CN110156628A - A kind of ring triol derivates and the preparation method and application thereof - Google Patents

A kind of ring triol derivates and the preparation method and application thereof Download PDF

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CN110156628A
CN110156628A CN201910533233.0A CN201910533233A CN110156628A CN 110156628 A CN110156628 A CN 110156628A CN 201910533233 A CN201910533233 A CN 201910533233A CN 110156628 A CN110156628 A CN 110156628A
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amyl
reaction
ring
dioxolen
benzene
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CN110156628B (en
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陈河如
李药兰
李满妹
吴东辉
唐维
林荣填
许丽宇
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Jinan University
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Abstract

The invention discloses a kind of ring triol derivates and the preparation method and application thereof, which has the structure as shown in general formula I, wherein R1、R2、R3For OH or AcNH；R1=OH, R2=R3=AcNH or R2=OH, R1=R3=AcNH or R3=OH, R1=R2=AcNH；* R configuration or S configuration are indicated；Ac indicates coffee acyl CAc or its derivative coffee sulfonyl SAc, coffee (mono-methyl) phosphono PAc.Ring triol derivates preparation method mild condition of the invention, easily realize automation, industrialized production, it is easy to operate and safe, obtained ring triol derivates can be acted on the F protein of anti respiratory syncytial virus, with strong anti-RSV activity, cytotoxicity is low, high stability, it can be used for preparing treatment virus infective medicament, be especially used to prepare treatment respiratory syncytial virus infection drug.

Description

A kind of ring triol derivates and the preparation method and application thereof
Technical field
The invention belongs to viral infection resisting drug field, in particular to a kind of ring triol derivates and preparation method thereof with answer With.
Background technique
Respiratory virus infection is one of the communicable disease for seriously endangering human health, wherein influenza virus, parainfluenza Virus and Respiratory Syncytial Virus(RSV) (RSV) are the main pathogens of respiratory virus infection.RSV is to be only second to influenza A virus The second largest respiratory tract infection virus, Susceptible population is mainly infant, can cause infant's acute tracheitis, bronchitis, The severes lower respiratory tract infection such as pneumonia.According to statistics, about 95% children infected RSV before 2 years old, and 100% children exist RSV (Piedimonte, G., et al.Pediatrics in Review 2014,35:519- was infected before adult 530).The whole world needs the infant of hospitalization up to 3,000,000 because of rsv infection every year, and causes hundreds of thousands of them dead.Human infection Lifetime immunity can not be obtained after RSV, therefore RSV is also the important disease for causing the elderly and hypoimmunity crowd's respiratory disease Substance.
Currently, the small-molecule drug of the RSV vaccine and specific treatment rsv infection that clinically there is no safety good.Li Ba Wei Lin (ribavirin) is generally acknowledged now to the small molecule broad-spectrum antiviral medicament of RSV tool certain curative effect, and suppression is mainly passed through The activity of host cell inosinyl phosphate inosine dehydrogenase (IMP dehydrogenase) processed achievees the effect that suppressing virus replication, therefore its It is higher to the toxicity of host cell.Therefore, medical field is still disputable to the clinical efficacy of Ribavirin at present, such as U.S.'s paediatrics It can be only recommended to be used to treat the spectrometry in high-risk infants being hospitalized.Except small-molecule drug, palivizumab (palivizumab, RSV-F The neutralizing antibody of albumen) it can be clinically used for the high-risk childrens of the rsv infections such as premature labor, broncho-pulmonary dysplasia, but pa benefit pearl is single Anti- there are service life drawbacks such as long, costly, not yet can clinically promote the use of (Vogel, A.M., et al.Journal of Paediatrics and Child Health 2002,38:550-554).Therefore, the specificity of exploitation efficiently, less toxic is anti- RSV small-molecule drug has important clinical meaning.
Elephants-foot (Elephantopus scaber) is composite family Elephantopus plant, is mainly distributed on China south China and west Southern area, has effects that heat-clearing, cool blood, dampness removing.Modern pharmacological studies have shown that elephants-foot is with antiviral, antibacterial, antitumor And the effects of antipyretic.Chinese invention patent CN102219687B discloses 1 α extracted from elephants-foot, 2 bis- caffeoyl rings of β-O, O- Amyl- 3 β -ol, anti-RSV virus activity are stronger than Ribavirin and smaller than Ribavirin to the toxicity of host cell.
Studies have shown that 1 α, 2 β-O, O- bis- are unstable in the amyl- 3 β -ol structure of caffeoyl ring, be easy in blood it is hydrolyzed, Half-life short directly affects its application clinically.According to medicine core similarity principle and bioisosterism, to 1 α, 2 β-O, O- bis- the amyl- 3 β -ol of caffeoyl ring carry out structure optimization, be to obtain the tool anti-RSV virus infection primer of clinical landscapes Quick approach.
Summary of the invention
The primary purpose of the present invention is that the shortcomings that overcoming the prior art and deficiency, provide a kind of ring triol derivates.
Another object of the present invention is to provide the preparation methods of above-mentioned ring triol derivates.
Another object of the present invention is to provide the applications of above-mentioned ring triol derivates.
The purpose of the invention is achieved by the following technical solution: a kind of ring triol derivates, has and ties as shown in general formula I Structure:
In general formula I, R1、R2、R3For OH or AcNH；Wherein, R1=OH, R2=R3=AcNH or R2=OH, R1=R3= AcNH or R3=OH, R1=R2=AcNH；* R configuration or S configuration are indicated.
The Ac indicates coffee acyl CAc or its derivative coffee sulfonyl SAc, coffee (mono-methyl) phosphono PAc, structure are as follows:
The ring triol derivates are preferably compound CLC-P01~CLC-P08, CLC-P09~CLC-P16, CLC- H01~CLC-H08, CLC-H09~CLC-H16, CLS-P01~CLS-P08, CLS-P09~CLS-P16, CLS-H01~CLS- H08, CLS-H09~CLS-H16, CLP-P01~CLP-P08, CLP-P09~CLP-P16, CLP-H01~CLP-H08, CLP- H09~CLP-H16, structure are as follows:
The ring triol derivates be more preferably compound CLC-P01~CLC-P08, CLC-H09~CLC-H16, CLS-P01~CLS-P08, CLS-H09~CLS-H16, CLP-P01~CLP-P08, CLP-H09~CLP-H16.
The preparation method of above-mentioned ring triol derivates, includes the following steps:
The synthesis of (1a) benzene a pair of horses going side by side [d] [1,3] dioxolen (piperonyl cyclonene):
Using catechol as starting material, it is dissolved in n,N-Dimethylformamide, adds reagent a and sodium bicarbonate, Reaction obtains parallel [d] [1, the 3] dioxolen of benzene；
The synthesis of (1b) 3,4- dioxymethylene benzaldehyde (piperonal):
Parallel [d] [1, the 3] dioxolen of benzene obtained in step (1a) is added dissolved in the isopropanol of catalyst, examination is added Agent b, reaction, obtains 3,4-methylenedioxy benzaldehyde；
The synthesis of (1c) (E) -3- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) acrylic acid:
3,4-methylenedioxy benzaldehyde and reagent c that step (1b) obtains are dissolved in alkali, reacts, obtains (E) -3- (benzene Parallel [d] [1,3] dioxolen -5- base) acrylic acid；
The synthesis of (1c ') (E) -2- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) ethylene -1- sulfonic acid:
3,4- dioxymethylene benzaldehyde and Loprazolam acid anhydride that step (1b) obtains are dissolved in dry tetrahydrofuran (THF), sodium hydride is added, reaction obtains (E) -2- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) ethylene -1- sulfonic acid；
The synthesis of (1c ") (E) -2- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) vinyl phosphonic dimethyl phthalate:
3,4- dioxymethylene benzaldehyde and dimethyl methyl phosphonate that step (1b) obtains are dissolved in dry tetrahydro furan It mutters, sodium hydride is added, reaction obtains (E) -2- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) vinyl phosphonic dimethyl phthalate；
The synthesis of (1d ") (E) -2- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) ethylene -1- phosphonic acids mono-methyl:
(E) -2- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) vinyl phosphonic dimethyl phthalate that step (1c ") is obtained is molten In dry tetrahydrofuran, reagent d " is added, obtains (E) -2- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) ethylene -1- phosphonic acids Mono-methyl；
The synthesis of (2a) 2- cyclopentene -1- alcohol:
Using 2- cyclopentene-1-one as raw material, it is dissolved in methanol, cerous chloride is added, sodium borohydride is added, instead in reaction It answers, obtains 2- cyclopentene -1- alcohol；
The synthesis of (2b) 2- cyclopentene -1- benzyl oxide:
2- cyclopentene -1- alcohol obtained in step (2a) is dissolved in and steams tetrahydrofuran again, tetrabutylammonium bromide, balance is added After sodium hydride is added, react, be added dropwise cylite, reaction, obtain 2- cyclopentene -1- benzyl oxide；
The synthesis of the amyl- 1- benzyl oxide of (2c) 2,3- dihydroxy basic ring:
2- cyclopentene -1- benzyl oxide obtained in step (2b) is dissolved in acetonitrile solution, reagent 2c is added after balance, reacts, Obtain the amyl- 1- benzyl oxide of 2,3- dihydroxy basic ring；
The synthesis of the amyl- 1,2- bis-mesylate of (2d) 3- benzyloxy basic ring:
The amyl- 1- benzyl oxide of 2,3- dihydroxy basic ring obtained in step (2c) is dissolved in and steams methylene chloride again, 4- (N, N- bis- is added Methyl) aminopyridine, triethylamine is added, reagent 2d is added dropwise again after balance, reacts, obtains amyl- 1,2-, bis- methylsulphur of 3- benzyloxy basic ring Acid esters；
The synthesis of the amyl- 1- benzyl oxide of (2e) 2,3- diazido ring
The amyl- 1,2- bis-mesylate of 3- benzyloxy basic ring obtained in step (2d) is dissolved in N,N-dimethylformamide (DMF) and the mixed solvent of hexamethylphosphoramide (HMPA), addition sodium azide, reaction obtain 1- benzyloxy -3- nitrine ring Amyl- 2- methanesulfonates；
The obtained amyl- 2- methanesulfonates of 1- benzyloxy -3- nitrine ring is dissolved in N,N-dimethylformamide (DMF) and pregnancy The mixed solvent of base phosphoric triamide (HMPA), is added sodium azide, and reaction obtains the amyl- 1- benzyl oxide of 2,3- diazido ring；
The synthesis of the amyl- 1- benzyl oxide of (2f) 2,3- diamino basic ring:
The amyl- 1- benzyl oxide of 2,3- diazido ring obtained in step (2e) is dissolved in methanol solution, triphenylphosphine is added, instead It answers, obtains the residue containing the amyl- 1- benzyl oxide of 2,3- diamino basic ring；
(E) -3- obtained in step (1c) (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) acrylic acid is dissolved in and being steamed again by (3a) N,N-Dimethylformamide, is added condensing agent and 1- hydroxy benzenes a pair of horses going side by side triazole (HOBt), and n,N-diisopropylethylamine is added in reaction (DIPEA), after the residue of the amyl- 1- benzyl oxide of 2,3- diamino basic ring obtained in step (2f) being dissolved in n,N-Dimethylformamide It is added dropwise into reaction system, reacts, the optics for obtaining amyl- 1,2- bis- [3 ', 4 '-dioxy methene] the coffee amide of 3- benzyloxy basic ring is different Structure body mixture；
The optics of amyl- 1,2- bis- [3 ', 4 '-dioxy methene] the coffee amide of the 3- benzyloxy basic ring that (3b) obtains step (3a) Isomer mixture is dissolved in and steams methylene chloride again, and deprotection agent is added dropwise after balance, and reaction obtains bis- coffee of 3- hydroxycyclopent -1,2- Optical isomer intermixture CLC-P01~CLC-P08 of coffee amide.
