reaction conditions compatibility, it comprises alkane ester and aromatic ester, alkane ether, heterocyclic ether and aryl oxide, hydrocarbon, alkanol and fragrant and mellow, alkyl halide compound and aryl halogenated compound, alkane nitrile or fragrant nitrile, alkane ketone and arone and non-proton heterocyclic solvents.For example suitable solvent comprises, but be not limited to, ethyl acetate, isobutyl acetate, isopropyl acetate, acetate just-butyl ester, hexone, glycol dimethyl ether, Di Iso Propyl Ether, chlorobenzene, dimethyl formamide, N,N-DIMETHYLACETAMIDE, propionitrile, butyronitrile, uncle-amylalcohol, acetate, diethyl ether, methyl-tert-butyl ether, phenyl ether, methyl phenyl ether, tetrahydrofuran (THF), the 2-methyltetrahydrofuran, 1, the 4-dioxane, pentane, hexane, heptane, methyl alcohol, ethanol, the 1-propyl alcohol, the 2-propyl alcohol, uncle-butanols, just-butanols, the 2-butanols, methylene dichloride, chloroform, 1, the 2-ethylene dichloride, acetonitrile, benzonitrile, benzene, toluene, methyl-phenoxide, dimethylbenzene and pyridine, or any mixture of above-mentioned solvent.In addition, water can be used as cosolvent, and its restricted condition is not for disturbing required conversion.At last, above-mentioned reaction can be under about 0 ℃ of temperature to about 75 ℃ of scopes, preferably approximately-20 ℃ to the temperature of about 32 ℃ of scopes, most preferably under room temperature or envrionment temperature, carry out.Selection to specific reductant, solvent and temperature can be depending on several factors, and it includes, but not limited to the characteristic and the functional group that is present in the described reactant of specific reactants.This being chosen in the scope that those skilled in the art can understand, and need not test in a large number.

Perhaps, formula (Ia) compound can react and make by making formula (II) compound and formula (Ixb) compound (wherein X is suitable leavings group).Suitable leavings group includes, but not limited to halogen (such as chlorine, bromine and iodine) and Acibenzolar (such as methanesulfonates, trifluoromethayl sulfonic acid ester and tosylate).Can in the presence of appropriate base, carry out above-mentioned reaction.Appropriate base comprises, but be not limited to, yellow soda ash, sodium bicarbonate, salt of wormwood, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, lithium hydride, potassium hydride KH, lithium diisopropylamine (lithium diisopropylamide), pyridine, triethylamine, Tributylamine, trolamine, N-methylmorpholine, N-ethyl-N, N-Diisopropylamine and 4-N, the N-Dimethylamino pyridine.And, suitable solvent comprise those skilled in the art known can with the solvent of reaction conditions compatibility, comprise alkane ether, heterocyclic ether and aryl oxide, hydrocarbon, alkyl halide compound and aryl halogenated compound, alkane nitrile or fragrant nitrile and non-proton heterocyclic solvents.For example suitable dissolving comprises, but be not limited to, glycol dimethyl ether, diisopropyl ether, chlorobenzene, dimethyl formamide, N,N-DIMETHYLACETAMIDE, propionitrile, butyronitrile, diethyl ether, methyl-tert-butyl ether, phenyl ether, methyl phenyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran, 1, any mixture of 4-dioxane, pentane, hexane, heptane, acetonitrile, benzonitrile, benzene, toluene, methyl-phenoxide, dimethylbenzene and pyridine or above-mentioned solvent.In addition, water can be used as cosolvent, and its restricted condition is not for disturbing required conversion.At last, described reaction can be under about 0 ℃ of temperature to about 150 ℃ of scopes, preferably under about 0 ℃ of temperature to about 32 ℃ of scopes, most preferably carries out under room temperature or envrionment temperature.This being chosen in the scope that those skilled in the art can understand, and need not test in a large number.

Formula (II) compound, wherein R ¹, R ⁴, R ⁵, R ⁶And R ⁷As defined above,

Can be by making formula (III) compound (R wherein ¹, R ⁴, R ⁵, R ⁶And R ⁷As defined above and R ¹⁴Be C ₁To C ₆Alkyl or benzyl) react with suitable acid or alkali and to prepare.

The alkali that is applicable to above-mentioned reaction comprises mineral alkali and organic bases.Suitable mineral alkali includes, but not limited to yellow soda ash, sodium bicarbonate, salt of wormwood, saleratus, sodium hydroxide, sodium hydride, potassium hydride KH and cesium carbonate.Described alkali is preferably salt of wormwood.Suitable organic bases includes, but not limited to pyridine, triethylamine, Tributylamine, trolamine, N-methylmorpholine, N-ethyl-N, N-Diisopropylamine, DBU and 4-N, N-Dimethylamino pyridine.This reaction also can be carried out in the presence of the appropriate acid of catalytic amount.Suitable acid comprise Bronsted-Lowry acid and Lewis acid the two.And these reactions are carried out in the solvent that can not disturb required chemical reaction or in the solvent mixture usually.And, suitable solvent comprise those skilled in the art known can with the solvent of reaction conditions compatibility, comprise alkane ester and aromatic ester, alkane ether, heterocyclic ether and aryl oxide, hydrocarbon, alkanol and fragrant and mellow, alkyl halide compound and aryl halogenated compound, alkane nitrile or fragrant nitrile, alkane ketone and arone and non-proton heterocyclic solvents.For example suitable solvent comprises, but be not limited to, ethyl acetate, isobutyl acetate, isopropyl acetate, acetate just-butyl ester, hexone, glycol dimethyl ether, Di Iso Propyl Ether, chlorobenzene, dimethyl formamide, N,N-DIMETHYLACETAMIDE, propionitrile, butyronitrile, uncle-amylalcohol, acetate, diethyl ether, methyl-tert-butyl ether, phenyl ether, methyl phenyl ether, tetrahydrofuran (THF), the 2-methyltetrahydrofuran, 1, the 4-dioxane, pentane, hexane, heptane, methyl alcohol, ethanol, the 1-propyl alcohol, the 2-propyl alcohol, uncle-butanols, just-butanols, the 2-butanols, methylene dichloride, chloroform, 1, the 2-ethylene dichloride, acetonitrile, benzonitrile, acetone, 2-butanone, benzene, toluene, methyl-phenoxide, the any mixture of dimethylbenzene and pyridine or above-mentioned solvent.In addition, water can be used as cosolvent, and its restricted condition is not for disturbing required conversion.At last, described reaction can be under about 0 ℃ of temperature to about 110 ℃ of scopes, or under about 25 ℃ of temperature to about 100 ℃ of scopes, or under about 35 ℃ of temperature to about 75 ℃ of scopes, or under about 45 ℃ of temperature to about 55 ℃ of scopes, or under about 50 ℃, carry out.Selection to specific solvent and temperature can be depending on several factors, and it includes, but not limited to the characteristic and the functional group that is present in the described reactant of specific reactants.This being chosen in the scope that those skilled in the art can understand, and need not test in a large number.

Perhaps, formula (II) compound (R wherein ¹, R ⁴, R ⁵, R ⁶And R ⁷As defined above) can be by making formula (III) compound (R wherein ¹, R ⁴, R ⁵, R ⁶And R ⁷As defined above and R ¹⁴Be hydrogen) react to realize that cyclisation makes with suitable reagent or composite reagent.

Above-mentioned reaction can be carried out in the presence of reagent that carboxylation-OH groups converted can be become suitable leavings group (such as chlorine or imidazolyl) or composite reagent.Term " suitable leavings group " refers to when the reaction of the carbonyl carbon on the carboxyl in suitable nucleophilic group (such as hydroxyl) and formula (III) compound, can substituted chemical group.Described suitable leavings group can be by formula (III) compound and suitable agent well known by persons skilled in the art or composite reagent be reacted introducing-type (III) compound (R wherein ¹⁴Be hydrogen).For example can make formula (III) compound (R wherein ¹⁴Be hydrogen) with carbonyl chloride (ClC (O) Cl), three carbonyl chlorides ((Cl) ₃C (O) (Cl) ₃), SOCl ₂Or (COCl) ₂React to obtain so-called acyl chlorides, that is to say, in described compound, the carboxylic hydroxyl is replaced by the chlorine atom.And, can make formula (III) compound change into the compound that carboxylic hydroxyl is wherein replaced by the suitable leavings group of another kind (such as imidazolyl).This compound can use suitable reagent or composite reagent (such as carbonyl dimidazoles) to prepare.This reaction can carried out in the presence of the appropriate base (such as triethylamine) and in the aprotic solvent that can not disturb required chemical reaction (for example chloroform or methylene dichloride).And this reaction can be under about-78 ℃ of temperature to about 75 ℃ of scopes, or under about 0 ℃ of temperature to about 50 ℃ of scopes, or carry out under about 0 ℃ of temperature to about 25 ℃ of scopes.To being chosen in the scope that those skilled in the art can understand of the suitable agent, suitable solvent and the suitable temp that this carboxyl are changed into acyl chlorides, and need not test in a large number.

Formula (III) compound then, wherein the carboxylic hydroxyl oneself be converted to suitable leavings group (for example acyl chlorides), can in the presence of appropriate base, transform an accepted way of doing sth (II) compound by reaction.Suitable alkali includes, but not limited to mineral alkali and organic bases.Suitable mineral alkali includes, but not limited to yellow soda ash, sodium bicarbonate, salt of wormwood, saleratus and cesium carbonate.Suitable organic bases includes, but not limited to pyridine, triethylamine, diethyl Isopropylamine and 4-N, N-dimethyl aminopyridine.And, suitable solvent comprise those skilled in the art known can with the solvent of reaction conditions compatibility, comprise alkane ester and aromatic ester, alkane ether, heterocyclic ether and aryl oxide, hydrocarbon, alkanol and fragrant and mellow, alkyl halide compound and aryl halogenated compound, alkane nitrile or fragrant nitrile, alkane ketone and arone and non-proton heterocyclic solvents.For example suitable solvent comprises, but be not limited to, ethyl acetate, isobutyl acetate, isopropyl acetate, acetate just-butyl ester, hexone, glycol dimethyl ether, Di Iso Propyl Ether, chlorobenzene, dimethyl formamide, N,N-DIMETHYLACETAMIDE, propionitrile, butyronitrile, uncle-amylalcohol, acetate, diethyl ether, methyl-tert-butyl ether, phenyl ether, methyl phenyl ether, tetrahydrofuran (THF), the 2-methyltetrahydrofuran, 1, the 4-dioxane, pentane, hexane, heptane, methyl alcohol, ethanol, the 1-propyl alcohol, the 2-propyl alcohol, uncle-butanols, just-butanols, the 2-butanols, methylene dichloride, chloroform, 1, the 2-ethylene dichloride, acetonitrile, benzonitrile, acetone, 2-butanone, benzene, toluene, methyl-phenoxide, the any mixture of dimethylbenzene and pyridine or above-mentioned solvent.To being chosen in especially in the scope that those skilled in the art can understand of the activator, solvent, alkali and the temperature that influence required conversion, and need not test in a large number.

As follows, can be by formula (IV) compound (R wherein ¹, R ⁴, R ⁵, R ⁶And R ⁷As defined above, P ¹Be hydrogen or suitable blocking group and R ¹³Be hydrogen, C ₁To C ₆Alkyl ,-Si (C ₁To C ₆Alkyl) ₃Or-CH ₂(C ₆To C ₁₀Aryl), wherein said C ₆To C ₁₀Aryl is optional by at least a halogen, the C of being selected from ₁To C ₆Alkyl ,-OH ,-OCH ₃With-N (C ₁To C ₆Alkyl) ₂Substituting group replace), or by formula (IVa) compound (R wherein ¹, R ⁴, R ⁵, R ⁶And R ⁷As defined above, P ¹For hydrogen or suitable and blocking group and L are suitable leavings group) make formula (III) compound, wherein R ¹, R ⁴, R ⁵, R ⁶And R ⁷As defined above, P ¹Be hydrogen or suitable blocking group and R ¹⁴Be C ₁To C ₆Alkyl ,-Si (C ₁To C ₆Alkyl) ₃Or-CH ₂(C ₆To C ₁₀Aryl), wherein said C ₆To C ₁₀Aryl is optional by at least a halogen, the C of being selected from ₁To C ₆Alkyl ,-OH ,-OCH ₃With-N (C ₁To C ₆Alkyl) ₂Substituting group replace.

Can make wherein R ¹³For formula (IV) compound of hydrogen and the reagent or the composite reagent that the carboxylic hydroxyl can be changed into suitable leavings group-OA react.Described leavings group comprises that Acibenzolar is (such as various benzoyl esters, for example 2,6-dinitrobenzene carbamoyl ester or perfluor benzoyl ester), mixed acid anhydride or react the intermediate of institute's deutero-by carboxyl and carbonization imide (such as diethyl carbonization imide or di-isopropyl carbonization imide).Can make an appointment with-78 ℃ to about 100 ℃ temperature, or under about 0 ℃ of temperature to about 75 ℃ of scopes, or under about 0 ℃ of temperature to about 50 ℃ of scopes, in the solvent that can not disturb required chemical reaction (such as chloroform, methylene dichloride or tetrahydrofuran (THF)), react by carboxyl and suitable agent (such as the carbonization imide) and to make above-mentioned midbody compound.Formula (IV) compound that contains suitable leavings group-OA can be handled by segregation or can be reacted in next step and need not be further purified.The compound that contains suitable leavings group-OA can react to obtain formula (III) compound with reagent or composite reagent.Described suitable reagent includes, but are not limited to: the malonate negatively charged ion, and it adopts suitable alkali to carry out the deprotonation reaction by the malonic ester derivative and derives; With malonic ester magnesium, such as propanedioic acid methyl esters magnesium and malonic ester magnesium.And, suitable solvent comprise those skilled in the art known can with the solvent of reaction conditions compatibility, comprise that alkane ester and aromatic ester, alkane ether, heterocycle are ether and aryl oxide, hydrocarbon, alkanol and fragrant and mellow, alkyl halide compound and aryl halogenated compound, alkane nitrile or fragrant nitrile, alkane ketone and arone and non-proton heterocyclic solvents.For example suitable solvent comprises, but be not limited to, ethyl acetate, isobutyl acetate, isopropyl acetate, acetate just-butyl ester, hexone, glycol dimethyl ether, Di Iso Propyl Ether, chlorobenzene, dimethyl formamide, N,N-DIMETHYLACETAMIDE, propionitrile, butyronitrile, uncle-amylalcohol, acetate, diethyl ether, methyl-tert-butyl ether, phenyl ether, methyl phenyl ether, tetrahydrofuran (THF), the 2-methyltetrahydrofuran, 1, the 4-dioxane, pentane, hexane, heptane, methyl alcohol, ethanol, the 1-propyl alcohol, the 2-propyl alcohol, uncle-butanols, just-butanols, the 2-butanols, methylene dichloride, chloroform, 1, the 2-ethylene dichloride, acetonitrile, benzonitrile, acetone, 2-butanone, benzene, toluene, methyl-phenoxide, the any mixture of dimethylbenzene and pyridine or above-mentioned solvent.And, this be reflected at about 0 ℃ to about 150 ℃ of scopes, or about 0 ℃ to about 75 ℃ of scopes, or about 20 ℃ to about 75 ℃ of scopes, or under about 25 ℃ of temperature to about 50 ℃ of scopes, or under about 40 ℃, carry out.Reagent or composite reagent group, solvent or all kinds of SOLVENTS and temperature specific is chosen in the scope that those skilled in the art can understand, and need do not test in a large number.

Perhaps, formula (III) compound can be by formula (IV) compound (R wherein ¹³Be C ₁To C ₆Alkyl, Si (C ₁To C ₆Alkyl) ₃Or-CH ₂(C ₆To C ₁₀Aryl), wherein said C ₆To C ₁₀Aryl is optional by at least a halogen, the C of being selected from ₁To C ₆Alkyl ,-OH ,-OCH ₃With-N (C ₁To C ₆Alkyl) ₂Substituting group replace) make by reacting with reagent or composite reagent.Described suitable reagent includes, but are not limited to, and malonic ester magnesium is such as propanedioic acid methyl esters magnesium and malonic ester magnesium.Suitable reagent includes, but are not limited to, the malonate negatively charged ion, and it is carried out deprotonation reaction and derives through appropriate base by the malonic ester derivative; With malonic ester magnesium, such as propanedioic acid methyl esters magnesium and malonic ester magnesium.And, suitable solvent comprise those skilled in the art known can with the solvent of reaction conditions compatibility, comprise alkane ester and aromatic ester, alkane ether, heterocyclic ether and aryl oxide, hydrocarbon, alkanol and fragrant and mellow, alkyl halide compound and aryl halogenated compound, alkane nitrile or fragrant nitrile, alkane ketone and arone and non-protonization heterocyclic solvents.For example suitable solvent comprises, but be not limited to, ethyl acetate, isobutyl acetate, isopropyl acetate, acetate just-butyl ester, hexone, glycol dimethyl ether, Di Iso Propyl Ether, chlorobenzene, dimethyl formamide, N,N-DIMETHYLACETAMIDE, propionitrile, butyronitrile, uncle-amylalcohol, diethyl ether, methyl-tert-butyl ether, phenyl ether, methyl phenyl ether, tetrahydrofuran (THF), the 2-methyltetrahydrofuran, 1, the 4-dioxane, pentane, hexane, heptane, methyl alcohol, ethanol, the 1-propyl alcohol, the 2-propyl alcohol, uncle-butanols, just-butanols, the 2-butanols, methylene dichloride, chloroform, 1, the 2-ethylene dichloride, acetonitrile, benzonitrile, acetone, 2-butanone, benzene, toluene, methyl-phenoxide, the any mixture of dimethylbenzene and pyridine or above-mentioned solvent.And, this be reflected at about 0 ℃ to about 150 ℃ of scopes, or about 0 ℃ to about 75 ℃ of scopes, or about 20 ℃ to about 75 ℃ of scopes, or under about 25 ℃ of temperature to about 50 ℃ of scopes, or under about 40 ℃, carry out.Reagent or composite reagent, solvent or all kinds of SOLVENTS and temperature specific is chosen in the scope that those skilled in the art can understand, and need do not test in a large number.

In addition, formula (III) compound can be by formula (IVa) compound (R wherein ¹, R ⁴, R ⁵, R ⁶And R ⁷As defined above, P ¹For hydrogen or suitable blocking group and L are suitable leavings group) make by reacting with reagent or composite reagent.Suitable leavings group includes, but are not limited to: chlorine, bromine, iodine and imidazoles.Compound with suitable leavings group can be by formula (IV) compound, wherein R ¹³Be-OH, make by reacting with activating reagent that can enough L substitutes the carboxylic hydroxyl or combination activating reagent.Described activating reagent includes, but not limited to thionyl chloride (SOCl ₂), carbonyl chloride, three carbonyl chlorides, oxalyl chloride and carbonyl dimidazoles.These reactions are by carrying out under the existence of the alkali that can not disturb required chemical reaction (such as triethylamine, ethyl diisopropyl amine, pyridine or 4-N, the N-Dimethylamino pyridine).In addition, this is reflected in the aprotonic solvent (such as tetrahydrofuran (THF), methyl butyl ether, diisopropyl ether, diethyl ether, toluene, chloroform, methylene dichloride or 1,2-ethylene dichloride) that can not disturb required chemical reaction and carries out.And this is reflected at approximately-78 ℃ to about 100 ℃ of scopes, or approximately-50 ℃ to about 100 ℃ of scopes, or about 0 ℃ to about 75 ℃ of scopes, or about 0 ℃ to about 50 ℃ of scopes, or carry out under about 0 ℃ of temperature to about 25 ℃ of scopes.After formula (IV) compound transformed an accepted way of doing sth (IVa) compound, formula (IVa) compound can react with the reagent or the composite reagent that this formula (IVa) compound can be transformed an one of accepted way of doing sth (III) compound.Described suitable reagent includes, but are not limited to, and malonic ester magnesium is such as propanedioic acid methyl esters magnesium and malonic ester magnesium.These are reflected in the solvent (such as diethyl ether, methyl-tert-butyl ether and tetrahydrofuran (THF) or its mixture) that can not disturb required chemical reaction or carry out in the solvent mixture.In addition, this be reflected at about 0 ℃ to about 100 ℃ of scopes, or about 0 ℃ to about 75 ℃ of scopes, or about 20 ℃ to about 75 ℃ of scopes, or under about 25 ℃ of temperature to about 50 ℃ of scopes or under about 40 ℃, carry out.Reagent or composite reagent, solvent or all kinds of SOLVENTS and temperature specific is chosen in the scope that those skilled in the art can understand, and need do not test in a large number.

The step that formula (IV), (IVa) compound or its suitable activated derivatives and reagent or composite reagent react to obtain formula (III) compound need import appropriate protection group, P ¹, with the tert-hydroxyl of protection (IV) compound.This blocking group should can selective protection introducing-type (IV) compound under the condition of described hydroxyl.Described reagent and condition are well known to those skilled in the art, and can be at for example T.Greeneand P.Wuts, Protective Groups in Organic Synthesis(the 3rd edition), John Wiley ﹠amp; Sons, NY finds in (1999).For example can be with in silyl protecting group (such as the triisopropyl silyl) introducing-type (IV) compound, to select the described tert-hydroxyl of protection.Can for example in aprotonic solvent (for example chloroform), use activation silane (such as the triisopropyl silyl chloride) in the presence of the alkali (such as triethylamine) to import above-mentioned group.Protected formula (IV) compound is reacted as mentioned above, to obtain formula (III) compound for protected form.Then the compound (III) through protection can use condition well known by persons skilled in the art to carry out deprotection.If for example the tert-hydroxyl group in formula (III) compound adopts for example silyl ether protection; then can use fluoride source (for example tetrabutyl ammonium fluoride); about 0 ℃ to about 100 ℃ of scopes, or under about 0 ℃ of temperature to about 25 ℃ of scopes in solvent (such as THF) deprotection.Whether the tert-hydroxyl in formula (IV) compound need be protected before transforming an accepted way of doing sth (III) compound and be in the scope that those skilled in the art can understand, and can carry out this selection and do not need a large amount of experiments.

Reagent such as malonic ester magnesium, propanedioic acid methyl esters magnesium or malonic ester magnesium, commercially availablely maybe can use method known to those skilled in the art and makes.Following showing, malonic ester magnesium can be made by ethoxyquin magnesium and malonic ester are reacted.

Formula (IV) compound (R wherein ¹, R ⁴, R ⁵, R ⁶And R ⁷As defined above, P ¹Be hydrogen and R ¹³Be hydrogen) can be by formula (IV) compound

R wherein ¹³Be C ₁To C ₆Alkyl ,-Si (C ₁To C ₆Alkyl) ₃Or-CH ₂(C ₆To C ₁₀Aryl), wherein said C ₆To C ₁₀Aryl is optional by at least a halogen, the C of being selected from ₁To C ₆Alkyl ,-OH ,-OCH ₃With-N (C ₁To C ₆Alkyl) ₂Substituting group replace, make by in aqueous solvent, adopting suitable acid or alkali to be hydrolyzed.Suitable alkali includes, but not limited to lithium hydroxide, sodium hydroxide, potassium hydroxide, yellow soda ash and salt of wormwood.Suitable acid includes, but not limited to spirit of salt, Hydrogen bromide, hydroiodic acid HI and sulfuric acid.These reactions can be carried out in the solvent that can not disturb required chemical reaction or in the solvent mixture, and described solvent includes, but not limited to diethyl ether, methyl-tert-butyl ether, tetrahydrofuran (THF), methyl alcohol, ethanol, Virahol, n Propanoic acid and uncle-butanols.In these reactions, preferably make water as cosolvent.And, these reactions by approximately-78 ℃ to about 50 ℃ of scopes, or approximately-35 ℃ to about 50 ℃ of scopes, or carry out under-35 ℃ of temperature to about 25 ℃ of scopes approximately.

Following showing, formula (IV) compound, wherein R ¹, R ⁴, R ⁵, R ⁶And R ⁷As defined above, P ¹Be hydrogen or suitable blocking group and R ¹³Be hydrogen, C ₁To C ₆Alkyl ,-Si (C ₁To C ₆Alkyl) ₃Or-CH ₂(C ₆To C ₁₀Aryl), wherein said C ₆To C ₁₀Aryl is optional by at least a halogen, the C of being selected from ₁To C ₆Alkyl ,-OH ,-OCH ₃With-N (C ₁To C ₆Alkyl) ₂Substituting group replace, can be by making formula V compound (R wherein ¹, R ⁴, R ⁵, R ⁶And R ⁷As defined above) with formula (X) compound (R wherein ¹³Be hydrogen, C ₁To C ₆Alkyl ,-Si (C ₁To C ₆Alkyl) ₃Or-CH ₂(C ₆To C ₁₀Aryl), wherein said C ₆To C ₁₀Aryl is optional by at least a halogen, the C of being selected from ₁To C ₆Alkyl ,-OH ,-OCH ₃With-N (C ₁To C ₆Alkyl) ₂Substituting group replace) react and make.