Reagent a described in step (1a) is formaldehyde, CH2Cl2、CH2Br2And CH2I2One of；Preferably CH2I2。
The dosage of reagent a described in step (1a) is 1.0~1.5:1.0 by the molar ratio of itself and the catechol Proportion；It is preferably 1.2:1.0 proportion by the molar ratio of itself and the 3,4- dioxymethylene benzaldehyde.
The temperature of reaction described in step (1a) is 70~100 DEG C；Preferably 80 DEG C.
The time of reaction described in step (1a) is 5~20h；Preferably 12h.
A pair of horses going side by side [d] [1, the 3] dioxolen of benzene described in step (1b) is to be added dropwise under the conditions of 55 DEG C dissolved with catalyst In isopropanol, drip within 0.5 hour.
Catalyst described in step (1b) is one of phosphorus oxychloride, nitric acid and acetic anhydride；Preferably acetic anhydride.
Reagent b described in step (1b) is one of N,N-dimethylformamide, glyoxalic acid and methenamine；It is preferred that For methenamine.
The dosage of reagent b described in step (1b) is by the molar ratio of itself and parallel [d] [1,3] dioxolen of the benzene 400~700:1.0 proportion；It is preferably 660:1.0 proportion by the molar ratio of itself and parallel [d] [1,3] dioxolen of the benzene.
The temperature of reaction described in step (1b) is 80~120 DEG C；Preferably 110 DEG C.
The time of reaction described in step (1b) is 0.5~3h；Preferably 1h.
Reagent c described in step (1c) is one of acetic anhydride and malonic acid；Preferably malonic acid.
Alkali described in step (1c) is the sodium salt or sylvite, piperidines/pyridine, sodium hydride, diisopropylaminoethyl of respective acids One of lithium (LDA) and potassium tert-butoxide；Preferably piperidines/pyridine.
The dosage of reagent c described in step (1c) is by the molar ratio of itself and the 3,4- dioxymethylene benzaldehyde 1.0~6.0:1.0 proportion；It is preferably 2:1 proportion by the molar ratio of itself and the 3,4- dioxymethylene benzaldehyde.
The dosage of 3,4- dioxymethylene benzaldehyde described in step (1c '), Loprazolam acid anhydride and sodium hydride is according to rubbing You match than 1.0:1.0~2.0:1.5~3.0 and calculate；It preferably matches and calculates according to molar ratio 1.0:1.5:1.5.
The dosage of 3,4- dioxymethylene benzaldehyde, dimethyl methyl phosphonate and sodium hydride described in step (1c ") is pressed It matches and calculates according to molar ratio 1.0:1.0~2.0:1.5~3.0；It preferably matches and calculates according to molar ratio 1.0:1.5:1.5.
Reaction described in step (1c), (1c ') and (1c ") is to be heated to reflux 4~1h at 90~130 DEG C of oil bath； Preferably 2h is heated to reflux at 115 DEG C of oil bath.
Reagent d described in step (1d ") " it is one of lithium hydroxide, lithium carbonate and tri butyl boron lithium hydride；It is preferred that For tri butyl boron lithium hydride.
Addition reagent d described in step (1d ") " it is to be added dropwise under nitrogen protection.
The dosage of cerous chloride, sodium borohydride and 2- cyclopentene-1-one described in step (2a) is according to molar ratio 1~2: 1~2:1 proportion calculates；It preferably matches and calculates according to molar ratio 1.2:1.2:1.
In step (2a), the reaction after the cerous chloride is added reacts 0.2~2h under the conditions of being -20~0 DEG C；It is preferred that 0.5h is reacted under the conditions of being -10 DEG C.
In step (2a), the reaction after the sodium borohydride is added reacts 1~5h under the conditions of being -20~0 DEG C；It is preferred that 2h is reacted under the conditions of being -10 DEG C.
Cerous chloride described in step (2a) is added in three times.
Tetrabutylammonium bromide described in step (2b), sodium hydride, cylite and 2- cyclopentene -1- alcohol molar ratio be 1: 30~50:8~15:5~15；Preferably molar ratio is 1:40:12:8.
In step (2b), the reaction after the sodium hydride is added reacts 5~30min under the conditions of being -15~0 DEG C；It is preferred that 10min is reacted under the conditions of being -5 DEG C.
In step (2b), the reaction after the cylite is added dropwise be prior to -15~0 DEG C under the conditions of react 20~50min, It then moves to and 3~6h of reaction is stirred at room temperature；Preferably prior to -5 DEG C under the conditions of react 30min；It then moves to and reaction 5h is stirred at room temperature.
Sodium hydride described in step (2b) is added in three times.
Acetonitrile solution described in step (2c) is that 3:1 matches to obtain by volume for acetonitrile and water.
Reagent 2c described in step (2c) is potassium osmate/N-methyl morpholine oxide/potassium carbonate, Peracetic acid, peroxide Change at least one of hydrogen, metachloroperbenzoic acid.
When the reagent 2c is potassium osmate/N-methyl morpholine oxide/potassium carbonate, N-methyl morpholine oxide, carbonic acid The dosage of potassium and 2- cyclopentene -1- benzyl oxide is calculated according to 0.8~1.5:0.8 of molar ratio~1.5:1 proportion；Preferably according to mole It matches and calculates than 1.2:1.2:1；The dosage of potassium osmate is catalytic amount.
Reaction described in step (2c) be condition of ice bath under react 20~50min, then move to be stirred at room temperature reaction 10~ 20h；30min preferably is reacted under condition of ice bath, then moves to and reaction 12h is stirred at room temperature.
Addition triethylamine described in step (2d) is that triethylamine is added under condition of ice bath.
Reagent 2d described in step (2d) is at least one of mesyl chloride and paratoluensulfonyl chloride.
The dosage of reagent 2d described in step (2d) presses the molar ratio of itself and the amyl- 1- benzyl oxide of 2,3- dihydroxy basic ring It matches and calculates for 1~5:1；It is preferably based on 3:1 proportion by the molar ratio of itself and the amyl- 1- benzyl oxide of 2,3- dihydroxy basic ring It calculates.
Reaction described in step (2d) is 20~50min to be reacted under condition of ice bath, then 5~20h of reaction is stirred at room temperature；It is excellent It is selected as reacting 30min under condition of ice bath and being stirred at room temperature again reacting 12h.
N,N-dimethylformamide described in step (2e) and the mixed solvent of hexamethylphosphoramide be by by N, Dinethylformamide and hexamethylphosphoramide match to obtain according to volume ratio 3:1.
In step (2e), the dosage for the sodium azide being added for the first time presses itself and amyl- 1, the 2- bis- of 3- benzyloxy basic ring The molar ratio of methanesulfonates is that 1~5:1 proportion calculates；Preferably press itself and amyl- bis- methanesulfonic acid of 1,2- of 3- benzyloxy basic ring The molar ratio of ester is that 3:1 proportion calculates.
In step (2e), the dosage of second of sodium azide being added is amyl- with the 1- benzyloxy -3- nitrine ring by it The molar ratio of 2- methanesulfonates is that 2~8:1 proportion calculates；Preferably press itself and the amyl- 2- first of 1- benzyloxy -3- nitrine ring The molar ratio of sulphonic acid ester is that 5:1 proportion calculates.
In step (2e), first set reaction is 5~20h of reaction under the conditions of 50~100 DEG C of oil baths；Preferably 70 DEG C of oil bath items 12h is reacted under part.
In step (2e), the second secondary response is 10~30h of reaction under the conditions of 100~150 DEG C of oil baths；Preferably 125 DEG C of oil It is reacted for 24 hours under the conditions of bath.
Methanol solution described in step (2f) is that first alcohol and water matches to obtain according to volume ratio 5:1.
The dosage of triphenylphosphine described in step (2f) is by its rubbing with the 2,3- amyl- 1- benzyl oxide of diazido ring You are than being that 0.5~2:1 proportion calculates；Preferably it is by the molar ratio of itself and the amyl- 1- benzyl oxide of 2,3- diazido ring 1.5:1 proportion calculates.
Reaction described in step (2f) is 3~10h of back flow reaction under the conditions of 50~80 DEG C of oil baths；Preferably 68 DEG C of oil baths Under the conditions of back flow reaction 5h.
Condensing agent described in step (3a) is N, N'- diisopropylcarbodiimide (DIC), 1- (3- dimethylamino third Base) one of -3- ethyl-carbodiimide hydrochloride (EDCI) and ethyl chloroformate；Preferably 1- (3- dimethylamino-propyl)- 3- ethyl-carbodiimide hydrochloride.
The dosage of condensing agent described in step (3a) is by itself and described (E) -3- (benzene a pair of horses going side by side [d] [1,3] dioxolen - 5- yl) acrylic acid molar ratio be 0.5~2:1 proportion calculate；Preferably press itself and (E) -3- (benzene a pair of horses going side by side [d] [1,3] two Oxygen amylene -5- base) acrylic acid molar ratio be 1.2:1 proportion calculate.
In step (3a), the time of the reaction after the condensing agent and 1- hydroxy benzenes a pair of horses going side by side triazole is added be 20min~ 50min；Preferably 30min.
In step (3a), after the residue of the amyl- 1- benzyl oxide of 2,3- diamino basic ring is dissolved in n,N-Dimethylformamide It is added dropwise into reaction system, the time reacted later is 5~20h；Preferably 12h.
It further include chromatographing described eight kinds of optical isomers of CLC-P01~CLC-P08 using column, efficiently in step (3b) One of liquid phase method and recrystallization method or at least two the step of isolating and purifying.
Deprotection agent described in step (3b) is BCl3And BBr3One of；Preferably BCl3。
The dosage of deprotection agent described in step (3b) presses itself and the amyl- 1,2- bis- [3 ', 4 '-of 3- benzyloxy basic ring Dioxy methene] coffee amide optical isomer intermixture molar ratio be 1~5:1 proportion calculate；Preferably by its with it is described Amyl- 1,2- bis- [3 ', 4 '-dioxy methene] the coffee amide of 3- benzyloxy basic ring optical isomer intermixture molar ratio be 2.5: 1 proportion calculates.
Reaction in step (3b) reacts 15~45min under the conditions of being 0~-20 DEG C, then move to be stirred at room temperature reaction 1~ 5h；30min is reacted under the conditions of preferably -10 DEG C, then moves to and reaction 2h is stirred at room temperature.