These reactions can at first be reacted with formula (X) compound in the presence of highly basic and be obtained negatively charged ion.The highly basic that is suitable for this reaction comprises hexamethyl dimethyl silanyl nitrine lithium (LiHMDS), hexamethyl two silicon sodium azides, hexamethyl two silicon nitrine potassium, diisopropylamine lithium and diisopropylaminoethyl magnesium.And this reaction can be carried out in the presence of the solvent that can not disturb required chemical reaction.Suitable solvent includes, but not limited to pure solution, diethyl ether, methyl-tert-butyl ether and the tetrahydrofuran (THF) of formula (X) compound.In addition, this reaction can approximately-78 ℃ to about 25 ℃ of scopes, or approximately-50 ℃ to about 25 ℃ of scopes, or approximately-35 ℃ to about 25 ℃ of scopes, or carry out under-35 ℃ of temperature to about 0 ℃ of scope approximately.

Perhaps, following showing, formula (IV) compound can (wherein R be for example C by making formula V compound and following formula silyl ketene acetal ₁To C ₆Alkyl and R ¹³Definition as mentioned) reacts and make.These reactions can be carried out in the presence of catalytic amount or stoichiometric suitable Lewis acid, and described Lewis acid includes, but not limited to lithium chloride (III), titanium chloride (II), titanium chloride (IV), tin chloride (II) and tin chloride (IV).And this reaction can be carried out in the presence of the solvent that can not disturb required chemical reaction.Suitable solvent includes, but not limited to diethyl ether, methyl-tert-butyl ether, methylene dichloride, ethylene dichloride and tetrahydrofuran (THF).In addition, this reaction can approximately-78 ℃ to about 25 ℃ of scopes, or approximately-50 ℃ to about 25 ℃ of scopes, or approximately-35 ℃ to about 25 ℃ of scopes, or carry out under-35 ℃ of temperature to about 0 ℃ of scope approximately.

Can split or stereoisomerism enrichment formula (IV) compound, wherein R ¹, R ⁴, R ⁵, R ⁶And R ⁷As defined above, P ¹Be hydrogen or suitable blocking group and R ¹³Be hydrogen.This compound can carry out the stereoisomerism enrichment by the mixture that itself and chiral non-racemic alkali are reacted to form diastereo-isomerism salt.Can use technology well known to those skilled in the art (such as fractional crystallizaton) to separate above-mentioned diastereo-isomerism salt then.The mixture of diastereo-isomerism salt is dissolved in the suitable solvent, and a kind of then diastereo-isomerism salt can be by crystallization in the solution, after this with its collection, washing and dry.Suitable chirality, non-racemize alkali comprise amine alkali, it comprises, but be not limited to a kind of enantiomer in the following all cpds: cis-1-amino-2-indanol, Xin Keniting, 1-aminoidan, uncle-bright amine alcohol, 2-amino-1,2-phenylbenzene ethanol, Alpha-Methyl benzylamine and 2-amino-1-(4-nitrophenyl)-1, ammediol.For example can in suitable solvent (such as tetrahydrofuran (THF)), make formula (IV) compound, wherein R ¹, R ⁴, R ⁵, R ⁶And R ⁷As defined above, P ¹Be hydrogen or suitable blocking group (such as trialkylsilyl ethers) and R ¹³Be hydrogen, with (1R, 2R)-(-)-2-amino-1-(4-nitrophenyl)-1, ammediol reacts to obtain the mixture of diastereo-isomerism salt.Only a kind of diastereo-isomerism salt the solution of the mixture that contains diastereo-isomerism salt slowly cooled off, so that can be dissolved in the cooling solvent in a large number.Then all the other get diastereo-isomerism salt and can be precipitated out from solution with crystalline solid forms, and this crystal contains a kind of pure basically diastereo-isomerism salt.Then can from sedimentary diastereo-isomerism salt or the diastereo-isomerism salt from remain in solution obtain desire formula (IV) compound of stereoisomerism enrichment.Follow wherein R ¹³For formula (IV) compound of hydrogen can be by pure basically diastereo-isomerism salt by obtaining by reacting with suitable acidic cpd (such as citric acid).

Formula (X) compound, wherein R ¹³Be hydrogen, C ₁To C ₆Alkyl ,-Si (C ₁To C ₆Alkyl) ₃Or-CH ₂(C ₆To C ₁₀Aryl), wherein said C ₆To C1 ₀Aryl is optional by at least a halogen, the C of being selected from ₁To C ₆Alkyl ,-OH ,-OCH ₃With-N (C ₁To C ₆Alkyl) ₂Substituting group replace, commercially available or can make according to method known to those skilled in the art.

Formula V compound (R wherein ¹, R ⁴, R ⁵, R ⁶And R ⁷As defined above) can be by making formula (VI) compound (R wherein ¹As defined above) with formula (VII) compound (R wherein ⁴, R ⁵, R ⁶And R ⁷As defined herein and X be the group in the Heck type linked reaction that is suitable for being used in via palladium-catalyzed (through Pd-catalysis)) react and make.Can use palladium-based catalyst to carry out Heck type linked reaction.Appropriate catalyst includes, but not limited to Pd (Oac) ₂, PdCl ₂And Pd (PPh ₃) ₄And this reaction can be carried out in the presence of alkali, and described alkali is such as being triethylamine, sodium acetate, lithium acetate, potassium acetate, yellow soda ash, salt of wormwood or cesium carbonate.These reactions can be carried out in the solvent that can not disturb required chemical reaction.And, suitable solvent comprise those skilled in the art known can with the solvent of reaction conditions compatibility, comprise alkane ester and aromatic ester, alkane ether, heterocyclic ether and aryl oxide, hydrocarbon, alkanol and fragrant and mellow, alkyl halide compound and aryl halogenated compound, alkane nitrile or fragrant nitrile, alkane ketone and arone, acid amides and non-proton heterocyclic solvents.For example suitable dissolving comprises, but be not limited to, ethyl acetate, isobutyl acetate, isopropyl acetate, acetate just-butyl ester, hexone, glycol dimethyl ether, diisopropyl ether, chlorobenzene, dimethyl formamide, N,N-DIMETHYLACETAMIDE, propionitrile, butyronitrile, uncle-amylalcohol, acetate, diethyl ether, methyl-tert-butyl ether, phenyl ether, N-Methyl pyrrolidone, methyl phenyl ether, tetrahydrofuran (THF), the 2-methyltetrahydrofuran, 1, the 4-dioxane, pentane, hexane, heptane, methyl alcohol, ethanol, the 1-propyl alcohol, the 2-propyl alcohol, uncle-butanols, just-butanols, the 2-butanols, methylene dichloride, chloroform, 1, the 2-ethylene dichloride, acetonitrile, benzonitrile, acetone, 2-butanone, benzene, toluene, methyl-phenoxide, the any mixture of dimethylbenzene and pyridine or above-mentioned solvent.Then, these reactions can about 0 ℃ to about 150 ℃ of scopes, or about 25 ℃ to about 150 ℃ of scopes, or about 25 ℃ to about 100 ℃ of scopes, or about 45 ℃ to about 100 ℃ of scopes, or carry out under about 45 ℃ of temperature to about 75 ℃ of scopes.At last, in formula (VII) compound, X is for being suitable for being used in group in the reaction of Heck type.Suitable group comprises chlorine, bromine, iodine and trifluoromethanesulfonic acid ester group (OSO ₂CF ₃).

Formula (VII) compound is commercially available maybe can be made by method known to those skilled in the art.

Following showing, formula (VI) compound (R wherein ¹As defined above) can be by making formula (X) compound (R wherein ¹As defined above) react and make with formula (XI) compound (wherein M is a suitable metal).

In formula (XI) compound, M is selected from suitable metal, such as magnesium derivative (such as magnesium bromide) or lithium.These reactions can be at aprotonic solvent, such as diethyl ether, methyl-tert-butyl ether or tetrahydrofuran (THF), in carry out.In addition, these reactions can approximately-78 ℃ to about 50 ℃ of scopes, or approximately-78 ℃ to about 25 ℃ of scopes, or approximately-78 ℃ to the temperature of about 0 ℃ of scope, carry out.

Formula (XI) compound, wherein M is suitable metal group, commercially availablely maybe can make by method known to those skilled in the art.For example can make formula (XI) compound of M wherein by bromine ethene and suitable magnesium presoma (such as magnesium metal or activation Reike magnesium) for-MgBr.These reactions can be at aprotonic solvent under about 0 ℃ of temperature to about 25 ℃ of scopes, such as diethyl ether, methyl-tert-butyl ether or tetrahydrofuran (THF), in carry out.Wherein M is that formula (XI) compound of lithium can be made by ethylene halide (such as bromine ethene or iodoethylene) and suitable alkyl lithium reagents (such as butyllithium or tert-butyl lithium).These reactions can be at aprotonic solvent under about 0 ℃ of temperature to about 25 ℃ of scopes, such as diethyl ether, methyl-tert-butyl ether or tetrahydrofuran (THF), in carry out.

Formula (X) compound, wherein R ¹As defined above, commercially available maybe can be by making formula (XII) compound (wherein L is suitable leavings group) and formula (XIII) compound (R wherein ¹As defined above and M be suitable metal) react and make.In formula (XII) compound, L is suitable leavings group, such as-N (CH ₃) ₂Group.In formula (XIII) compound, M is suitable metal, such as-MgBr or Li.This reaction can be carried out in aprotonic solvent (such as diethyl ether, methyl-tert-butyl ether or tetrahydrofuran (THF)) under about 0 ℃ of temperature to about 25 ℃ of scopes.

Formula (XII) compound is commercially available maybe can be made by method known to those skilled in the art.

Formula (XIII) compound, wherein M is suitable metal, commercially availablely maybe can make by method known to those skilled in the art.Formula (XIII) compound for example, wherein M is-MgBr, can be by ethene bromine and suitable magnesium presoma (such as magnesium metal or active Rieke magnesium) and make.This reaction can be carried out in aprotonic solvent (such as diethyl ether, methyl-tert-butyl ether or tetrahydrofuran (THF)) under about 0 ℃ of temperature to about 25 ℃ of scopes.Formula (XIII) compound, wherein M is Li, can be by suitable halogenide (such as bromide or iodide) and suitable alkyl lithium reagents (such as butyllithium or the 3rd-butyllithium) and make.This reaction can be carried out in aprotonic solvent (such as diethyl ether, methyl-tert-butyl ether or tetrahydrofuran (THF)) under about 0 ℃ of temperature to about 25 ℃ of scopes.

Formula (IX) compound such as following (Ixa) compound, commercially availablely maybe can use method known to those skilled in the art and makes.For example formula (Ixa) compound can be made as follows: oxyacetic acid and aminoguanidin carbonate are reacted to obtain (5-amino-1H-1,2,4-triazole-3-yl) methyl alcohol.Make this product and 2 then, the 4-diacetylmethane react with obtain (5,7-dimethyl [1,2,4] methyl alcohol triazolo [1,5-a] pyrimidine-2-base), then use 2,2,6,6-tetramethyl--piperidino oxygen and the oxidation of iodobenzene diacetate ester are to obtain 5,7-dimethyl [1,2,4] triazolo [1,5-a] pyrimidine-2-formaldehyde.

(2-(2 can to bestow (R)-6-cyclopentyl-6-according to available any one the acceptable pattern of those skilled in the art, 6-parvoline-4-yl) ethyl)-3-((5,7-dimethyl-[1,2,4] triazolo [1,5-a] pyrimidine-2-base) methyl)-4-hydroxyl-5, the crystal formation of 6-dihydropyrane-2-ketone or its pharmaceutically-acceptable salts.That the illustrative example of suitable dispensing pattern comprises is oral, interanasal administration, non-enteron aisle dispensing, topical administration, transdermal dispensing and rectal administration.Preferred oral and vein are sent.