The synthesis of penta triol of (2b ') 1,2,3- ring:
2- cyclopentene -1- the alcohol that step (2a) is obtained according to step (2c), use identical reagent/auxiliary agent/solvent with And the molar ratio between each substance is synthesized, and 1,2,3- ring, penta triol is obtained；
The synthesis of (2c ') 2- hydroxycyclopent -1,3- bis-mesylate:
1 that step (2b ') is obtained, 2,3- ring, penta triol is according to step (2d), using identical reagent/auxiliary agent/solvent And the molar ratio between each substance is synthesized, and 2- hydroxycyclopent -1,3- bis-mesylate is obtained；
The synthesis of the amyl- 2- alcohol of (2d ') 1,3- diazido ring:
2- hydroxycyclopent -1,3- bis-mesylate that step (2c ') is obtained is according to step (2e), using identical examination Molar ratio between agent/auxiliary agent/solvent and each substance is synthesized, and the amyl- 2- alcohol of 1,3- diazido ring is obtained；
The synthesis of the amyl- 2- benzyl oxide of (2e ') 1,3- diazido ring:
The amyl- 2- alcohol of 1,3- diazido ring that step (2d ') is obtained is according to step (2b), using identical reagent/help Molar ratio between agent/solvent and each substance is synthesized, and the amyl- 2- benzyl oxide of 1,3- diazido ring is obtained；
The synthesis of the amyl- 2- benzyl oxide of (2f ') 1,3- diamino basic ring:
The amyl- 2- benzyl oxide of 1,3- diazido ring that step (2e ') is obtained according to step (2f), using identical reagent/ Molar ratio between auxiliary agent/solvent and each substance is synthesized, and the residue of the amyl- 2- benzyl oxide of 1,3- diamino basic ring is obtained.
The preparation process of 1,3- diamino hexamethylene -2- benzyl oxide is carried out by step (2a), (2b ')~(2f '), wherein starting is former Material is changed to 2- cyclohexene -1- ketone by 2- cyclopentene-1-one, between other reagents, auxiliary agent and solvent type and each substance Molar ratio is identical.
The preparation process of 2,3- diamino hexamethylene -1- benzyl oxides is carried out by step (2a)~(2f), and wherein starting material is by 2- Cyclopentene-1-one is changed to 2- cyclohexene -1- ketone, the molar ratio between other reagents, auxiliary agent and solvent type and each substance It is identical.
The preparation process of two coffee amide (CLC-P09~CLC-P16) of 2- hydroxycyclopent -1,3- according to step (3a) and (3b) is carried out, and the amyl- 1- benzyl oxide of 2,3- diamino basic ring that wherein starting material is obtained by step (2f) is changed to step (2f ') and obtains The amyl- 2- benzyl oxide of 1,3- diamino basic ring, the molar ratio between other reagents, auxiliary agent and solvent type and each substance is identical.
The preparation of two coffee amide (CLC-H01~CLC-H08) of 3- hydroxy cyclohexylphenyl -1,2- by step (3a) and (3b) into Row, the amyl- 1- benzyl oxide of 2,3- diamino basic ring that wherein starting material is obtained by step (2f) are changed to 2, the 3- diamino basic ring Hex- 1- benzyl oxide, the molar ratio between other reagents, auxiliary agent and solvent type and each substance are identical.
The preparation process of two coffee amide (CLC-H09~CLC-H16) of 2- hydroxy cyclohexylphenyl -1,3- according to step (3a) and (3b) is carried out, and the amyl- 1- benzyl oxide of 2,3- diamino basic ring that wherein starting material is obtained by step (2f) is changed to 2, the 3- bis- Aminocyclohexyl -1- benzyl oxide, the molar ratio between other reagents, auxiliary agent and solvent type and each substance are identical.
The preparation process of two coffee sulfonamide (CLS-P01~CLS-P08) of 3- hydroxycyclopent -1,2- according to step (3a) and (3b) is carried out, (E) -3- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) acrylic acid that wherein starting material is obtained by step (1c) It is changed to (E) -2- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) ethylene -1- sulfonic acid that step (1c ') obtains, other reagents help Molar ratio between agent and solvent type and each substance is identical.
The preparation process of two coffee sulfonamide (CLS-P09~CLS-P16) of 2- hydroxycyclopent -1,3- according to step (3a) and (3b) is carried out, (E) -3- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) acrylic acid that wherein starting material is obtained by step (1c) It is changed to (E) -2- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) ethylene -1- sulfonic acid that step (1c ') obtains, step (2f) obtains The amyl- 1- benzyl oxide of 2,3- diamino basic ring arrived is changed to the amyl- 2- benzyl oxide of 1,3- diamino basic ring that step (2f ') obtains, other reagents, Molar ratio between auxiliary agent and solvent type and each substance is identical.
The preparation process of two coffee sulfonamide (CLS-H01~CLS-H08) of 3- hydroxy cyclohexylphenyl -1,2- according to step (3a) and (3b) is carried out, (E) -3- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) acrylic acid that wherein starting material is obtained by step (1c) It is changed to (E) -2- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) ethylene -1- sulfonic acid that step (1c ') obtains, step (2f) obtains The amyl- 1- benzyl oxide of 2,3- diamino basic ring arrived is changed to 2, the 3- diamino hexamethylene -1- benzyl oxide, other reagents, auxiliary agent and molten Molar ratio between agent type and each substance is identical.
The preparation process of two coffee sulfonamide (CLS-H09~CLS-H16) of 2- hydroxy cyclohexylphenyl -1,3- according to step (3a) and (3b) is carried out, (E) -3- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) acrylic acid that wherein starting material is obtained by step (1c) It is changed to (E) -2- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) ethylene -1- sulfonic acid that step (1c ') obtains, step (2f) obtains The amyl- 1- benzyl oxide of 2,3- diamino basic ring arrived is changed to 1, the 3- diamino hexamethylene -2- benzyl oxide, other reagents, auxiliary agent and molten Molar ratio between agent type and each substance is identical.
The preparation process of two coffee phosphine (mono-methyl) amide (CLP-P01~CLP-P08) of 3- hydroxycyclopent -1,2- is according to step Suddenly (3a) and (3b) is carried out, (E) -3- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- that wherein starting material is obtained by step (1c) Base) acrylic acid is changed to (E) -2- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) ethylene -1- phosphonic acids list that step (1d ") obtains Methyl esters, the molar ratio between other reagents, auxiliary agent and solvent type and each substance are identical.
The preparation process of two coffee phosphine (mono-methyl) amide (CLP-P09~CLP-P16) of 2- hydroxycyclopent -1,3- is according to step Suddenly (3a) and (3b) is carried out, (E) -3- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- that wherein starting material is obtained by step (1c) Base) acrylic acid is changed to (E) -2- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) ethylene -1- phosphonic acids list that step (1d ") obtains Methyl esters, it is amyl- that the amyl- 1- benzyl oxide of 2,3- diamino basic ring that step (2f) obtains is changed to 1, the 3- diamino basic ring that step (2f ') obtains 2- benzyl oxide, the molar ratio between other reagents, auxiliary agent and solvent type and each substance are identical.
The preparation process of two coffee phosphine (mono-methyl) amide (CLP-H01~CLP-H08) of 3- hydroxy cyclohexylphenyl -1,2- is according to step Suddenly (3a) and (3b) is carried out, (E) -3- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- that wherein starting material is obtained by step (1c) Base) acrylic acid is changed to (E) -2- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) ethylene -1- phosphonic acids list that step (1d ") obtains Methyl esters, the amyl- 1- benzyl oxide of 2,3- diamino basic ring that step (2f) obtains are changed to 2, the 3- diamino hexamethylene -1- benzyl oxide, Molar ratio between his reagent, auxiliary agent and solvent type and each substance is identical.
The preparation process of two coffee phosphine (mono-methyl) amide (CLP-H09~CLP-H16) of 2- hydroxy cyclohexylphenyl -1,3- is according to step Suddenly (3a) and (3b) is carried out, (E) -3- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- that wherein starting material is obtained by step (1c) Base) acrylic acid is changed to (E) -2- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) ethylene -1- phosphonic acids list that step (1d ") obtains Methyl esters, the amyl- 1- benzyl oxide of 2,3- diamino basic ring that step (2f) obtains are changed to 1, the 3- diamino hexamethylene -2- benzyl oxide, Molar ratio between his reagent, auxiliary agent and solvent type and each substance is identical.
Institute in (E) -3- described in step (1c) (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) acrylic acid, step (1c ') (E) -2- (benzene described in (E) -2- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) ethylene -1- sulfonic acid and step (1d ") stated Parallel [d] [1,3] dioxolen -5- base) vinyl phosphonic acid mono-methyl synthetic route as shown in approach 1:
2,3- diamino hexamethylene -1- benzyl oxide step and the amyl- 1- benzyl oxide of 2,3- diamino basic ring, 1,3- diamino described in (2f) The synthetic route of the amyl- 2- benzyl oxide of 1,3- diamino basic ring described in basic ring hex- 2- benzyl oxide and step (2f ') such as approach 2, approach 3 It is shown:
Institute in (E) -3- described in step (1c) (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) acrylic acid, step (1c ') (E) -2- (benzene described in (E) -2- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) ethylene -1- sulfonic acid and step (1d ") stated Parallel [d] [1,3] dioxolen -5- base) vinyl phosphonic acid mono-methyl is amyl- with 2,3- diamino basic ring described in step (2f) respectively It is the amyl- 2- benzyl oxide of 1,3- diamino basic ring described in 1- benzyl oxide, (2f '), the 2,3- diamino hexamethylene -1- benzyl oxide, described Benzyl is sloughed after the condensation of 1,3- diamino hexamethylene -2- benzyl oxide, obtains the route of ring triol derivates as shown in approach 4:
Application of the above-mentioned ring triol derivates in preparation antiviral drugs.
The virus is Respiratory Syncytial Virus(RSV) (RSV).
A kind of antiviral drugs, including above-mentioned ring triol derivates.
The antiviral drugs can also contain a kind of or at least two pharmaceutically acceptable carrier or auxiliary materials.
The auxiliary material be preferably sustained release agent, excipient, filler, adhesive, wetting agent, disintegrating agent, sorbefacient, Absorption carrier, surfactant or lubricant etc..
The carrier is at least one of micro-capsule, microballoon, nanoparticle and liposome.
Various dosage forms can be further made in the antiviral drugs, and the drug of various dosage forms can be according to pharmaceutical field Conventional method be prepared.
The present invention has the following advantages and effects with respect to the prior art:
(1) present invention is according to medicine core similarity principle and bioisostere principle, with natural 1 α, 2 β- The amyl- 3 β -ol of bis- caffeoyl ring of O, O- is primer, and design synthesis has the ring triol derivates of antivirus action.Utilize plaque The Anti-viral activity in vitro of subtrahend experiment detection series of loops triol derivates, and assess series of loops triol respectively using MMT method and spread out The cytotoxicity of biology.The result shows that the designed ring triol derivates synthesized of the present invention all have strong preventing respiratory and close born of the same parents Viral (RSV) activity, and cytotoxicity is low, selectivity index (SI value, the SI=CC of anti-RSV50/IC50) right higher than positive According to medicine Ribavirin, natural primer 1 α, 2 bis- amyl- 3 β -ol of caffeoyl ring of β-O, O-.
(2) ring triol derivates stability with higher of the invention, stability in fetal calf serum is than 1 α, and 2 The amyl- 3 β -ol of bis- caffeoyl ring of β-O, O- is high.
(3) ring triol derivates of the invention can be acted on the F protein of RSV virus, and action intensity is greater than 1 α, 2 β- The amyl- 3 β -ol of bis- caffeoyl ring of O, O-.
(4) the preparation method reaction condition of ring triol derivates of the invention is mild, easy to operate and safe, work easy to accomplish Industry metaplasia produces.