(2-(2 can to bestow (R)-6-cyclopentyl-6-with the pharmaceutical compositions of any proper drug form, 6-parvoline-4-yl) ethyl)-3-((5,7-dimethyl-[1,2,4] triazolo [1,5-a] pyrimidine-2-base) methyl)-4-hydroxyl-5, the crystal type of 6-dihydropyrane-2-ketone or its pharmaceutically-acceptable salts.The proper drug form comprises solid, semisolid, liquid or LdamantineL preparation, such as tablet, powder, capsule, suppository, suspension, liposome and aerosol.The HCV inhibitor can use any method to be made into solution.For example the HCV inhibitor can adopt acid (for example 1M HCl) dissolving, and adopts the solution dilution of 5% dextrose in water (D5W) of appropriate amount, to obtain the HCV inhibitor of required ultimate density (for example about 15 mM).Perhaps, can use the D5W solution that contains about 15mM HCl, so that the HCV inhibitor solution of suitable concn to be provided.And, for example can use 1% carboxymethyl cellulose (CMC) solution that the HCV inhibitor is made suspension.

The acceptable method of suitable medicine type of preparation pharmaceutical compositions is known or is determined routinely by those skilled in the art.For example can be according to common technology system that Pharmaceutical Chemist adopted by pharmaceutical formulations, described technology may further comprise the steps: such as mixing, granulation with when being pressed into tablet form; Or mix, fill and dissolve various compositions to obtain being suitable for the required product of dispensing in dispensing in oral, non-enteron aisle dispensing, topical administration, intravaginal dispensing, interanasal administration, the segmental bronchus, intraocular dispensing, the ear and/or rectal administration.

According to end-use, pharmaceutical compositions of the present invention also comprises suitable adjuvant, thinner, mediator and supporting agent, and other promoting agent pharmaceutically.Pharmaceutically acceptable solid or liquid carrier, thinner, mediator or adjuvant can be used in the pharmaceutical compositions.The example of solid carriers comprises that starch, lactose, calcium sulfate reach a booth (calcium sulfate damantin), carclazyte, sucrose, talcum, gelatin, pectin, Sudan Gum-arabic (acacia), Magnesium Stearate and stearic acid.The example of liquid carrier comprises syrup, peanut oil, sweet oil, salt brine solution and water.This supporting agent or thinner can comprise suitable long-acting material, and such as glyceryl monostearate or distearin, it can use separately or be used in combination with wax.When using liquid carrier, said preparation can be syrup, elixir, emulsion, soft gelatin capsule, aseptic parenteral solution (for example solution) or form non-aqueous or waterborne liquid suspension.

The medicament of pharmaceutical compositions can contain the HCV inhibitor for the treatment of significant quantity at least, and preferably is made up of one or more pharmaceutical doses units.Can be by any known or suitable method of bestowing medicament, to bestowing selected dosage by the Mammals (for example people) that the activity that suppresses HCV is treated, described method comprises, for example with ointment or emulsion carry out topical administration, oral, for example with suppository carry out rectal administration, by injection carry out non-enteron aisle dispensing, intravenously dispensing or by in intravaginal, the nose, in the segmental bronchus, Er Nei or intraocular transfusion offer medicine continuously.When composition was bestowed with the cytotoxic medicine, said composition can be before the cytotoxic medicine be imported into, simultaneously and/or bestow later on.Yet when said composition is bestowed together with radiotherapy, preferably bestowed said composition in the past in the beginning radiotherapy.

Prepare various methods and be known or be tangible those skilled in the art with specified quantitative active compound.For example see Remington ' s Pharmaceutical Sciences, Mack PublishingCompany, Easter, Pa., the 15th edition (1975).

Will be appreciated that the actual dose of the HCV inhibitor in pharmaceutical compositions of the present invention can be according to the particular composition of being prepared, dosing mode and specific dispensing position, and host to be treated and illness and select.With regard to particular disorder, optimal dose can use the routine dose determination test to confirm by those skilled in the art.With regard to oral, for example doses available is about 0.001 to about 1000 milligrams/kg body weight, or about 0.1 to about 100 milligrams/kg body weight, or about 1 to about 50 milligrams/kg body weight, or about 0.1 to about 1 milligram/kg body weight, and this therapeutic process repeats with appropriate intervals.The formulation of the preparation of pharmacy described in the literary composition can contain a certain amount of (R)-6-cyclopentyl-6-, and (2-(2,6-parvoline-4-yl) ethyl)-3-((5,7-dimethyl-[1,2,4] triazolo [1,5-a] pyrimidine-2-base) methyl)-4-hydroxyl-5, the crystal formation of 6-dihydropyrane-2-ketone or its pharmaceutically-acceptable salts, it is suitable that this consumption those skilled in the art think.For example this formulation can contain 1 milligram of extremely about 1500 milligrams compound or its pharmaceutically-acceptable salts of having an appointment, can contain and have an appointment 20 milligrams to about 1600 milligrams, or about 5 milligrams to about 1500 milligrams, or about 5 milligrams to about 1250 milligrams, or about 10 milligrams to about 1250 milligrams, or about 25 milligrams to about 1250 milligrams, or about 25 milligrams to about 1000 milligrams, or about 50 milligrams to about 1000 milligrams, or about 50 milligrams to about 750 milligrams, or about 75 milligrams to about 750 milligrams, or about 100 milligrams to about 750 milligrams, or about 125 milligrams to about 750 milligrams, or about 150 milligrams to about 750 milligrams, or about 150 milligrams to about 500 milligrams compound or its pharmaceutically-acceptable salts or solvate.

(R)-(2-(2 for 6-cyclopentyl-6-, 6-parvoline-4-yl) ethyl)-3-((5,7-dimethyl-[1,2,4] triazolo [1,5-a] pyrimidine-2-base) methyl)-4-hydroxyl-5, the crystal formation of 6-dihydropyrane-2-ketone or its pharmaceutically-acceptable salts can be used as independent therapy and use, maybe can comprise one or more other antiviral substances, for example be selected from following material: HCV inhibitor for example, such as Interferon, rabbit alphacon-1, natural interferon, interferon beta-1a, Interferon, rabbit ω, gamma interferon 1-b, the INF-α of polyethyleneglycol modified form (Pegasys or PEG-INTRON), interleukin-10 (interleukin-10), BILN 2061 (serine protease), amantadine (Symmetrel), thymosin alpha 1, ribavirin (ribavirin), than drawing pyridine (viramidine); Hiv inhibitor, such as viracept see nelfinaivr (nelfinavir), La Weiding (delavirdine), Indinavir (indinavir), nevirapine (nevirapine), Saquinavir (saquinavir) and tenofovir disoproxil (tenofovir).Can be by simultaneously, bestow the used individual components of treatment continuously or individually and reach above-mentioned conjoint therapy.

Though embodiments of the present invention one skilled in the art will recognize that by illustrating with reference to following specific embodiment, can and put into practice by normal experiment of the present invention described embodiment is changed and revises.Therefore, the present invention is subject to following embodiment, but limits by additional claims of institute and equivalent thereof.

Unless otherwise stated, in following example, the amount of all compositions used in this bright book and claims, character (such as molecular weight), reaction conditions etc. is appreciated that by term " about " in all examples to be revised.Therefore, unless otherwise stated, the numerical parameter that is disclosed in following specification sheets and appended claims is for can be according to the approximation that changes by the required character that the present invention obtained.At least and the application that the scope with these claims is equal to limit, each numerical parameter should make an explanation according to the numerical value and the conventional approximation method of application of the significant figure of being reported at least.

Embodiment

In the following embodiments, unless otherwise stated, below all temperature in the explanation be degree centigrade (℃), and unless otherwise stated, all umbers and per-cent are weight ratio.

Unless otherwise stated, various raw materials and other reagent are provided, and are not needed to be further purified and can use by commercial supplier such as AldrichChemical Company or Lancaster Synthesis Ltd..

Following being reflected under the envrionment temperature (unless otherwise stated) is in anhydrous solvent, under nitrogen, argon gas positive pressure or use drying tube to carry out.On 60 ℉ of the silica gel at the bottom of the woven fiber glass, 254 flat boards (Analtech (0.25 millimeter)), carry out thin-layer chromatographic analysis and adopt suitable solvent ratio (v/v) wash-out.By high pressure lipuid chromatography (HPLC) (HPLC) or tlc (TLC) analytical reaction, and, consumption of raw materials comes termination reaction by being judged.Make the dull and stereotyped video picture of TLC by ultraviolet ray, phospho-molybdic acid dyeing or iodine staining.

Record on the Bruker instrument of operating with 300MHz ¹H-NMR spectrum, and under 75MHz record ¹³C-NMR spectrum.Use chloroform (7.25ppm and 77.00ppm) or DMSO-d ₆(2.50ppm and 39.52ppm) obtains DMSO-d as with reference to standard ₆Or CDCl ₃The NMR spectrum (representing) of solution with ppm.If necessary, can use other NMR solvent.When reporting the multiplicity of crest, use following abbreviation: s=is unimodal, d=doublet, t=triplet, m=multiplet, br=broad peak, dd=double doublet, the two triplets of dt=.Given coupling constant is represented with hertz (Hertz).

With pure oil, KBr bead or CDCl ₃The form of solution writes down infrared spectrum on Perkin-Elmer FT-IR spectrometer, and with wave number (centimetre ^-1) expression.Use LC/MS to obtain mass spectrum with APCI or ESI ionization method.All fusing points are not calibrated.

In following examples and preparation method, " Et " refers to ethyl, and " Ac " refers to ethanoyl, " Me " nail base, and " Ph " refers to phenyl, and " HCl " refers to hydrochloric acid, and " EtOAc " refers to ethyl acetate, " Na ₂CO ₃" refer to yellow soda ash, " NaOH " refers to sodium hydroxide, " NaCl " refers to sodium-chlor, " Net ₃" refer to triethylamine, " THF " refers to tetrahydrofuran (THF), " H ₂O " refer to water, " NaHCO ₃" refer to sodium bicarbonate, " K ₂CO ₃" refer to salt of wormwood, " MeOH " nail alcohol, " i-PrOAc " refers to isopropyl acetate, " MgSO ₄" refer to sal epsom, " DMSO " refers to dimethyl sulfoxide (DMSO), " CH ₂Cl ₂" refer to methylene dichloride, " MTBE " nail base tert-butyl ether, " DMF " refers to dimethyl formamide, " CH ₃CN " refer to acetonitrile; " KOH " refers to potassium hydroxide; " CDI " refers to carbonyl dimidazoles; " DABCO " refers to 1,4-diazabicyclo [2.2.2] octane, and " IPE " refers to isopropyl ether; " L-DBTA " refers to that dibenzoyl-L-tartrate, " IPAC " refer to isopropyl acetate; " h " refers to hour, and " min " refers to minute, and " mol " refers to that mole and " rt " refer to room temperature.

Embodiment 1: the preparation method of the hydroxyl acetate of (5-amino-1H-1,2,4-triazole-3-yl) methyl alcohol

Hydroxyl acetate

Add oxyacetic acid (1 liter, in water 70%, 11.51 mole) to 5 liters of flasks.Portion-wise addition aminoguanidin carbonate (783.33 grams, 5.755 moles) is to control obvious foaming.When adding solid, because this solution cooling of heat absorption dissolving.During the interpolation, leniently heated solution is 25 ℃ to keep internal temperature.Aminoguanidin carbonate add finish after 10 minutes, add concentrated nitric acid (6.8 milliliters) carefully.It is 104-108 ℃ (gentle reflux) 22 hours that this solution is heated to internal temperature.Interrupt heating, and under agitation make the solution cooling.Under about 81 ℃ internal temperature, solid begins crystallization.Should in temperature just in time after below 80 ℃, slowly add ethanol (pure, 375 milliliters) to this mixture.After internal temperature has been cooled to about 68 ℃, utilize ice/water-bath to quicken cooling.Be cooled to be lower than room temperature after, this solution becomes gets dense thick, but still can stir.Stirred these slurries 2 hours down in T＜10 ℃, filter then and wash this solid with ethanol (first, 250 milliliters under the room temperature of usefulness) then with cold 900 milliliters.This solid drying in vacuum drying oven (about 25 mm Hg, 45 to 50 ℃) obtains (5-amino-1H-1,2,4-triazole-3-yl) methyl alcohol of 815.80 gram (75%) oxyacetic acid salt forms whole night. ¹H(300MHz，d ₆-DMSO)：3.90(s，2)、4.24(s，2)。

Embodiment 2: the preparation method of (5,7-dimethyl [1,2,4] triazolo [1,5-a] pyrimidine-2-base) methyl alcohol

With the hydroxyl acetate (99.93 grams, 0.526 mole), 2 of (5-amino-1H-1,2,4-triazole-3-yl) methyl alcohol, 4-diacetylmethane (0.578 mole, 60 milliliters), acetate (6.70 milliliters) and EtOH (550 milliliters) pack in 2 liters of 3 mouthfuls of flasks.With this mixture heating up to gentle reflux.Added after the mentioned reagent one hour, and made formed solution be cooled to envrionment temperature, and add CH ₂Cl ₂(500 milliliters) and Celite (25.03 gram).Stir after one hour, make this mixture by fill Celite (20 gram) 4 " B filters, and washes with EtOH (100 milliliters).This solution is distilled to 5 volumes, is cooled to 0 ℃ then and kept 1 to 2 hour.Filter this slurries, and with cold EtOH (2 * 100 milliliters) flush cake.Drying solid obtains 76.67 gram (81.7%) title compounds.