Specific embodiment
Below with reference to embodiment, the present invention is described in further detail, it will be appreciated by those skilled in the art that Following embodiments and embodiment are merely to illustrate the present invention, and are not construed as limiting the scope of the invention.Specific item is not specified Part person carries out according to conventional conditions or manufacturer's recommended conditions.Reagents or instruments used without specified manufacturer, being can With the conventional products obtained by commercially available purchase.
It the preparation of 1 3- hydroxycyclopent -1,2- of embodiment, two coffee amide (CLC-P01~CLC-P08) and isolates and purifies
(1) preparation of (E) -3- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) acrylic acid
The preparation of (1a) benzene a pair of horses going side by side [d] [1,3] dioxolen (piperonyl cyclonene)
It weighs catechol (110.1mg, 1.0mmol) to be placed in 50mL round-bottomed flask, n,N-Dimethylformamide is added 15mL, stirring dissolve catechol, add diiodomethane (321.4mg, 1.2mmol) and sodium bicarbonate (210.0mg, 2.5mmol), 12h is reacted in 80 DEG C of heating.After completion of the reaction, product is poured slowly into ice water while stirring, ethyl acetate extraction 3 times, organic layer is dry with anhydrous sodium sulfate, and vacuum rotary steam removes ethyl acetate, silica gel column chromatography (Beijing Xin Weier glass apparatus Co., Ltd) (petroleum ether: ethyl acetate=10:1, V:V) is isolated and purified, faint yellow solid 75.8mg is obtained, yield is 62.1%.1H NMR(300MHz,CDCl3)δ:6.83-6.79(m,4H),5.90(s,2H)；13CNMR(300MHz,CDCl3)δ: 147.5,121.7,108.7,100.7。
The preparation of (1b) 3,4- dioxymethylene benzaldehyde (piperonal)
75.0g catalyst acetic acid acid anhydride is added in 200mL there-necked flask, is added with stirring isopropanol 10mL, heats to 55 DEG C, parallel [d] [1,3] dioxolen (5.0g, 40.9mmol) of benzene that step (1a) obtains is slowly added dropwise, drips off within 0.5 hour, is added Methenamine (3.8g, 27.0mol), charging finishes, and is warming up to 110 DEG C, keeps the temperature 1 hour, samples liquid phase analysis, cool to 60~ 70 DEG C, water 700mL is added, stirs 3 hours, ethyl acetate is added and extracts twice, merges organic phase, saturated common salt washing is added It washs, separates organic phase, anhydrous sodium sulfate 5g is added and is dried, filters, ethyl acetate, extraction raffinate oil pump is concentrated in filtrate at 40 DEG C Vacuum distillation is to get piperonal 3.58g, yield 58.2%, purity 96%.1HNMR(300MHz,CDCl3)δ:9.82(s,1H), 7.43(d,1H),7.34(s,1H),6.95(d,1H),6.08(s,2H)；13C NMR(75MHz,CDCl3)δ:190.3,153.1, 148.7,130.9,128.7,108.3,106.9,102.1。
The preparation of (1c) (E) -3- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) acrylic acid
In 250mL round-bottomed flask, piperonal (12g, 79.9mmol) that step (1b) is obtained, malonic acid (16.6g, 159.9mmol) with reaction solution is obtained after 7.2mL piperidines and 140mL pyridinium dissolution, reaction solution is moved to 115 DEG C of oil bath and is heated back Stream about 2 hours.Reaction process is monitored to piperonal with thin-layer chromatography TLC and is completely disappeared, and shows fully reacting.Reaction solution is cooled to After room temperature, reaction solution is slowly poured into 200mL hydrochloric acid solution (2mol/L) under ice bath, there are a large amount of yellowish-white solids to analyse Out.Through filter obtain faint yellow solid filter cake, after faint yellow solid filter cake wash with 400mL water dispersion, then through suction filtration obtain Yellowish-white solid filter cake, and repeating above operation to filter cake pH value is neutrality.It is recrystallized with hot water, collects yellowish-white solid It dries under filter cake to infrared lamp to constant weight, obtains yellowish-white solid 11.9g, yield 77.1%.1H NMR(300MHz,CDCl3) δ:12.05(s,1H),7.45(d,1H),7.12(s,1H),7.06(d,1H),6.95(d,1H),6.27(d,1H),6.07(s, 2H)；13C NMR(75MHz,CDCl3)δ:171.5,151.1,148.6,144.9,127.6,122.7,116.5,108.3, 106.9,102.1。
(2) preparation of the amyl- 2- benzyl oxide of 1,3- diamino basic ring
The preparation of (2a) 2- cyclopentene -1- alcohol
2- cyclopentene-1-one (0.42mL, 5mmol) is measured in dry 50mL round-bottomed flask, with suitable dry first Alcohol dissolution, flask are placed in cryogenic thermostat stirring reactive bath, then weigh cerous chloride (1.48g, 6mmol) and flask is added, protect - 10 DEG C of condition stirring 0.5h are held, then divides 3 times and is slowly added to sodium borohydride (227mg, 6mmol), it is anti-under the conditions of being maintained at -10 DEG C Answer 2h.It is complete wait react, the saturated ammonium chloride solution quenching reaction of 3mL is slowly added dropwise under conditions of -10 DEG C, then by reaction solution Move in separatory funnel, extracted with methylene chloride (DCM, 3 × 50mL), merge organic phase after with saturated salt solution (2 × It 100mL) washs, organic phase anhydrous Na2SO4It dries, filters, vacuum revolving removes solvent, and TLC solvent condition is EtOAc: PE=1:5 (V:V), RfValue is 0.32, separates (EtOAc:PE=1:10, V:V) through silica gel column chromatography, obtains colourless oil liquid 374mg, yield 88.9%.1H NMR(300MHz,CDCl3)δ:5.96(m,1H,H-2),5.80(m,1H,H-3),4.84(m, 1H,H-1),1.71-2.54(m,4H,H-4,5)；13C NMR(75MHz,CDCl3)δ:135.4,133.5,77.8,33.5, 31.2。
The preparation of (2b) 2- cyclopentene -1- benzyl oxide
2- cyclopentene -1- alcohol (336mg, 4mmol) that step (2a) obtains is weighed in dry 100mL round-bottomed flask, It is dissolved with suitable heavy steaming tetrahydrofuran, and tetrabutylammonium bromide (161mg, 0.5mmol) is added, flask is then placed in low temperature 5min is balanced under conditions of -5 DEG C of reactive bath technique.Ready to balance is finished, be slowly added into reaction solution points for 3 times sodium hydride (480mg, 20mmol), -5 DEG C of the reaction was continued 10min are kept.Then it measures cylite (0.71mL, 6mmol) and is slowly dropped to reaction system In, after keeping cryogenic conditions 30min, room temperature is then moved to, continues to stir 5h.It is complete wait react, 5mL is slowly added dropwise under condition of ice bath Methanol quenching reaction, then reaction solution is moved in separatory funnel, suitable saturated salt solution dilute reaction solution is added, use DCM (3 × 50mL) is extracted, and is washed after merging organic phase with saturated salt solution (2 × 100mL), organic phase anhydrous Na2SO4 It dries, filters, vacuum revolving removes solvent, and TLC solvent condition is EtOAc:PE=1:50 (V:V), RfValue is 0.40.Through silicon Plastic column chromatography separates (pure petroleum ether) and obtains colourless oil liquid 588mg, yield 84.5%.1H NMR(300MHz,CDCl3)δ: 7.42-7.55(m,5H,H-Ph),6.17(m,1H,H-2),6.08(m,1H,H-3),4.82(m,1H,H-1),4.67(s,2H,- CH2-Ph),1.98-2.75(m,4H,H-4,5)；13C NMR(75MHz,CDCl3)δ:138.8,135.3,130.8,128.1 (2C),127.4(2C),127.2,84.2,70.2,30.9,29.7。
The preparation of the amyl- 1- benzyl oxide of (2c) 2,3- dihydroxy basic ring
2- cyclopentene -1- benzyl oxide (522mg, 3mmol) that step (2b) obtains is weighed in dry 100mL round-bottomed flask In, with the mixed solution (CH of appropriate acetonitrile and water3CN:H2O=3:1, V:V) dissolution, and flask is placed under condition of ice bath and is balanced Then 5min is successively slowly added to N-methyl morpholine oxide (421mg, 3.6mmol), potassium osmate 30mg (catalytic amount), carbonic acid Potassium (498mg, 3.6mmol) keeps under condition of ice bath then moving to room temperature after the reaction was continued 30min, continuing to stir 12h.Wait react Finish, reaction solution is moved in separatory funnel, suitable saturated salt solution dilute reaction solution is added, is extracted with DCM (3 × 50mL) It takes, is washed after merging organic phase with saturated salt solution (2 × 100mL), organic phase anhydrous Na2SO4It dries, filters, vacuum revolving Solvent is removed, TLC solvent condition is CHCl3: MeOH=15:1 (V:V), RfValue is 0.35.It is separated through silica gel column chromatography (CHCl3: MeOH=30:1, V:V) obtain colourless oil liquid 535mg, yield 85.7%.1H NMR(300MHz,CDCl3)δ: 7.26-7.39(m,5H,H-Ph),4.56(s,2H,-CH2-Ph),4.09(m,1H,H-2),3.92(m,2H,H-1,3),1.50- 2.20(m,4H,H-4,5)；13C NMR(75MHz,CDCl3)δ:138.4,128.5(2C),127.9(2C),127.8,84.2, 78.1,72.0,71.8,29.0,26.8。
The preparation of the amyl- 1,2- bis-mesylate of (2d) 3- benzyloxy basic ring
It is round in dry 100mL to weigh the amyl- 1- benzyl oxide (500mg, 2.4mmol) of 2,3- dihydroxy basic ring that step (2c) obtains In the flask of bottom, dissolved with suitable heavy steaming methylene chloride, and 4- (N, N- diformazan) aminopyridine (37mg, 0.3mmol) is added, so Flask is placed under condition of ice bath afterwards, is added acid binding agent triethylamine (1mL, 7.2mmol), 5min is balanced, then in reaction solution It is slowly added dropwise mesyl chloride (0.56mL, 7.2mmol), after keeping condition of ice bath reaction 30min, then moves to room temperature, continue to stir 12h.It is complete wait react, 5mL pure water quenching reaction is slowly added dropwise in condition of ice bath, then moves to reaction solution in separatory funnel, Suitable saturated salt solution dilute reaction solution is added, is extracted with DCM (3 × 50mL), uses saturated common salt after merging organic phase Water (2 × 100mL) washing, organic phase anhydrous Na2SO4It dries, filters, vacuum revolving removes solvent, and TLC solvent condition is EtOAc:PE=1:2 (V:V), RfValue is 0.31.Pale yellowish oil is obtained through silica gel column chromatography separation (EtOAc:PE=1:5, V:V) Liquid 678mg, yield 77.6%.1H NMR(300MHz,CDCl3) δ: 7.27-7.36 (m, 5H, H-Ph), 5.06 (q, J= 6.0Hz, 1H, H-2), 4.86 (t, J=6.0Hz, 1H, H-3), 4.54 (s, 2H ,-CH2-Ph),4.18(m,1H,H-1),3.04 (s,3H,-SO2CH3),3.03(s,3H,-SO2CH3),1.60-2.31(m,4H,H-4,5)；13C NMR(75MHz,CDCl3)δ: 137.4,128.6(2C),128.1,127.8(2C),83.3,80.2,79.8,72.2,38.4(2C),27.2,25.6；ESI-MS (m/z):387.9[M+Na]+。
The preparation of the amyl- 1- benzyl oxide of (2e) 2,3- diazido ring
Amyl- 1, the 2- bis-mesylate (546mg, 1.5mmol) of 3- benzyloxy basic ring that step (2d) obtains is weighed in dry In 50mL round-bottomed flask, with the mixed solvent of appropriate n,N-Dimethylformamide (DMF) and hexamethylphosphoramide (HMPA) (DMF:HMPA=3:1, V:V) dissolution, and sodium azide (293mg, 4.5mmol) is added, it is reacted under the conditions of 70 DEG C of oil bath 12h.It is complete wait react, 5mL pure water quenching reaction is slowly added dropwise under condition of ice bath, reaction solution is then moved into separatory funnel In, suitable saturated salt solution dilute reaction solution is added, is extracted with DCM (3 × 50mL), is eaten after merging organic phase with saturation Salt water (2 × 100mL) washing, organic phase anhydrous Na2SO4It dries, filters, vacuum revolving removes low boiling point solvent, TLC expansion Agent condition is EtOAc:PE=1:5 (V:V), RfValue is 0.32.Residue is purified with RP-HPLC, the eluant, eluent of RP-HPLC purifying Condition is MeOH:H2O=70:30 (V:V), RT=20.3min obtain yellow oil 385mg, yield 82.5%.1H NMR (300MHz,CDCl3) δ: 7.25-7.37 (m, 5H, H-Ph), 4.80 (t, J=6.0Hz, 1H, H-2), 4.56 (s, 2H ,-CH2- Ph),4.01(m,1H,H-1),3.89(m,1H,H-3),3.03(s,3H,-SO2CH3),1.79-2.13(m,4H,H-4,5)；13C NMR(75MHz,CDCl3)δ:137.5,128.7(2C),128.1,128.0(2C),89.2,81.4,71.8,64.2,38.7, 27.7,27.0, this is the amyl- 2- methanesulfonates of 1- benzyloxy -3- nitrine ring.
The amyl- 2- methanesulfonates (373mg, 1.2mmol) of 1- benzyloxy -3- nitrine ring is weighed in dry 50mL round-bottomed flask In, dissolved with the mixed solvent (DMF:HMPA=3:1, V:V) of appropriate DMF and HMPA, and be added sodium azide (390mg, 6mmol), it is reacted for 24 hours under the conditions of 125 DEG C of oil bath.It is complete wait react, 5mL pure water is slowly added dropwise in condition of ice bath and is quenched instead Answer, then move to reaction solution in separatory funnel, suitable saturated salt solution dilute reaction solution is added, with DCM (3 × 50mL) into Row extraction, is washed after merging organic phase with saturated salt solution (2 × 100mL), organic phase anhydrous Na2SO4It dries, filters, vacuum Revolving removes low boiling point solvent, and TLC solvent condition is EtOAc:PE=1:8 (V:V), RfValue is 0.51.Residue RP- HPLC purifying, the eluant, eluent condition of RP-HPLC purifying are MeOH:H2O=75:25 (V:V), RT=24.3min obtain deep yellow oil Shape object 227mg, yield 73.4%.1H NMR(300MHz,CDCl3)δ:7.26-7.40(m,5H,H-Ph),4.57(s,2H,- CH2- Ph), 3.96 (m, 1H, H-1), 3.84 (t, J=6.0Hz, 1H, H-2), 3.67 (m, 1H, H-3), 1.86-2.01 (m, 4H, H-4,5)；13C NMR(75MHz,CDCl3)δ:137.5,128.7(2C),128.1,128.0(2C),89.2,81.4,71.8, 64.2,38.7,27.7,27.0；ESI-MS(m/z):281.3[M+Na]+,297.5[M+K]+, this is that 2,3- diazido ring is amyl- 1- benzyl oxide.
The preparation of the amyl- 1- benzyl oxide of (2f) 1,3- diamino basic ring
The amyl- 1- benzyl oxide (220mg, 0.85mmol) of 2,3- diazido ring that step (2e) obtains is weighed in dry 50mL In round-bottomed flask, with the mixed solvent (MeOH:H of proper amount of methanol and water2O=5:1, V:V) dissolution, and triphenylphosphine is added (336mg, 1.275mmol) flows back under the conditions of 68 DEG C of oil bath, reacts 5h.It is complete wait react, suitable distilled water is added Then reaction solution is adjusted to faintly acid with the hydrochloric acid solution of 0.1M, then is extracted with DCM (2 × 50mL) by dilute reaction solution, abandon Organic phase is gone, water phase is retained.Water phase is adjusted to alkalescent with the sodium hydroxide solution of 0.1M, is extracted with DCM (3 × 50mL), It is washed after merging organic phase with saturated salt solution (2 × 100mL), organic phase anhydrous Na2SO4It dries, filters, vacuum revolving is removed Solvent is removed, TLC solvent condition is MeOH:CHCl3=1:5 (V:V), RfValue is 0.62.Since there are two trips in product structure From amino, stability is poor, and is not easy to separate, therefore residue is directly used in and is reacted in next step.
(3) it the preparation of two coffee amide (CLC-P01~CLC-P08) of 3- hydroxycyclopent -1,2- and isolates and purifies
(3a) weighs (E) -3- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) acrylic acid that step (1c) obtains (384.3mg, 2.0mmol) is dissolved in dry 50mL round-bottomed flask with suitable heavy steaming DMF, and is respectively added slowly to 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride (EDCI, 460mg, 2.4mmol) and 1- hydroxy benzenes a pair of horses going side by side triazole (HOBt, 324mg, 2.4mmol), reacts 30min under room temperature, be subsequently added into n,N-diisopropylethylamine (DIPEA, 0.42mL, 2.4mmol), and step (2f) is reacted into the drying of gained 2,3- diamino basic ring amyl- 1- benzyl oxide (about 0.8mmol) DMF dissolution, is then slowly dropped in reaction system, the reaction was continued at room temperature 12h.To end of reaction, in ice bath item 5mL pure water quenching reaction is slowly added dropwise under part, then moves to reaction solution in separatory funnel, suitable saturated salt solution is added Dilute reaction solution is extracted with DCM (3 × 50mL), is washed after merging organic phase with saturated salt solution (2 × 100mL), organic Mutually use anhydrous Na2SO4It dries, filters, vacuum revolving removes solvent, and TLC solvent condition is MeOH:CHCl3=1:5 (V:V), RfValue is 0.55.Residue is purified with RP-HPLC, and the eluant, eluent condition of RP-HPLC purifying is MeOH:H2O=60:40 (V:V), RT=25.3min obtains white solid 327.4mg, yield 73.8%.1H NMR(300MHz,CDCl3)δ:7.23-7.43(m, 7H,H-Ph,2’,2”),6.99(m,2H,H-4’,4”),6.87(m,2H,H-7’,7”),6.75(m,2H,H-8’,8”),6.53 (d, J=15Hz, 1H, H-1 '), 6.35 (d, J=15Hz, H-1 "), 6.08 (s, 4H), 4.48-4.63 (m, 3H, H-2 ,-CH2- Ph),4.07(m,1H,H-3),3.18(m,1H,H-1),1.82-2.17(m,4H,H-4,5)；13C NMR(75MHz,CDCl3)δ: 148.9(2C),146.8(2C),142.9,142.5,139.7,130.2,130.1,129.6(2C),129.3(2C),129.0, 128.5,128.4,122.4,122.3,118.7,118.5,116.6(2C),115.3(2C),102(2C),80.7,72.5, 55.2,52.1,29.7,28.4；ESI-MS(m/z):555.6[M+H]+.All data confirm thats substance is that 3- benzyloxy basic ring is amyl- The optical isomer intermixture of 1,2- bis- [3 ', 4 '-dioxy methene] coffee amide.
Step (3a) is reacted gained amyl- 1,2- bis- [3 ', 4 '-dioxy methene] the coffee amide of 3- benzyloxy basic ring by (3b) (265mg, 0.5mmol) is placed in dry 100mL round-bottomed flask, is dissolved with suitable heavy steaming methylene chloride (DCM), and will be burnt Bottle is placed under conditions of -10 DEG C, balances 5min.Ready to balance finishes, be slowly added dropwise into reaction solution boron chloride (1.8mL, Concentration 1.8mmol) is that the DCM solution of 1M then moves to room temperature after keeping -10 DEG C of conditioned response 30min, continues to stir 2h. To end of reaction, 3mL methanol quenching reaction is slowly added dropwise under condition of ice bath, then reaction solution is moved in separatory funnel, is added Enter suitable saturated salt solution dilute reaction solution, extracted with DCM (3 × 50mL), uses saturated salt solution after merging organic phase (2 × 100mL) washing, organic phase anhydrous Na2SO4It dries, filters, vacuum revolving removes solvent, and TLC solvent condition is MeOH:CHCl3=1:3 (V:V), RfValue is 0.34.Residue is isolated and purified with RP-HPLC, the eluant, eluent item of RP-HPLC purifying Part is MeOH:H2O=33:77 (V:V), RT=25.8min obtain light green solid 195mg, yield 88.5%.1H NMR (300MHz,CDCl3) δ: 7.41 (d, J=9Hz, 1H, H-2 '), 7.36 (d, J=9Hz, 1H, H-2 "), 7.00 (m, 2H, H-4 ', 4 "), 6.90 (m, 2H, H-7 ', 7 "), 6.74 (m, 2H, H-8 ', 8 "), 6.50 (d, J=15Hz, 1H, H-1 '), 6.40 (d, J= 15Hz,H-1”),4.56(m,3H,H-2),4.33(m,1H,H-3),4.23(m,1H,H-1),1.88-2.17(m,4H,H-4, 5)；13C NMR(75MHz,CDCl3)δ:169.4,168.9,148.9(2C),146.8(2C),142.8,142.8,131.0 (2C),128.5(2C),122.4(2C),118.8(2C),118.5(2C),116.6(2C),115.3(2C),73.5,56.7, 51.9,32.0,30.9；ESI-MS(m/z):439.3[M-H]-,879.4[2M-H]-,915.4[2M+Cl]-；HRMS-ESI(m/ z):calcd for C23H25N2O7 441.1656,found:441.1648[M+H]+.All data confirm thats substance is 3- hydroxyl The optical isomer intermixture of the amyl- bis- coffee amide of 1,2- of basic ring.
The optical isomer intermixture of obtained two coffee amide of 3- hydroxycyclopent -1,2- is divided using RP-HPLC From purifying: using C18Chromatographic column；Mobile phase A is mutually the water containing isopropanol and oxalic acid, and isopropanol concentration expressed in percentage by volume is 0.6%, concentration of oxalic acid 0.5g/mL；Mobile phase B is mutually the methanol containing isopropanol and oxalic acid, isopropanol concentration expressed in percentage by volume It is 0.6%, concentration of oxalic acid 0.5g/mL；Elution program: 0-5min, 5%B phase；5-10min, 5% → 25%B phase；10- 12min, 25% → 38%B phase；12-35min, 38%B phase；Flow velocity is 0.8mL/min；
Two coffee amide (CLC-P01) of (1S, 2S, 3R) -3- hydroxycyclopent -1,2-: retention time RT=27.2min is collected Fraction, vacuum revolving remove solvent, and residue freeze-drying obtains light green solid 70.9mg.