¹H NMR (300MHz, d ₆-DMSO): 2.57 (s, 3), 2.71 (d, 3, J=0.8), 4.63 (non-homogeneous d, 2, J=5.7), 5.49 (t, 1, J=6.2), 7.13 (d, 1, J=0.8).

Embodiment 3: 5, the preparation method of 7-dimethyl [1,2,4] triazolo [1,5-a] pyrimidine-2-formaldehyde

With CH ₂Cl ₂In (5.1 liters), (5,7-dimethyl [1,2,4] triazolo [1,5-a] pyrimidine-2-base) methyl alcohol (680 grams, 3.816 moles) and iodobenzene diacetate salt (1352 grams, 4.197 moles) the 10 liters of reactors of packing into successively.When this iodobenzene diacetate salt dissolving, has tangible heat absorption phenomenon (dropping to 15-16 ℃ usually).Heat insulation sheath is set to 23 ℃.This mixture is warmed to envrionment temperature, and adds Tempo once (2,2,6,6-tetramethyl--piperidino oxygen, free radical, 43.75 grams, 0.28 mole).Stir this reaction, till measuring residue 5% initial alcohol by HPLC.In case raw material begins to find excessively oxidated product less than about 5%.This reaction is further finished, caused the overall yield of required product to reduce.For this reaction, in 2.75 hours, finish required reaction.Then MTBE (5.1 liters) slowly is added in the reactor, it causes product precipitation, and these slurries of restir 30 minutes.Mixture is filtered, with 1:1 DCM/BTBE (2 * 1 liters) washed twice, and under 50 ℃ in vacuum drying oven drying obtain 500.3 grams (74%) solid shape 5,7-dimethyl [1,2,4] triazolo [1,5-a] pyrimidine-2-formaldehyde whole night near white. ¹H NMR(300MHz，d ₆-DMSO)：2.64(s，3)、2.78(d，3，J＝0.8)、7.36(d，1，J＝0.9)、10.13(s，1)。

Embodiment 4: the preparation method of the dibenzoyl-L-tartrate of 1-cyclopentyl-3-(2,6-parvoline-4-yl) third-1-ketone

With LiBr (112.42 grams, 1.2944 moles), 1-cyclopentyl-third-2-alkene-1-alcohol (89.84 grams, 0.7119 mole), DMAc (625 milliliters) and H ₂O (55.0 milliliters) packs into successively and contains 4-bromo-2, and 6-parvoline (250.0 grams, 0.6472 mole) is in 5 liters of 3 mouthfuls of flasks of nitrogen purging.Mixture is cooled to 5-10 ℃, uses N then ₂Purged (under the liquid level) 30 minutes.With Et ₃N (198.5 milliliters, 1.4242 moles) and Pd (Oac) ₂In (3.63 grams, 0.0162 mole) this flask of packing into, purge upper space then carefully.Heat this reaction, reach 95 ℃ up to internal temperature.95 ℃ down stir 3 hours after, take out equal portions and analyze by HPLC, the result shows〉99% changed into 1-cyclopentyl-3-(2,6-parvoline-4-yl) third-1-ketone.Make then this reaction be cooled to 30 ℃ 20 minutes.With H ₂O (1500 milliliters) and MTBE (1500 milliliters) pack in this flask.Fully stirred this solution 5 minutes, make this mixture sedimentation then and remove water layer.Celite (62.50 gram) and Darco G-60 (6.25 gram) are added in the organic layer.Stirred these slurries 20 minutes down at 20 to 25 ℃.Use the B that Celite is housed to filter this slurries then.With MTBE (250 milliliters) flush cake.Extract organic layer and separate each phase with 5% sodium hydrogen carbonate solution (500 milliliters).This organic layer being transferred in 5 liters of 3 mouthfuls of flasks, and adding MTBE, is 1750 milliliters to obtain total reaction volume.Add MTBE (1500 milliliters) again and under atmosphere, distill, reach 1750 milliliters up to internal volume.After being cooled to below 40 ℃, take out sample, carry out the analysis of water-content.After being cooled to 20-25 ℃; add MTBE (250 milliliters) so that cumulative volume reaches 2000 milliliters; and the crystal of the dibenzoyl-L-tartrate of 1-cyclopentyl-3-(2, the 6-parvoline-4-yl) third-1-ketone (130 milligrams) that will make according to said process adds and thinks this solution sowing.In 25 minutes, add the solution of dibenzoyl-L-tartrate (231.89 grams, 0.6472 mole) in THF (900 milliliters).Make this slurries granulation 1 hour, filter this mixture, and with MTBE (450 milliliters) washing leaching cake.Under 50 ℃,, obtain 366.70 gram (92% productive rate) title compounds this solid of vacuum oven 12 hours. ¹H NMR (300MHz, d ₆-DMSO): 1.19 (t, 6, J=7.6), 1.47 to 1.81 (m, 8), 2.73 (q, 4, J=7.6), 2.73 to 2.98 (m, 5), 5.86 (s, 2), 7.00 (s, 2), 7.55 to 7.63 (m, 4), 7.68 to 7.75 (m, 2), 7.98 to 8.04 (m, 4).

Embodiment 5: the preparation method of 3-cyclopentyl-5-(2,6-parvoline-4-yl)-3-hydroxypentanoic acid

With 1-cyclopentyl-3-(2; 6-parvoline-4-yl) dibenzoyl of third-1-ketone-L-tartrate (174.95 grams; 0.2832 mole), MTBE (875 milliliters), water (875 milliliters) and trolamine (113.0 milliliters, 0.8513 mole) are packed in 3 liters of 3 mouthfuls of flasks.After at room temperature stirring 2 hours, take out an equal portions water, and analyze by HPLC, the result shows that detection is less than raw material.This solution is moved in the separating funnel, and separate each layer.Abandon lower aqueous, and water (150 milliliters) washing top organic phase.This organic layer is added into and carries out in the distillatory flask.Distill this solution, make it reduce to about 183 milliliters, and take out equal portions to carry out the analysis of water-content.The anhydrous solution of this 1-cyclopentyl-3-(2,6-parvoline-4-yl) third-1-ketone (theoretical wt=73.47 gram) in MTBE directly uses in next step.

LiHMDS (1.0M in THF, 355 milliliters, 0.355 mole) is packed in 2 liters of clean 3 mouthfuls of flasks, and use nitrogen purging.This flask is cooled to-34 ℃.Slowly be added in the reaction vessel then with in EtOAc (35 milliliters, the 0.3583 mole) feed hopper of packing into, and with this reagent, interpolation speed can be kept this container and be in low temperature.After EtOAc adds fully, 1-cyclopentyl-3-(2,6-parvoline-4-yl) third-1-ketone solution (is derived from the rough MTBE solution of previous reaction, theoretical yield 73.47 grams, 0.2832 mole) in another feed hopper of packing into, and wash with THF (anhydrous, 5 milliliters).This 1-cyclopentyl-3-(2,6-parvoline-4-yl) third-1-ketone solution slowly is added in this reaction flask, adds speed and can keep inner cryogenic.Finish and added back 5 minutes, taking-up one is reacted equal portions and is analyzed by HPLC, and the result shows content＜1% of 1-cyclopentyl-3-(2,6-parvoline-4-yl) third-1-ketone.Finish ketone and added back 10 minutes, make the bath temperature be converted to 0 ℃.In case internal temperature is warmed to-10 ℃, add 1M NaOH (510 milliliters).After NaOH solution adds fully, this reaction is heated to 50 ℃.After 21 hours, this reaction soln is cooled to below 30 ℃, and also whether analytical reaction are complete to take out equal portions bilayer.This mixture is added in the separating funnel that contains MTBE (350 milliliters), and each also separation mutually of thorough mixing.One equal portions organic phase is analyzed by HPLC, and result's proof does not have a large amount of products, therefore abandons this layer.Water is added into has CH ₂Cl ₂In the flask of (350 milliliters).The dense HCl aqueous solution (about 100 milliliters) slowly is added into this water, up to pH=5.Refund in the separating funnel this mixture and thorough mixing.Separate each phase, and use CH ₂Cl ₂(150 milliliters) extract this water layer for the second time.Merge each organic layer, and in the clean flask of packing into, distill.Distill this solution, make its volume reduce to 370 milliliters, replace by adding many parts of solvent THF then, after each time added, continue to be distilled to 370 milliliters then.When this distillation upper end temperature is stablized 30 minutes under 65 ℃, take out equal portions and pass through ¹H NMR analyzes, and the result shows THF:CH ₂Cl ₂Ratio is 12.5:1.This 3-cyclopentyl-5-(2,6-parvoline-4-the yl)-solution of 3-hydroxypentanoic acid in THF directly is used in the next step.

Embodiment 6a: (R)-3-cyclopentyl-5-(2,6-parvoline-4-yl)-3-hydroxypentanoic acid (1R, 2R)-(-)-2-amino-1-(4-nitrophenyl)-1, the preparation method of ammediol salt

With 3-cyclopentyl-5-(2,6-parvoline-4-yl)-the 3-hydroxypentanoic acid (derives from the rapid crude product of previous step, theoretical yield 95.28 grams, 0.1792 mole, in about 300 milliliters), (1R, 2R)-(-)-and 2-amino-1-(4-nitrophenyl)-1, ammediol (38.03 grams, 0.1792 mole) and THF (415 milliliters) pack in 2 liters of 3 mouthfuls of flasks successively.(R)-3-cyclopentyl-5-that interpolation is made according to this process (2,6-parvoline-4-yl)-3-hydroxypentanoic acid (1R, 2R)-(-)-2-amino-1-(4-nitrophenyl)-1, ammediol salt crystal seed, and, be heated to 65 ℃ with this mixture stirring, be maintained at this temperature then following 16 hours.These slurries are slowly cooled to room temperature, and stirred at least 1 hour.Filter this slurries, and with THF (100 milliliters) flush cake.This filtrate ((S)-3-cyclopentyl-5-(2,6-parvoline-4-the yl)-solution of 3-hydroxypentanoic acid in THF) is directly used in next process.With solid drying, obtain 67.09 grams (42%) near (R)-3-cyclopentyl-5-(2,6-parvoline-4-the yl)-3-hydroxypentanoic acid of the crystalline solid shape of white (1R, 2R)-(-)-2-amino-1-(4-nitrophenyl)-1, ammediol salt.The chirality HPLC analysis revealed of this product, be somebody's turn to do (R)-3-cyclopentyl-5-(2,6-parvoline-4-yl)-(1R of 3-hydroxypentanoic acid, 2R)-(-)-2-amino-1-(4-nitrophenyl)-1, ammediol salt pair (S)-3-cyclopentyl-5-(2,6-parvoline-4-yl)-the 3-hydroxypentanoic acid (1R, 2R)-(-)-2-amino-1-(4-nitrophenyl)-1, the ratio of ammediol salt is 92.1:7.9.