Two coffee amide (CLC-P02) of (1S, 2R, 3R) -3- hydroxycyclopent -1,2-: retention time RT=25.4min is collected Fraction, vacuum revolving remove solvent, and residue freeze-drying obtains light green solid 41.1mg.
Two coffee amide (CLC-P03) of (1R, 2S, 3R) -3- hydroxycyclopent -1,2-: retention time RT=24.6min is collected Fraction, vacuum revolving remove solvent, and residue freeze-drying obtains light green solid 25.2mg.
Two coffee amide (CLC-P04) of (1R, 2R, 3R) -3- hydroxycyclopent -1,2-: retention time RT=23.3min is collected Fraction, vacuum revolving remove solvent, and residue freeze-drying obtains light green solid 11.1mg.
Two coffee amide (CLC-P05) of (1S, 2S, 3S) -3- hydroxycyclopent -1,2-: retention time RT=22.2min is collected Fraction, vacuum revolving remove solvent, and residue freeze-drying obtains light green solid 13.2mg.
Two coffee amide (CLC-P06) of (1S, 2R, 3S) -3- hydroxycyclopent -1,2-: retention time RT=21.4min is collected Fraction, vacuum revolving remove solvent, and residue freeze-drying obtains light green solid 14.5mg.
Two coffee amide (CLC-P07) of (1R, 2S, 3S) -3- hydroxycyclopent -1,2-: retention time RT=20.2min is collected Fraction, vacuum revolving remove solvent, and residue freeze-drying obtains light green solid 9.3mg.
Two coffee amide (CLC-P08) of (1R, 2R, 3S) -3- hydroxycyclopent -1,2-: retention time RT=19.3min is collected Fraction, vacuum revolving remove solvent, and residue freeze-drying obtains light green solid 8.7mg.
It the preparation of 2 2- hydroxycyclopent -1,3- of embodiment, two coffee amide (CLC-P09~CLC-P16) and isolates and purifies
(1) preparation of (E) -3- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) acrylic acid, according to the step in embodiment 1 (1) it carries out.
(2) preparation of the amyl- 2- benzyl oxide of 1,3- diamino basic ring
The preparation of (2a) 2- cyclopentene -1- alcohol is carried out according to (2a) in 1 step of embodiment (2).
The preparation of penta triol of (2b ') 1,2,3- ring
2- cyclopentene -1- alcohol (252.4mg, 3mmol) is weighed in dry 100mL round-bottomed flask, with appropriate acetonitrile and Mixed solution (the CH of water3CN:H2O=3:1, V:V) dissolution, and flask is placed under condition of ice bath and balances 5min, then successively delay It is slow that N-methyl morpholine oxide (421mg, 3.6mmol) is added, potassium osmate 30mg (catalytic amount), potassium carbonate (498mg, 3.6mmol), it keeps under condition of ice bath then moving to room temperature after the reaction was continued 30min, continuing to stir 12h.It is complete wait react, it will react Liquid moves in separatory funnel, and suitable saturated salt solution dilute reaction solution is added, and is extracted, is associated with DCM (3 × 50mL) Machine Xiang Houyong saturated salt solution (2 × 100mL) washing, organic phase anhydrous Na2SO4It drying, filtering, vacuum revolving removes solvent, TLC solvent condition is CHCl3: MeOH=15:1 (V:V), RfValue is 0.23.(CHCl is separated through silica gel column chromatography3: MeOH= 30:1, V:V) obtain colourless oil liquid 316.1mg, yield 89.2%.1H NMR(300MHz,CDCl3)δ:5.82(br,1H), 4.23(br,2H),4.09(m,1H),3.92(m,2H),1.50-2.20(m,4H)；13CNMR(75MHz,CDCl3)δ:79.5, 73.1,72.3,29.0,27.3。
The preparation of (2c ') 2- hydroxycyclopent -1,3- bis-mesylate
Step (2b ') obtains 1 is weighed, 2,3- ring, penta triol (283.5mg, 2.4mmol) is burnt in dry 100mL round bottom It in bottle, is dissolved with suitable heavy steaming methylene chloride, and 4- (N, N- diformazan) aminopyridine (37mg, 0.3mmol) is added, then will Flask is placed under condition of ice bath, is added acid binding agent triethylamine (1mL, 7.2mmol), and 5min is balanced.Then to slow in reaction solution It is added dropwise mesyl chloride (0.56mL, 7.2mmol), after keeping condition of ice bath reaction 30min, then moves to room temperature, continue to stir 12h. It is complete wait react, 5mL pure water quenching reaction is slowly added dropwise in condition of ice bath, then moves to reaction solution in separatory funnel, is added Suitable saturated salt solution dilute reaction solution is extracted with DCM (3 × 50mL), uses saturated salt solution (2 after merging organic phase × 100mL) washing, organic phase anhydrous Na2SO4It dries, filters, vacuum revolving removes solvent, and TLC solvent condition is EtOAc:PE=1:2 (V:V), RfValue is 0.26.Pale yellowish oil is obtained through silica gel column chromatography separation (EtOAc:PE=1:5, V:V) Liquid 534.6mg, yield 81.2%.1H NMR(300MHz,CDCl3) δ: 5.82 (br, 1H), 5.07 (q, J=6.0Hz, 1H), 4.85 (t, J=6.0Hz, 1H), 4.19 (m, 1H), 3.06 (s, 3H ,-SO2CH3),3.04(s,3H,-SO2CH3),2.31- 1.60(m,4H,H-4,5)；13C NMR(75MHz,CDCl3)δ:80.3,79.7,72.3,38.5(2C),27.3,25.8；ESI- MS(m/z):297.3[M+Na]+。
The preparation of the amyl- 2- alcohol of (2d ') 1,3- diazido ring
2- hydroxycyclopent -1,3- bis-mesylate (411.5mg, 1.5mmol) that step (2c ') obtains is weighed in dry In 50mL round-bottomed flask, dissolved with the mixed solvent (DMF:HMPA=3:1, V:V) of appropriate DMF and HMPA, and Azide is added Sodium (293mg, 4.5mmol), reacts 12h under the conditions of 70 DEG C of oil bath.It is complete wait react, 5mL is slowly added dropwise under condition of ice bath Pure water quenching reaction, then moves to reaction solution in separatory funnel, and suitable saturated salt solution dilute reaction solution is added, and uses DCM (3 × 50mL) is extracted, and is washed after merging organic phase with saturated salt solution (2 × 100mL), organic phase anhydrous Na2SO4 It dries, filters, vacuum revolving removes low boiling point solvent, and TLC solvent condition is EtOAc:PE=1:8 (V:V), RfValue is 0.42.Residue is purified with RP-HPLC, and the eluant, eluent condition of RP-HPLC purifying is MeOH:H2O=75:25 (V:V), RT= 24.3min obtains buff grease 180.1mg, yield 71.4%.1HNMR(300MHz,CDCl3)δ:4.81(br,1H), 3.97 (m, 1H), 3.83 (t, J=6.0Hz, 1H), 3.68 (m, 1H), 2.05-1.86 (m, 4H)；13C NMR(75MHz,CDCl3) δ:73.6,62.8,58.3,28.3,28.1；ESI-MS(m/z):191.2[M+Na]+,207.5[M+K]+。
The preparation of the amyl- 2- benzyl oxide of (2e ') 1,3- diazido ring
The amyl- 2- alcohol (672.6mg, 4mmol) of 1,3- diazido ring that step (2d ') obtains is weighed in dry 100mL It in round-bottomed flask, is dissolved with suitable heavy steaming tetrahydrofuran, and tetrabutylammonium bromide (161mg, 0.5mmol) is added, then will Flask is placed under conditions of low-temp reaction bathes -5 DEG C and balances 5min.Ready to balance is finished, and divides 3 times and is slowly added to sodium hydride into reaction solution (480mg, 20mmol) keeps -5 DEG C of the reaction was continued 10min.Then cylite (0.71mL, 6mmol) is measured to be slowly dropped to instead It answers in system, after keeping cryogenic conditions 30min, then moves to room temperature, continue to stir 5h.It is complete wait react, under condition of ice bath slowly The methanol quenching reaction of 5mL is added dropwise, then reaction solution is moved in separatory funnel, suitable saturated salt solution diluting reaction is added Liquid is extracted with DCM (3 × 50mL), is washed after merging organic phase with saturated salt solution (2 × 100mL), and organic phase is with anhydrous Na2SO4It dries, filters, vacuum revolving removes solvent, and TLC solvent condition is EtOAc:PE=1:8 (V:V), RfValue is 0.48. Residue is purified with RP-HPLC, and the eluant, eluent condition of RP-HPLC purifying is MeOH:H2O=75:25 (V:V), RT= 24.5min obtains buff grease 851.3mg, yield 82.4%.1H NMR(300MHz,CDCl3)δ:7.41-7.27(m, 5H,H-Ph),4.56(s,2H,-CH2- Ph), 3.97 (m, 1H), 3.83 (t, J=6.0Hz, 1H), 3.68 (m, 1H), 2.02- 1.87(m,4H)；13CNMR(75MHz,CDCl3)δ:137.6,128.8(2C),128.3,128.1(2C),89.3,81.5, 71.9,64.3,38.6,27.8,27.1；ESI-MS(m/z):281.4[M+Na]+,297.5[M+K]+。
The preparation of the amyl- 2- benzyl oxide of (2f ') 1,3- diamino basic ring
The amyl- 2- benzyl oxide (220mg, 0.85mmol) of 1,3- diazido ring that step (2e ') obtains is weighed in dry In 50mL round-bottomed flask, with the mixed solvent (MeOH:H of proper amount of methanol and water2O=5:1, V:V) dissolution, and triphenylphosphine is added (336mg, 1.275mmol) flows back under the conditions of 68 DEG C of oil bath, reacts 5h.It is complete wait react, suitable distilled water is added Then reaction solution is adjusted to faintly acid with the hydrochloric acid solution of 0.1M, then is extracted with DCM (2 × 50mL) by dilute reaction solution, abandon Organic phase is gone, water phase is retained.Water phase is adjusted to alkalescent with the sodium hydroxide solution of 0.1M, is extracted with DCM (3 × 50mL), It is washed after merging organic phase with saturated salt solution (2 × 100mL), organic phase anhydrous Na2SO4It dries, filters, vacuum revolving is removed Solvent is removed, TLC solvent condition is MeOH:CHCl3=1:5 (V:V), RfValue is 0.61.Since there are two trips in product structure From amino, stability is poor, and is not easy to separate, therefore residue is directly used in and is reacted in next step.