The HPLC condition: solid is dissolved in the methyl alcohol.The HPLC condition: Chirobiotic TAG post, 4.6 * 250 millimeters, 40 ℃ of column compartments, flow rate=0.5 ml/min, moving phase=100%MeOH (0.05%TEA, 0.05%HOAc).Gradient: first flow rate=0.5 ml/min; 10 minutes flow rate=0.5 ml/min; 10.10 minute flow rate=2.00 ml/min; 35 minutes flow rate=2.00 ml/min; 36 minutes flow rate=0.5 ml/min.At 265 nanometers report percentage.Retention time: (1R, 2R)-(-)-2-amino-1-(4-nitrophenyl)-1, ammediol=〉 30 minutes; (S)-3-cyclopentyl-5-(2,6-parvoline-4-yl)-3-hydroxypentanoic acid=5.8 minute; (R)-3-cyclopentyl-5-(2,6-parvoline-4-yl)-3-hydroxypentanoic acid=7.2 minute. ¹H NMR (300MHz, d ₆-DMSO): 1.19 (t, 6, J=7.6), 1.38 to 1.62 (m, 8), 1.65 to 1.75 (m, 2), 1.93 to 2.07 (m, 1), 2.23 (d, 1, J=14.4), 2.31 (d, 1, J=14.4), 2.56 (m, 2), 2.64 (q, 4, J=7.6), 2.91 to 2.99 (m, 1), 3.22 (dd, 1, J=5.8,11.1), 3.42 (dd, 1, J=4.8,11.1), 4.77 (d, 1, J=6.2), 6.0 (brs, 6), 6.84 (s, 2), 7.62 (d, 2, J=8.7), 8.20 (d, 2, J=8.8).

Embodiment 6b: (R)-3-cyclopentyl-5-(2,6-parvoline-4-yl)-3-hydroxypentanoic acid (1R, 2R)-(-)-2-amino-1-(4-nitrophenyl)-1, the recrystallization of ammediol salt

With (R)-3-cyclopentyl-5-(2,6-parvoline-4-yl)-(1R of 3-hydroxypentanoic acid, 2R)-(-)-and 2-amino-1-(4-nitrophenyl)-1, in ammediol salt (66.20 grams, 0.1245 mole) and 2B EtOH (970 milliliters of pure EtOH+5 milliliter toluene) the 2 liters of 3 mouthfuls of flasks of packing into.Stir this slurries, and be heated to backflow.Keep after 40 minutes under refluxing, all solids dissolves, and with this solution be cooled to internal temperature be about 65 ℃ 30 minutes.Adopt title crystal to be this solution sowing then.Making this solution be cooled to 50 ℃ also additionally kept 2 hours.Make this solution slowly cool to room temperature approximately then in 2 hours.At room temperature this cold soln of restir is 10 hours.Filtering mixt then, and with 2B EtOH (75 milliliters) flushing solid.Make solid drying, obtain 52.72 grams (80%) near product of white crystalline solid shape, then this product under 50 ℃ under nitrogen gas stream dry 12 hours of vacuum (30 mm Hg).Chirality HPLC analysis revealed, product have 96% ee.For measuring e.e, solid is dissolved among the MeOH.The HPLC condition: Chirobiotic TAG post, 4.6 * 250 millimeters, 40 ℃ of column compartments, flow rate=0.5 ml/min, 100%MeOH (0.05%TEA, 0.05%HOAc).Gradient: first flow rate=0.5 ml/min; 10 minutes flow rate=0.5 ml/min; 10.10 minute flow rate=2.00 ml/min; 35 minutes flow rate=2.00 ml/min; 36 minutes flow rate=0.5 ml/min.At 265 nanometers report percentage.Retention time: (1R, 2R)-(-)-2-amino-1-(4-nitrophenyl)-1, ammediol=〉 30 minutes, (S)-3-cyclopentyl-5-(2,6-parvoline-4-yl)-3-hydroxypentanoic acid=5.8 minute, (R)-3-cyclopentyl-5-(2,6-parvoline-4-yl)-3-hydroxypentanoic acid=7.2 minute.

Embodiment 7: the method for preparing 1-cyclopentyl-3-(2,6-parvoline-4-yl) third-1-ketone by (S)-3-cyclopentyl-5-(2,6-parvoline-4-yl)-3-hydroxypentanoic acid

With (S)-3-cyclopentyl-5-(2,6-parvoline-4-yl)-(derive from the raw product of final step, theoretical yield 15 restrains 0.0470 mole to the 3-hydroxypentanoic acid, in about 200 milliliters of THF) solution and ethanol (100 milliliters, the 1.7126 moles) flask of packing in.Slowly add H ₂SO ₄(5.0 milliliters, 0.0938 mole) are to solution.This solution of heating is 18 hours under refluxing.When judging that by HPLC this reaction is finished, make the cooling of this solution and be added in the have 0.5M NaOH separating funnel of (400 milliliters), use MTBE (200 milliliters) extraction then.Separate each phase, and use acetate H ₂O (100 milliliters of H ₂O+3.0 milliliter HOAc) washing organic layer.Separate each phase, and wash organic layer with 0.5M NaOH (100 milliliters).Separate each layer, and wash organic layer with the saturated NaCl aqueous solution (25 milliliters).Under normal pressure, distill organic layer, make its internal volume reduce to 150 milliliters.By adding toluene (100 milliliters), be distilled to 200 milliliters of such air distillations of internal volume solvent is replaced by toluene, and repeat this process more than twice.It is 130 milliliters that final solution is distilled to internal volume.Take out equal portions and analyze by the KF titration.Make solution be cooled to room temperature, and the solution of disposable interpolation KotBu (1.0M in THF, 4.7 milliliters, 0.0047 mole).After 5 minutes, take out equal portions and analyze by HPLC.Add this solution to separating funnel with 1M HCl (60 milliliters).Each also separates thorough mixing mutually, and this process makes product be transferred to water.Water (10 milliliters) extracted organic phase once and merges water.Abandon organic phase.Add MTBE (60 milliliters) and 1M NaOH (70 milliliters) to water, and each phase of thorough mixing.Separate each phase, and with the saturated NaCl aqueous solution (25 milliliters) extracted organic phase.Adding MTBE makes its volume up to 125 milliliters.Make this solution be cooled to room temperature, and adopt the dibenzoyl-L-tartrate salt crystals (according to embodiment 4 preparations) of 1-cyclopentyl-3-(2,6-parvoline-4-yl) third-1-ketone to be this solution sowing.In another independent container, L-DBTA (16.89 grams, 0.0471 mole) is dissolved among the THF (65 milliliters).In 45 minutes, L-DBTA solution is added in 1-cyclopentyl-3-(2,6-parvoline-4-yl) third-1-ketone solution, and these slurries of granulation one hour.Filter slurries, and with MTBE (50 milliliters) washing leaching cake.Make solid drying, obtain the dibenzoyl-L-tartrate (67%) of 1-cyclopentyl-3-(2,6-parvoline-4-yl) third-1-ketone of 19.54 gram broken white solid state.

Embodiment 8a: (R)-and 6-cyclopentyl-6-(2-(2,6-parvoline-4-yl) ethyl)-4-hydroxyl-5, the preparation method of the dibenzoyl of 6-dihydropyrane-2-ketone-L-tartrate

With CH ₂Cl ₂(200 milliliters) and H ₂O (100 milliliters) packs into and contains (R)-3-cyclopentyl-5-(2,6-parvoline-4-yl)-(1R of 3-hydroxypentanoic acid, 2R)-(-)-and 2-amino-1-(4-nitrophenyl)-1, in ammediol salt (20.00 gram, 0.0376 mole), the flask crossed by nitrogen purging.Use 40% water-based citric acid (10 milliliters) that the pH of this mixture is adjusted to pH 4.75, and stirred 60 minutes.Make each layer sedimentation 30 minutes and separation.With CH ₂Cl ₂In the layer of (50 milliliters) tops of packing into (water), stirred 15 minutes, make its sedimentation then.This organic layer and first organic layer are merged, and use dried over sodium sulfate.Under reduced pressure concentrate this exsiccant organic layer.Make (R)-3-cyclopentyl-5-(2,6-parvoline-4-yl)-3-hydroxypentanoic acid resistates is dissolved among the THF (47 milliliters), and (9.00 restrain in 5 minutes this solution to be added into carbonyl dimidazoles, 0.0555 mole) and 4-N, N-Dimethylamino pyridine (DMAP, 0.45 gram, 0.0037 mole) in the slurries in THF (106 milliliters).In case after the formation of acyl group-imidazoles is finished, in 5 minutes, this solution is added in malonic ester potassium (12.57 grams, 0.0738 mole) and the slurries of magnesium chloride (7.38 grams, 0.0775 mole) in 106 milliliters of THF.Stirred these slurries 30 hours down at 20 to 25 ℃.Take out equal portions and analyze by HPLC, the result shows that 96% has changed into 5-cyclopentyl-7-(2,6-parvoline-4-yl)-5-hydroxyl-3-oxo enanthic acid (R)-ethyl ester.With H ₂In O (64 milliliters) and MTBE (118 milliliters) flask of packing into.Fully stir this mixture 5 minutes, make its sedimentation then, and remove (descending) layer that anhydrates.Salt solution (52 milliliters) is added in the organic layer.Fully stir this mixture 5 minutes, make its sedimentation then, and remove (descending) layer that anhydrates.Then, make methyl alcohol (2 * 210 milliliters) replace organic layer, reach 140 milliliters up to cumulative volume by air distillation.Successively add MTBE (105 milliliters) and powdered potassium carbonate (7.65 grams, 0.0554 mole), and these slurries are heated to backflow 12 hours.After being cooled to 40 ℃, add MTBE (140 milliliters) and water (140 milliliters).Fully stir this mixture 5 minutes, make its sedimentation then, and divide dried up (descending) layer.Water (30 milliliters) extraction organic layer, and combining water layer.Add CH ₂Cl ₂(140 milliliters) to this water layer, and uses 40% water-based citric acid (29 milliliters) that pH is adjusted to 6.4.Use CH ₂Cl ₂(25 milliliters) are aqueous layer extracted for the second time.By air distillation the organic layer of merging is replaced fully by MTBE (140 milliliters of final volumes) then, make its cooling, and slowly be added in the solution of dibenzoyl-D-tartrate (9.92 grams, 0.0277 mole) in MTBE (100 milliliters).These slurries are heated to backflow one hour, make it be cooled to 20-25 ℃ then.Filter this mixture, and with MTBE (50 milliliters) flush cake.Under 50 ℃,, obtain 16.40 gram (62%) title compounds vacuum oven solid 12 hours.

Embodiment 8b: (R)-and 6-cyclopentyl-6-(2-(2,6-parvoline-4-yl) ethyl)-4-hydroxyl-5, the preparation method of the dibenzoyl of 6-dihydropyrane-2-ketone-L-tartrate