(3) it the preparation of two coffee amide (CLC-P09~CLC-P16) of 2- hydroxycyclopent -1,3- and isolates and purifies
(3a) weigh (E) -3- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) acrylic acid that step (1) obtains (384.3mg, 2.0mmol) in dry 50mL round-bottomed flask, dissolved with suitable heavy steaming DMF, and be respectively added slowly to EDCI (460mg, 2.4mmol) with HOBt (324mg, 2.4mmol), 30min is reacted under room temperature.Be subsequently added into DIPEA (0.42mL, 2.4mmol), and by step (2f ') it is molten with dry DMF to react the amyl- 2- benzyl oxide (about 0.8mmol) of gained 1,3- diamino basic ring Solution, is then slowly dropped in reaction system, the reaction was continued at room temperature 12h.To end of reaction, delay under condition of ice bath It is slow that 5mL pure water quenching reaction is added dropwise, then reaction solution is moved in separatory funnel, it is anti-that suitable saturated salt solution dilution is added Liquid is answered, is extracted with DCM (3 × 50mL), is washed after merging organic phase with saturated salt solution (2 × 100mL), organic phase nothing Water Na2SO4It dries, filters, vacuum revolving removes solvent, and TLC solvent condition is MeOH:CHCl3=1:5 (V:V), RfValue is 0.58.Residue is purified with RP-HPLC, and the eluant, eluent condition of RP-HPLC purifying is MeOH:H2O=60:40, RT= 26.8min obtains white solid 345.0mg, yield 78.2%.1H NMR(300MHz,CDCl3)δ:7.45-7.24(m,7H,H- ), Ph 6.98 (m, 2H), 6.86 (m, 2H), 6.74 (m, 2H), 6.52 (d, J=15Hz, 1H), 6.35 (d, J=15Hz, 1H), 6.08(s,4H),4.62-4.49(m,3H),4.07(m,1H),3.18(m,1H),2.18-1.84(m,4H)；13C NMR (75MHz,CDCl3)δ:169.5,168.98,148.8(2C),146.7(2C),142.8,142.5,139.7,130.2, 130.1,129.6(2C),129.3(2C),129.0,128.5,128.4,122.4,122.3,118.7,118.5,116.6 (2C),115.3(2C),102(2C),80.7,72.5,55.2,52.1,29.7,28.4；ESI-MS(m/z):555.6[M+H]+。 All data confirm thats substance is that the optical isomer of amyl- 1,3- bis- [3 ', 4 '-dioxy methene] the coffee amide of 2- benzyloxy basic ring is mixed Close object.
Step (3a) is reacted the light of gained amyl- 1,3- bis- [3 ', 4 '-dioxy methene] the coffee amide of 2- benzyloxy basic ring by (3b) Isomer mixture (265mg, 0.5mmol) is learned in dry 100mL round-bottomed flask, it is molten with suitable heavy steaming methylene chloride Solution, and under conditions of flask is placed in -10 DEG C, balance 5min.Ready to balance is finished, and boron chloride is slowly added dropwise into reaction solution The concentration of (1.8mL, 1.8mmol) is that the DCM solution of 1M then moves to room temperature after keeping -10 DEG C of conditioned response 30min, is continued Stir 2h.It is complete wait react, 3mL methanol quenching reaction is slowly added dropwise under condition of ice bath, reaction solution is then moved into separatory funnel In, suitable saturated salt solution dilute reaction solution is added, is extracted with DCM (3 × 50mL), is eaten after merging organic phase with saturation Salt water (2 × 100mL) washing, organic phase anhydrous Na2SO4It dries, filters, vacuum revolving removes solvent, TLC solvent condition For MeOH:CHCl3=1:3 (V:V), RfValue is 0.36.Residue is purified with RP-HPLC, the eluant, eluent condition of RP-HPLC purifying For MeOH:H2O=33:77 (V:V), RT=27.2min obtain light green solid 198.4mg, yield 90.1%.1H NMR (300MHz,CDCl3) δ: 7.42 (d, J=9Hz, 1H), 7.37 (d, J=9Hz, 1H), 7.02 (m, 2H), 6.90 (m, 2H), 6.74 (m, 2H), 6.50 (d, J=15Hz, 1H), 6.40 (d, J=15Hz, 1H), 4.56 (m, 3H), 4.33 (m, 1H), 4.23 (m,1H),2.18-1.97(m,4H)；13C NMR(75MHz,CDCl3)δ:169.5,168.98,148.8(2C),146.8(2C), 142.8,142.8,131.0(2C),128.5(2C),122.4(2C),118.8(2C),118.5(2C),116.6(2C),115.3 (2C),73.5,56.7,51.8,32.1,30.8；ESI-MS(m/z):439.4[M-H]-,879.5[2M-H]-,915.5[2M+ Cl]-；HRMS-ESI(m/z):calcd for C23H25N2O7 441.1656,found:441.1652[M+H]+.All data cards The real substance is the optical isomer intermixture of two coffee amide of 2- hydroxycyclopent -1,3-.
The optical isomer intermixture of obtained two coffee amide of 2- hydroxycyclopent -1,3- is divided using RP-HPLC From purifying: using C18Chromatographic column；Mobile phase A is mutually the water containing isopropanol and oxalic acid, and isopropanol concentration expressed in percentage by volume is 0.6%, concentration of oxalic acid 0.5g/mL；Mobile phase B is mutually the methanol containing isopropanol and oxalic acid, isopropanol concentration expressed in percentage by volume It is 0.6%, concentration of oxalic acid 0.5g/mL；Elution program: 0-5min, 5%B phase；5-10min, 5% → 25%B phase；10- 12min, 25% → 38%B phase；12-35min, 38%B phase；Flow velocity is 0.8mL/min；
Two coffee amide (CLC-P09) of (1S, 2R, 3R) -2- hydroxycyclopent -1,3-: retention time RT=28.1min is collected Fraction, vacuum revolving remove solvent, and residue freeze-drying obtains light green solid 72.5mg.
Two coffee amide (CLC-P10) of (1R, 2R, 3R) -2- hydroxycyclopent -1,3-: retention time RT=26.2min is collected Fraction, vacuum revolving remove solvent, and residue freeze-drying obtains light green solid 42.6mg.
Two coffee amide (CLC-P11) of (1S, 2R, 3S) -2- hydroxycyclopent -1,3-: retention time RT=25.5min is collected Fraction, vacuum revolving remove solvent, and residue freeze-drying obtains light green solid 25.6mg.
Two coffee amide (CLC-P12) of (1R, 2R, 3S) -2- hydroxycyclopent -1,3-: retention time RT=24.6min is collected Fraction, vacuum revolving remove solvent, and residue freeze-drying obtains light green solid 11.4mg.
Two coffee amide (CLC-P13) of (1S, 2S, 3R) -2- hydroxycyclopent -1,3-: retention time RT=23.6min is collected Fraction, vacuum revolving remove solvent, and residue freeze-drying obtains light green solid 13.2mg.
Two coffee amide (CLC-P14) of (1R, 2S, 3R) -2- hydroxycyclopent -1,3-: retention time RT=22.8min is collected Fraction, vacuum revolving remove solvent, and residue freeze-drying obtains light green solid 14.7mg.
Two coffee amide (CLC-P15) of (1S, 2S, 3S) -2- hydroxycyclopent -1,3-: retention time RT=21.4min is collected Fraction, vacuum revolving remove solvent, and residue freeze-drying obtains light green solid 9.5mg.
Two coffee amide (CLC-P16) of (1R, 2S, 3S) -2- hydroxycyclopent -1,3-: retention time RT=20.2min is collected Fraction, vacuum revolving remove solvent, and residue freeze-drying obtains light green solid 8.9mg.
It the preparation of 3 3- hydroxy cyclohexylphenyl -1,2- of embodiment, two coffee amide (CLC-H01~CLC-H08) and isolates and purifies
(1) preparation of (E) -3- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) acrylic acid, according to the step in embodiment 1 (1) it carries out.
(2) preparation of 2,3- diamino hexamethylene -1- benzyl oxide
The preparation of (2a) 2- cyclohexene -1- alcohol
2- cyclohexene -1- ketone (0.49mL, 5mmol) is measured in dry 50mL round-bottomed flask, with suitable dry first Alcohol dissolution, flask are placed in cryogenic thermostat stirring reactive bath, then weigh cerous chloride (1.48g, 6mmol) and flask is added, protect - 10 DEG C of condition stirring 0.5h are held, then divides 3 times and is slowly added to sodium borohydride (227mg, 6mmol), it is anti-under the conditions of being maintained at -10 DEG C Answer 2h.It is complete wait react, the saturated ammonium chloride solution quenching reaction of 3mL is slowly added dropwise under conditions of -10 DEG C, then by reaction solution It moves in separatory funnel, is extracted with DCM (3 × 50mL), washed after merging organic phase with saturated salt solution (2 × 100mL), Organic phase anhydrous Na2SO4Dry, filter, vacuum revolving remove solvent, TLC solvent condition be EtOAc:PE=1:5 (V: V), RfValue is 0.34.Colourless oil liquid 437.2mg, yield are obtained through silica gel column chromatography separation (EtOAc:PE=1:10, V:V) It is 89.1%.1H NMR(300MHz,CDCl3)δ:5.97(m,1H),5.82(m,1H),4.85(m,1H),2.56-1.72(m, 4H),1.70-1.52(m,2H)；13C NMR(75MHz,CDCl3)δ:135.5,133.6,77.9,33.6,31.5,20.2。
The preparation of (2b) 2- cyclohexene -1- benzyl oxide
2- cyclohexene -1- alcohol (392.6mg, 4mmol) that step (2a) obtains is weighed in dry 100mL round-bottomed flask In, it is dissolved with suitable heavy steaming tetrahydrofuran, and tetrabutylammonium bromide (161mg, 0.5mmol) is added, is then placed in flask Low-temp reaction balances 5min under conditions of bathing -5 DEG C.Ready to balance is finished, be slowly added into reaction solution points for 3 times sodium hydride (480mg, 20mmol), -5 DEG C of the reaction was continued 10min are kept.Then it measures cylite (0.71mL, 6mmol) and is slowly dropped to reaction system In, after keeping cryogenic conditions 30min, room temperature is then moved to, continues to stir 5h.It is complete wait react, 5mL is slowly added dropwise under condition of ice bath Methanol quenching reaction, then reaction solution is moved in separatory funnel, suitable saturated salt solution dilute reaction solution is added, use DCM (3 × 50mL) is extracted, and is washed after merging organic phase with saturated salt solution (2 × 100mL), organic phase anhydrous Na2SO4 It dries, filters, vacuum revolving removes solvent, and TLC solvent condition is EtOAc:PE=1:50 (V:V), RfValue is 0.42.Through silicon Plastic column chromatography separates (pure petroleum ether) and obtains colourless oil liquid 650.7mg, yield 86.4%.1H NMR(300MHz,CDCl3) δ:7.56-7.45(m,5H,H-Ph),6.18(m,1H),6.09(m,1H),4.83(m,1H),4.67(s,2H,-CH2-Ph), 2.72-1.94(m,4H),1.82-1.76(m,2H)；13C NMR(75MHz,CDCl3)δ:138.7,135.4,130.7,128.3 (2C),127.4(2C),127.2,84.2,70.2,30.9,29.7,20.3。
The preparation of (2c) 2,3- dihydroxy hexamethylene -1- benzyl oxide
2- cyclohexene -1- benzyl oxide (564.8mg, 3mmol) that step (2b) obtains is weighed in dry 100mL round-bottomed flask In, with the mixed solution (CH of appropriate acetonitrile and water3CN:H2O=3:1, V:V) dissolution, and flask is placed under condition of ice bath and is balanced Then 5min is successively slowly added to N-methyl morpholine oxide (421mg, 3.6mmol), potassium osmate 30mg (catalytic amount), carbonic acid Potassium (498mg, 3.6mmol) keeps under condition of ice bath then moving to room temperature after the reaction was continued 30min, continuing to stir 12h.Wait react Finish, reaction solution is moved in separatory funnel, suitable saturated salt solution dilute reaction solution is added, is extracted with DCM (3 × 50mL) It takes, is washed after merging organic phase with saturated salt solution (2 × 100mL), organic phase anhydrous Na2SO4It dries, filters, vacuum revolving Solvent is removed, TLC solvent condition is CHCl3: MeOH=15:1 (V:V), RfValue is 0.38.It is separated through silica gel column chromatography (CHCl3: MeOH=30:1, V:V) obtain colourless oil liquid 582.2mg, yield 87.3%.1H NMR(300MHz,CDCl3) δ:7.41-7.27(m,5H,H-Ph),5.83(br,1H),4.58(s,2H,-CH2-Ph),4.32(br,1H),4.10(m,1H), 3.94(m,2H),2.23-1.52(m,4H),1.50-1.42(m,2H)；13C NMR(75MHz,CDCl3)δ:138.5,128.6 (2C),127.8(2C),127.6,84.3,78.2,72.1,71.8,29.0,26.8,20.4。
The preparation of (2d) 3- benzyloxy hexamethylene -1,2- bis-mesylate
2,3- dihydroxy hexamethylene -1- benzyl oxide (533.5mg, 2.4mmol) that step (2c) obtains is weighed in dry 100mL In round-bottomed flask, dissolved with suitable heavy steaming methylene chloride, and 4- (N, N- diformazan) aminopyridine (37mg, 0.3mmol) is added, Then flask is placed under condition of ice bath, is added acid binding agent triethylamine (1mL, 7.2mmol), 5min is balanced, then to reaction solution In be slowly added dropwise mesyl chloride (0.56mL, 7.2mmol), keep condition of ice bath reaction 30min after, then move to room temperature, continue to stir Mix 12h.It is complete wait react, 5mL pure water quenching reaction is slowly added dropwise in condition of ice bath, reaction solution is then moved into separatory funnel In, suitable saturated salt solution dilute reaction solution is added, is extracted with DCM (3 × 50mL), is eaten after merging organic phase with saturation Salt water (2 × 100mL) washing, organic phase anhydrous Na2SO4It dries, filters, vacuum revolving removes solvent, TLC solvent condition For EtOAc:PE=1:2 (V:V), RfValue is 0.33.Light yellow oil is obtained through silica gel column chromatography separation (EtOAc:PE=1:5, V:V) Shape liquid 713.9mg, yield 78.6%.1H NMR(300MHz,CDCl3)δ:7.37-7.28(m,5H,H-Ph),5.07(q,J =6.0Hz, 1H), 4.85 (t, J=6.0Hz, 1H), 4.56 (s, 2H ,-CH2-Ph),4.19(m,1H),3.05(s,3H,- SO2CH3),3.04(s,3H,-SO2CH3),2.32-1.61(m,4H),1.52-1.43(m,2H)；13C NMR(75MHz,CDCl3) δ:137.5,128.7(2C),128.2,127.9(2C),83.4,80.3,79.7,72.3,38.5(2C),27.3,25.7, 20.4；ESI-MS(m/z):401.4[M+Na]+。
The preparation of (2e) 2,3- diazido hexamethylene -1- benzyl oxide.