With CH ₂Cl ₂(500 milliliters) and H ₂O (250 milliliters) packs into and contains (R)-3-cyclopentyl-5-(2,6-parvoline-4-yl)-(1R of 3-hydroxypentanoic acid, 2R)-(-)-and 2-amino-1-(4-nitrophenyl)-1, ammediol salt (50.00 gram, 0.0940 mole), by in the flask of nitrogen purging.Use 40% water-based citric acid (21 milliliters) that the pH of formation suspension is adjusted to pH4.6-4.8 (after measured, preferred pH is 4.75), and stirred 30 minutes.Make each layer sedimentation 30 minutes and separation.With CH ₂Cl ₂In (water) layer, stirred 15 minutes and make its sedimentation in (100 milliliters) adding.This organic layer and first organic layer are merged.Again with CH ₂Cl ₂In (water) layer, stirred 15 minutes, and make its sedimentation in (100 milliliters) adding.This organic layer is merged with first organic layer again.Take out each sample that merges organic layer and water layer and carry out the HPLC analysis.Make the organic layer air distillation of merging, reach 120 milliliters up to cumulative volume.Add THF (100 milliliters) and continue air distillation, reach 120 milliliters up to cumulative volume.Repeat the interpolation of THF and replace 3 times.Take out sample and analyze by NMR and KF.In 15 minutes institute being formed solution is added in CDI (22.86 grams, 0.1410 mole) and the slurries of DMAP (1.15 grams, 0.0094 mole) in THF (250 milliliters).With 10 milliliters of THF flushing feed hoppers, then it is added in the CDI slurries then.Stir after 15 minutes, take out sample and analyze by HPLC.In case when the formation of acyl group-imidazoles is finished, under 20 to 25 ℃, in 25 minutes, this solution is added in malonic ester potassium (32.00 grams, 0.1880 mole) and the slurries of magnesium chloride (18.80 grams, 0.1974 mole) in 250 milliliters of THF.Stirred these slurries 21 hours down at 20 to 25 ℃.Take out equal portions and analyze by HPLC, the result shows that 96% has changed into 5-cyclopentyl-7-(2,6-parvoline-4-yl)-5-hydroxyl-3-oxygen base enanthic acid (R)-ethyl ester.With H ₂In O (162 milliliters) and MTBE (300 milliliters) flask of packing into.Fully stir this mixture 5 minutes, make its sedimentation then, and remove yellow water (descending) layer.In salt solution (100 milliliters) organic layer of packing into.Fully stir this mixture 5 minutes, make its sedimentation then, and remove (descending) layer that anhydrates.The air distillation organic layer makes its cumulative volume reduce to 350 milliliters then.Add MTBE (250 milliliters), and this solution is distilled to cumulative volume is 350 milliliters.Add MTBE (250 milliliters) again, and this solution is distilled to cumulative volume is 350 milliliters under at least 55 ℃ temperature.Take out sample and carry out the KF titration.Add methyl alcohol (250 milliliters), this solution of air distillation reaches 350 milliliters up to cumulative volume then.Add methyl alcohol (250 milliliters), this solution of air distillation then reaches 350 milliliters and temperature up to cumulative volume to reach～66 ℃.Add powdered potassium carbonate (19.49 grams, 0.1410 mole), and these slurries are heated to backflow 4 hours.Take out sample and analyze to carry out HPLC, the result shows〉99% finish.After being cooled to 22 ℃, add MTBE (350 milliliters) and water (350 milliliters).Fully stirred this mixture 5 minutes, make its sedimentation then, and water (descending) leafing that is rich in product is analysed.Water (100 milliliters) extraction organic layer, and combining water layer.MTBE (100 milliliters) is added in the water layer that merges.Fully stirred this mixture 5 minutes, make its sedimentation then and water (descending) leafing that is rich in product is analysed.Add CH ₂Cl ₂(350 milliliters) to this water layer, and uses 40% water-based citric acid (75 milliliters) that pH is adjusted to 6.0-6.4.Use CH ₂Cl ₂(100 milliliters) extract this water layer for the second time.The organic layer that merges of air distillation then, making its cumulative volume is 250 milliliters.Add MTBE (400 milliliters) and under at least 55 ℃ temperature this solution of air distillation, reach 250 milliliters up to final volume.After making this solution be cooled to 20 to 25 ℃, added the solution of made dibenzoyl-D-tartrate (23.58 grams, 0.0658 mole) in MTBE (125 milliliters) at 10 minutes.Institute is formed slurries be heated to and refluxed 4 hours, make it be cooled to 20 to 25 ℃ then, and restir 4 hours.Filter this slurries, and with MTBE (125 milliliters) flush cake.Under 50 ℃,, obtain 38.19 gram (58%) title compounds vacuum oven solid 12 hours.HPLC condition: take out sample aliquot and be dissolved in CH ₃CN/H ₂Among the O (40:60).HPLC condition: Kromasil C4 post, 5 microns, 4.6 * 150 millimeters, 40 ℃ of column compartments, flow rate=1.0 ml/min, 40%CH ₃The CN/60% aqueous solution (1.0 milliliters, 70%HclO ₄At 1 liter of H ₂Among the O) isocratic elution liquid.At 254 nanometers report percentage.The approximate residence time: (R)-3-cyclopentyl-5-(2,6-parvoline-4-yl)-3-hydroxypentanoic acid=3.4 minute; 5-cyclopentyl-7-(2,6-parvoline-4-yl)-5-hydroxyl-3-oxo enanthic acid (R)-ethyl ester=7.3 minute; (R)-and 6-cyclopentyl-6-(2-(2,6-parvoline-4-yl) ethyl)-4-hydroxyl-5,6-dihydropyrane-2-ketone=3.9 minute; D-DBTA=5.5 minute.

Embodiment 9a: (R)-and 6-cyclopentyl-6-(2-(2,6-parvoline-4-yl) ethyl)-3-((5,7-dimethyl-[1,2,4] triazolo [1,5-a] pyrimidine-2-base) methyl)-4-hydroxyl-5, the preparation method of 6-dihydropyrane-2-ketone

(2-(2 with (R)-6-cyclopentyl-6-; 6-parvoline-4-yl) ethyl)-4-hydroxyl-5; (this material contains 1.5 equivalent DBTA gegenions to the dibenzoyl of 6-dihydropyrane-2-ketone-L-tartrate; 4.00 gram, 0.00454 mole of theoretical yield), in 2-MeTHF (40 milliliters), MTBE (40 milliliters) and water (20 milliliters) flask of packing into.Add 5% NaHCO ₃The aqueous solution (about 20 milliliters) is 7.4 up to pH.Use a spot of 40% citric acid solution with the reverse pH=7.2 of being adjusted to of this solution.Separate each phase, and extract aqueous layer with 2-MeTHF (25 milliliters).At Na ₂SO ₄The last dry organic layer that merges, and be condensed into oil.This oil can be directly used in condensation step subsequently.Add methyl alcohol (32 milliliters) to this rough (R)-6-cyclopentyl-6-(2-(2,6-parvoline-4-yl) ethyl)-4-hydroxyl-5, in 6-dihydropyrane-2-ketone, and make this solution be cooled to-40 ℃.Add pyridine-borane complexes (1.30 milliliters, 0.01287 mole) and 5,7-dimethyl-[1,2,4] triazolo [1,5-a] pyrimidine-2-formaldehyde (1.41 grams, 0.00800 mole) is to this cold soln.In 45 minutes, this solution is warmed to 0 ℃, and then stirred 2 hours.End this reaction by adding water (10 milliliters), and at room temperature stir this mixture whole night.Add 1M HCl (10 milliliters) to this mixture, and stirred this solution 3 hours.Add isopropyl acetate (57 milliliters) and pH is adjusted to 7 by adding 1MNaOH.Separate each phase, and water (25 milliliters * 2) extraction organic layer.Use CH again ₂Cl ₂(100 milliliters, 2 * 25 milliliters) aqueous phase extracted.At Na ₂SO ₄Last dry IPAc and the CH that merges ₂Cl ₂Layer filters, and concentrates, and obtains rough (R)-6-cyclopentyl-6-(2-(2,6-parvoline-4-yl) ethyl)-3-((5,7-dimethyl-[1,2,4] triazolo [1,5-a] pyrimidine-2-base) the methyl)-4-hydroxyl-5 of 3.41 grams, 6-dihydropyrane-2-ketone.Add isopropyl acetate (46 milliliters) and EtOH (2.5 milliliters) to resistates, and this mixture heating up is extremely refluxed, up to forming homogeneous phase.Make this solution slowly cool to room temperature, and stirred overnight.Filter this slurries, with IPAc (13 milliliters) flushing solid, and be dried, obtain 1.74 gram (76%) broken white solid state (R)-6-cyclopentyl-6-(2-(2,6-parvoline-4-yl) ethyl)-3-((5,7-dimethyl-[1,2,4] methyl triazolo [1,5-a] pyrimidine-2-base))-and 4-hydroxyl-5,6-dihydropyrane-2-ketone.

Embodiment 9b: (R)-and 6-cyclopentyl-6-(2-(2,6-parvoline-4-yl) ethyl)-3-((5,7-dimethyl-[1,2,4] triazolo [1,5-a] pyrimidine-2-base) methyl)-4-hydroxyl-5, the preparation method of 6-dihydropyrane-2-ketone

Should (R)-6-cyclopentyl-6-(2-(2; 6-parvoline-4-yl) ethyl)-4-hydroxyl-5; the dibenzoyl of 6-dihydropyrane-2-ketone-L-tartrate (15.00 grams; 0.02137 mole), THF (75 milliliters), MeOH (75 milliliters), pyridine-borine (4.25 milliliters, 0.034 mole) and 5,7-dimethyl-[1; 2; 4] in triazolo [1,5-a] pyrimidine-2-formaldehyde (5.65 grams, 0.03207 mole) (adding at last) 500 ml flasks of packing into.At room temperature stir the mixture that forms, and took out equal portions after 1.25 hours, and analyze by HPLC, the result shows (R)-6-cyclopentyl-6-(2-(2,6-parvoline-4-yl) ethyl)-4-hydroxyl-5, and 6-dihydropyrane-2-ketone is 13.5%.Continue to stir 2 hours again, and equal portions are carried out HPLC analyze, the result shows (R)-6-cyclopentyl-6-(2-(2,6-parvoline-4-yl) ethyl)-4-hydroxyl-5 of residual 4.8%, 6-dihydropyrane-2-ketone.With CH ₂Cl ₂(150 milliliters) and water (150 milliliters) are packed in this reaction soln, and stir each and spend the night mutually.Take out lower floor's organic layer, and add CH ₂Cl ₂(25 milliliters) to the water layer of upper strata, each also separates thorough mixing mutually, and abandons water layer.Merge organic layer and pack into and contain in the flask of water (150 milliliters) and trolamine (7.1 milliliters, 0.0535 mole), thorough mixing separates then.Take out lower floor's organic layer and add CH ₂Cl ₂(25 milliliters) to the upper strata water layer, each phase of thorough mixing is separated, and is abandoned water layer.Add water (100 milliliters) and 1M NaOH (25 milliliters) to the organic layer that merges, each phase of thorough mixing is separated, and is abandoned lower floor's organic layer.With CH ₂Cl ₂(75 milliliters) add in the upper aqueous layer, and add 1N HCl, and up to pH=6.91 (adding～25 milliliters), each phase of thorough mixing is separated, and abandoned water layer.The organic layer that water (3.2 volume) extraction merges.Separate each layer, and organic layer is transferred in the clean flask with 75 ml volumes mark lines.With this organic layer air distillation to 75 milliliter.Isopropyl acetate (75 milliliters * 2) is added in this flask, after each time added it is distilled to then, cumulative volume is 75 milliliters.Room temperature, stirred overnight are then sowed and be cooled to this flask.Filter this reaction, and with isopropyl acetate (25 milliliters) washing leaching cake.Drying solid, (2-(2 to obtain pulverous (the R)-6-of 7.20 gram (67%) broken whites cyclopentyl-6-, 6-parvoline-4-yl) ethyl)-3-((5,7-dimethyl-[1,2,4] methyl triazolo [1,5-a] pyrimidine-2-base))-4-hydroxyl-5,6-dihydropyrane-2-ketone, they in vacuum drying oven (under 50 ℃～25 inches of mercury) dry 12 hours.For carrying out the HPLC monitoring, take out sample aliquot and make it be dissolved in CH ₃CN/H ₂In the O (40:60).HPLC condition: Kromasil C4 post, 5 microns, 4.6 * 150 millimeters, 40 ℃ of column compartments, flow rate=1.0 ml/min, 40%CH ₃The CN/60% aqueous solution (1.0 milliliters, 70%HclO ₄At 1 liter of H ₂Among the O) isocratic elution liquid.At 254 nanometers report percentage.Retention time: (R)-6-cyclopentyl-6-(2-(2,6-parvoline-4-yl) ethyl)-4-hydroxyl-5,6-dihydropyrane-2-ketone=3.85 minute; (R)-and 6-cyclopentyl-6-(2-(2,6-parvoline-4-yl) ethyl)-3-((5,7-dimethyl-[1,2,4] triazolo [1,5-a] pyrimidine-2-base) methyl)-4-hydroxyl-5,6-dihydropyrane-2-ketone=3.56 minute; DBTA=5.14 minute; BH ₃Pyr=3.36 minute.

Embodiment 10: (R)-and 6-cyclopentyl-6-(2-(2,6-parvoline-4-yl) ethyl)-3-((5,7-dimethyl-[1,2,4] triazolo [1,5-a] pyrimidine-2-base) methyl)-4-hydroxyl-5, the recrystallization of 6-dihydropyrane-2-ketone

(2-(2 with (R)-6-cyclopentyl-6-, 6-parvoline-4-yl) ethyl)-3-((5,7-dimethyl-[1,2,4] triazolo [1,5-a] pyrimidine-2-base) methyl)-4-hydroxyl-5,6-dihydropyrane-2-ketone (10.05 grams, 0.01995 a mole) mouthful THF (70 milliliters) packs in 200 ml flasks.Stir this mixture and be heated to 30-35 ℃ to obtain homogeneous phase solution.This solution is filtered via 0.45 micron Teflon strainer, and wash with THF (10 milliliters).This filtrate is added in order in the flask that carries out air distillation, and adds isopropyl acetate (IPAC, 50 milliliters).Making this solution concentration to internal volume by distillation is 100 milliliters.Add isopropyl acetate (50 milliliters), and under normal pressure, continue distillation, reach 100 milliliters up to internal volume.Employing (R)-6-cyclopentyl-6-(2-(2,6-parvoline-4-yl) ethyl)-3-((5,7-dimethyl-[1,2,4] methyl triazolo [1,5-a] pyrimidine-2-base))-4-hydroxyl-5,6-dihydropyrane-2-ketone is this solution sowing, and adds IPAC (30 milliliters) again.This solution being distilled to internal volume once more is 100 milliliters, and makes it be cooled to 50 ℃ at about 1 hour.Kept this solution 1.5 hours down at 50 ℃, in about 2 hours, make it be cooled to room temperature, and stirred overnight.Filter the slurries that form, and wash with IPAC (30 milliliters).The dry solid that forms obtains the pulverous title compound of 9.41 gram (94%) broken whites, and it was through vacuum-drying (50 ℃ ,～25 inches of mercury) 12 hours.

Embodiment 11: to (R)-6-cyclopentyl-6-(2-(2,6-parvoline-4-yl) ethyl)-3-((5,7-dimethyl-[1,2,4] triazolo [1,5-a] pyrimidine-2-base) methyl)-4-hydroxyl-5,6-dihydropyrane-2-ketone crystalline characterizes

(2-(2 to using made (the R)-6-cyclopentyl-6-of aforesaid method by powder x-ray diffraction (PXRD), solid state NMR (ssNMR) and dsc (DSC), 6-parvoline-4-yl) ethyl)-3-((5,7-dimethyl-[1,2,4] triazolo [1,5-a] pyrimidine-2-base) methyl)-4-hydroxyl-5, the solid form of 6-dihydropyrane-2-ketone characterizes.Found that this material is crystal and does not contain crystal water.The result of various analyses hereinafter is provided.

The A.X ray powder diffraction

Use utilizes the Siemens D5000 diffractometer of copper radiation to produce X-ray powder diffraction figure.This apparatus preparation has line style focusing X-ray pipe.This tube voltage and amperage are set to 38kV and 38mA respectively.Divergent slit and scatter slit are set to 1 millimeter, and the reception slit is set to 0.6 millimeter.Use Sol-X energy dispersive X-ray detector to detect through the Cu of diffraction K _{α 1}Radiation (λ=1.54056

).Carry out the two θ continuous sweeps of θ with 2.4 ° of 2 θ/minute (1 second/0.04 ° 2 θ step-length) by 3.0 to 40 ° of 2 θ.Under room temperature (it is considered to about 24 ℃ to 28 ℃ usually), analyze.Analyze aluminum oxide standard substance (NIST standard reference materials 1976) with calibration instrument.The preparation sample also is placed in the quartzy frame sample to analyze.Use Bruker AXS Diffrac Plus software 2.0 versions are collected data and are analyzed.Characteristic peak and relative intensity thereof are shown in the following table 1.The representative powder X-ray diffractogram is illustrated among Fig. 1.

Table 1. derives from 2 θ spike and intensity levels of x-ray diffractogram of powder

B. deprotonation coupled ¹³C CPMAS

About 80 milligrams sample closely is pressed in 4 millimeters ZrO gyroscopes.Collecting spectrum on 4 millimeters BL triple resonant of Bruker-Biospin CPMAS probe in wide bore Bruker-Biospin Avance DSX 500 MHz NMR spectrometers under envrionment temperature and the pressure.Make this sample be positioned at magic angle (magic angle) and locate, and rotate with 15.0kHz.Adjust number of scans to obtain suitable S/N.

Use deprotonation coupled intersection polarization evil spirit angle rotation spin experiment (CPMAS) collection ¹³The C solid state spectrum.Apply the deprotonation coupled field of about 85kHz.Use the intersection polarization duration of contact of 2ms.Collect 1024 scanning.Relaxation time of recovery (recycle delay) is adjusted to 20 seconds.Use Ldamantine crystal external standard as the spectrographic reference, its High-Field resonance is set at 29.5ppm.Characteristic peak and relative intensity thereof are shown in the following table 2.According to this structure, in the expection carbon spectrum 29 peaks are arranged.At this ¹³Can find at least 44 peak and peak shoulders with suitable uniform strength in the C CPMAS experiment, this represents that there are two molecules in each asymmetric unit.Representational ssNMR spectrum is shown among Fig. 2.

¹³C chemical shift ± 0.2 ^a [ppm]	Intensity ^b
¹³C chemical shift ± 0.2 ^a [ppm]	Intensity ^b	168.6	5.8
168.1	7.3	168.6	5.8
168.1	7.3	166.6	3.0
165.6	3.0	166.6	3.0
165.6	3.0	164.4	3.1
163.8	3.1	164.4	3.1
163.8	3.1	162.3	3.0
161.3	2.6	162.3	3.0
161.3	2.6	154.6	2.8
153.0	3.1	154.6	2.8
153.0	3.1	151.2	3.0
146.4	2.8	151.2	3.0
146.4	2.8	146.0	2.9
121.6	2.1	146.0	2.9
121.6	2.1	120.4	2.5
119.7	2.4	120.4	2.5
119.7	2.4	118.8	2.0

110.2	3.5
110.2	3.5	100.7	3.8
100.3	3.8	100.7	3.8
100.3	3.8	80.4	4.2
79.2	4.2	80.4	4.2
79.2	4.2	50.6	2.2
48.6	0.4	50.6	2.2
48.6	0.4	46.3	2.4
44.7	1.9	46.3	2.4
44.7	1.9	41.1	2.1
37.6	1.6	41.1	2.1
37.6	1.6	33.5	2.2
32.4 ^c	4.9	33.5	2.2
32.4 ^c	4.9	32.1 ^c	6.5
32.0	7.1	32.1 ^c	6.5
32.0	7.1	30.9	4.9
28.6	3.0	30.9	4.9
28.6	3.0	28.0	2.4
26.4	6.0	28.0	2.4
26.4	6.0	25.1	8.2
24.5	3.4	25.1	8.2
24.5	3.4	23.8	2.1
23.3	1.9	23.8	2.1
23.3	1.9	16.2	4.4
15.3	4.9	16.2	4.4
15.3	4.9	14.7	12.0
12.8	4.4	14.7	12.0

(a) reference is at the outside sample of the solid phase Ldamantine of 29.5ppm.

(b) be defined as peak height.Intensity can change according to the actual set of CPMAS experiment parameter and the character of sample (comprising this intersection polarization and relaxation rate).CPMAS intensity needn't be quantitative.

(c) peak shoulder.

C. dsc

(TA Instruments, New castle DE) carry out this experiment to use DSC Q1000 instrument.Use nitrogen as sweeping gas, its flow rate in the DSC chamber is 50 ml/min, and the flow rate in the refrigerated cooling system is 110 ml/min.Use indium (156.61 ℃ of fusing points, fusion enthalpy 28.71 joule/gram) to calibrate the temperature and the chamber constant (cell constant) of this calorimeter.Use has the hermetic aluminum pan of pin hole, and with 10 ℃/minute speed sample (3 to 5 milligrams) is heated.Use TAInstruments ' Universal Analysis 2000 softwares (Windows Version 4.2E) to carry out data analysis.The fusing point of this sample about 162 ℃ to about 165 ℃ of scopes.Thermogravimetric analysis shows that the fusion of this sample and decomposition take place simultaneously.Representational DSC stitching is shown among Fig. 3.

Claims

1. the method for a preparation formula (Ia) compound:

Wherein:

R ¹Be C ₁To C ₆Alkyl or C ₃To C ₆Cycloalkyl;

Each R ^12aAnd R ^12bIndependently be selected from hydrogen, C ₁To C ₆Alkyl; And

Each n is independently selected for use, is 0 to 5 integer;

Described method comprises:

A) with the anionic treatments formula V compound of formula (X) compound, to obtain formula (IV) compound, R in formula (X) compound ¹³Be hydrogen, C ₁To C ₆Alkyl ,-Si (C ₁To C ₆Alkyl) ₃Or-CH ₂(C ₆To C ₁₀Aryl), wherein said C ₆To C ₁₀Aryl is alternatively by at least a halogen, the C of being selected from ₁To C ₆Alkyl ,-OH ,-OCH ₃With-N (C ₁To C ₆Alkyl) ₂Substituting group replace R in the formula V compound ¹Definition as mentioned;

C) handle described formula (IV) compound to obtain formula (III) compound, wherein P with composite reagent ¹Be hydrogen or suitable blocking group, and R ¹⁴Be C ₁To C ₆Alkyl or-CH ₂(C ₆To C ₁₀Aryl), wherein said C ₆To C ₁₀Aryl is optional by at least a halogen, the C of being selected from ₁To C ₆Alkyl ,-OH ,-OCH ₃With-N (C ₁To C ₆Alkyl) ₂Substituting group replace;

E) with the described formula of formula (IXa) compound treatment (II) compound to obtain formula (Ia) compound.

2. the method for claim 1, in wherein said formula (Ia) compound, R ¹Be C ₃To C ₆Cycloalkyl.

3. method as claimed in claim 2, in wherein said formula (Ia) compound, R ¹Be cyclopentyl

4. method as claimed in claim 3, in wherein said formula (Ia) compound:

R ^2aBe C ₁To C ₆Alkyl;

R ^2bBe hydrogen;

R ^2cBe C ₁To C ₆Alkyl;

R ⁴Be hydrogen;

R ⁵Be C ₁To C ₆Alkyl;

R ⁶Be hydrogen; And

R ⁷Be C ₁To C ₆Alkyl.

5. method as claimed in claim 4, in wherein said formula (Ia) compound, R ^2aAnd R ^2cFor-CH ₃, and R ^2bBe hydrogen.

6. method as claimed in claim 5, wherein said formula (Ia) compound is:

7. method for preparing formula (IV) compound of stereoisomerism enrichment,

Wherein:

R ¹Be C ₁To C ₆Alkyl or C ₃To C ₆Cycloalkyl;

P ¹Be hydrogen or suitable blocking group; And

Each n is selected for use independently, is 0 to 5 integer;

Described method comprises:

A) with chiral non-racemic alkaline purification formula (IV) compound to obtain the mixture of diastereo-isomerism salt;

B) make described diastereo-isomerism salt separated from one another;

8. method as claimed in claim 7, wherein said chiral non-racemic alkali is chiral non-racemic amine.

9. method as claimed in claim 8, wherein said chiral non-racemic amine is selected from cis-1-amino-indanol, Xin Keniting, 1-aminoidan, uncle-bright amine alcohol, 2-amino-1,2-phenylbenzene ethanol, Alpha-Methyl benzylamine and 2-amino-1-(4-nitrophenyl)-1, ammediol.

10. method as claimed in claim 9, wherein said chiral non-racemic amine is selected from (1R, 2S)-(+)-cis-1-amino-2-indanol, (-)-Xin Keniting, (R)-1-aminoidan, (S)-uncle-bright amine alcohol, (1R, 2S)-2-amino-1,2-phenylbenzene ethanol, (S)-Alpha-Methyl benzylamine and (1R, 2R)-(-)-and 2-amino-1-(4-nitrophenyl)-1, ammediol.

11. method as claimed in claim 10, wherein said chiral non-racemic amine be (1R, 2R)-(-)-2-amino-1-(4-nitrophenyl)-1, ammediol.

12. a formula (IV) compound,

Wherein:

P ¹Be hydrogen or suitable blocking group; And

Each n is selected for use independently, is 0 to 5 integer.

13. compound as claimed in claim 12, wherein:

R ⁴Be hydrogen;

R ⁵Be C ₁To C ₆Alkyl;

R ⁶Be hydrogen;

R ⁷Be C ₁To C ₆Alkyl; And

R ¹³Be hydrogen or C ₁To C ₆Alkyl.

14. compound as claimed in claim 13, wherein R ⁵And R ⁷For-CH ₂CH ₃

15. (R)-6-cyclopentyl-6-(2-(2,6-parvoline-4-yl) ethyl)-3-((5,7-dimethyl-[1,2,4] triazolo [1,5-a] pyrimidine-2-base) methyl)-4-hydroxyl-5, the crystal formation of 6-dihydropyrane-2-ketone.