3- benzyloxy hexamethylene -1,2- bis-mesylate (567.7mg, 1.5mmol) that step (2d) obtains is weighed in drying 50mL round-bottomed flask in, dissolved with the mixed solvent (DMF:HMPA=3:1, V:V) of appropriate DMF and HMPA, and nitrine is added Change sodium (293mg, 4.5mmol), reacts 12h under the conditions of 70 DEG C of oil bath.It is complete wait react, it is slowly added dropwise under condition of ice bath 5mL pure water quenching reaction, then moves to reaction solution in separatory funnel, and suitable saturated salt solution dilute reaction solution is added, It is extracted with DCM (3 × 50mL), is washed after merging organic phase with saturated salt solution (2 × 100mL), organic phase is with anhydrous Na2SO4It dries, filters, vacuum revolving removes low boiling point solvent, and TLC solvent condition is EtOAc:PE=1:5 (V:V), RfValue It is 0.35.Residue is purified with RP-HPLC, and the eluant, eluent condition of RP-HPLC purifying is MeOH:H2O=70:30 (V:V), RT= 21.2min obtaining yellow oil 411.4mg, yield 84.3%.1H NMR(300MHz,CDCl3)δ:7.38-7.26(m,5H, ), H-Ph 4.81 (t, J=6.0Hz, 1H), 4.57 (s, 2H ,-CH2-Ph),4.02(m,1H),3.88(m,1H),3.04(s, 3H,-SO2CH3),2.12-1.78(m,4H),1.52-1.43(m,2H)；13C NMR(75MHz,CDCl3)δ:137.6,128.8 (2C), 128.2,128.1 (2C), 89.3,81.5,71.9,64.3,38.8,27.8,27.2,20.5. this be 1- benzyloxy -3- Nitrine ring hex- 2- methanesulfonates.
1- benzyloxy -3- nitrine ring hex- 2- methanesulfonates (390.4mg, 1.2mmol) is weighed to burn in dry 50mL round bottom In bottle, dissolved with the mixed solvent (DMF:HMPA=3:1, V:V) of appropriate DMF and HMPA, and be added sodium azide (390mg, 6mmol), it is reacted for 24 hours under the conditions of 125 DEG C of oil bath.It is complete wait react, 5mL pure water is slowly added dropwise in condition of ice bath and is quenched instead Answer, then move to reaction solution in separatory funnel, suitable saturated salt solution dilute reaction solution is added, with DCM (3 × 50mL) into Row extraction, is washed after merging organic phase with saturated salt solution (2 × 100mL), organic phase anhydrous Na2SO4It dries, filters, vacuum Revolving removes low boiling point solvent, and TLC solvent condition is EtOAc:PE=1:8 (V:V), RfValue is 0.53.Residue RP- HPLC purifying, the eluant, eluent condition of RP-HPLC purifying are MeOH:H2O=75:25 (V:V), RT=25.1min obtain deep yellow oil Shape object 247.0mg, yield 75.6%.1H NMR(300MHz,CDCl3)δ:7.42-7.27(m,5H,H-Ph),4.58(s, 2H,-CH2- Ph), 3.97 (m, 1H), 3.85 (t, J=6.0Hz, 1H), 3.68 (m, 1H), 2.02-1.87 (m, 4H), 1.54- 1.45(m,2H)；13C NMR(75MHz,CDCl3)δ:137.6,128.6(2C),128.2,128.1(2C),89.3,81.5, 71.7,64.3,38.8,27.8,27.2,20.6；ESI-MS(m/z):295.3[M+Na]+,311.5[M+K]+, this is 2,3- bis- Azido hexamethylene -1- benzyl oxide.
The preparation of (2f) 2,3- diamino hexamethylene -1- benzyl oxide.
2,3- diazido hexamethylene -1- benzyl oxide (231.5mg, 0.85mmol) that step (2e) obtains is weighed in dry In 50mL round-bottomed flask, with the mixed solvent (MeOH:H of proper amount of methanol and water2O=5:1, V:V) dissolution, and triphenylphosphine is added (336mg, 1.275mmol) flows back under the conditions of 68 DEG C of oil bath, reacts 5h.It is complete wait react, suitable distilled water is added Then reaction solution is adjusted to faintly acid with the hydrochloric acid solution of 0.1M, then is extracted with DCM (2 × 50mL) by dilute reaction solution, abandon Organic phase is gone, water phase is retained.Water phase is adjusted to alkalescent with the sodium hydroxide solution of 0.1M, is extracted with DCM (3 × 50mL), It is washed after merging organic phase with saturated salt solution (2 × 100mL), organic phase anhydrous Na2SO4It dries, filters, vacuum revolving is removed Solvent is removed, TLC solvent condition is MeOH:CHCl3=1:5 (V:V), RfValue is 0.64.Since there are two trips in product structure From amino, stability is poor, and is not easy to separate, therefore residue is directly used in and is reacted in next step.
(3) it the preparation of two coffee amide (CLC-H01~CLC-H08) of 3- hydroxy cyclohexylphenyl -1,2- and isolates and purifies
(3a) weigh (E) -3- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) acrylic acid that step (1) obtains (384.3mg, 2.0mmol) in dry 50mL round-bottomed flask, dissolved with suitable heavy steaming DMF, and be respectively added slowly to EDCI (460mg, 2.4mmol) and HOBt (324mg, 2.4mmol), react 30min under room temperature, be subsequently added into DIPEA (0.42mL, 2.4mmol), and it is resulting 2, the 3- diamino hexamethylene -1- benzyl oxide (about 0.82mmol) of 2f step reaction is molten with dry DMF Solution, is then slowly dropped in reaction system, the reaction was continued at room temperature 12h.It is complete wait react, under condition of ice bath slowly 5mL pure water quenching reaction is added dropwise, then reaction solution is moved in separatory funnel, suitable saturated salt solution diluting reaction is added Liquid is extracted with DCM (3 × 50mL), is washed after merging organic phase with saturated salt solution (2 × 100mL), and organic phase is with anhydrous Na2SO4It dries, filters, vacuum revolving removes solvent, and TLC solvent condition is MeOH:CHCl3=1:5 (V:V), RfValue is 0.57.Residue is purified with RP-HPLC, and the eluant, eluent condition of RP-HPLC purifying is MeOH:H2O=60:40 (V:V), RT= 26.5min obtains white solid 351.6mg, yield 75.4%.1H NMR(300MHz,CDCl3)δ:8.32(br,2H),7.30- 7.25 (m, 5H, H-Ph), 6.99 (m, 2H), 6.87 (m, 2H), 6.75 (m, 2H), 6.53 (d, J=15Hz), 6.35 (d, J= 15Hz,1H),6.08(s,4H),4.63-4.48(m,3H,H-2,-CH2-Ph),4.08(m,1H),3.18(m,1H),2.19- 1.83(m,4H),1.54-1.45(m,2H)；13C NMR(75MHz,CDCl3)δ:169.5,168.98,148.7(2C),146.9 (2C),142.9,142.5,139.7,130.2,130.1,129.6(2C),129.3(2C),129.0,128.5,128.4, 122.4,122.3,118.7,118.5,116.6(2C),115.3(2C),102(2C),80.7,72.5,55.2,52.1,29.6, 28.3,20.5；ESI-MS(m/z):571.5[M+H]+.All data confirm thats substance be 3- benzyloxy hexamethylene -1,2- two [3 ', 4 '-dioxy methenes] coffee amide optical isomer intermixture.
(3b) weighs 3- benzyloxy hexamethylene -1,2- bis- [3 ', 4 '-dioxy methene] coffee amide (285.3mg, 0.5mmol) It in dry 100mL round-bottomed flask, is dissolved with suitable heavy steaming methylene chloride, and under conditions of flask is placed in -10 DEG C, put down Weigh 5min.Ready to balance is finished, and the concentration that boron chloride (1.8mL, 1.8mmol) is slowly added dropwise into reaction solution is the DCM solution of 1M, After keeping -10 DEG C of conditioned response 30min, room temperature is then moved to, continues to stir 2h.It is complete wait react, it is slowly dripped under condition of ice bath Add 3mL methanol quenching reaction, then move to reaction solution in separatory funnel, suitable saturated salt solution dilute reaction solution is added, It is extracted with DCM (3 × 50mL), is washed after merging organic phase with saturated salt solution (2 × 100mL), organic phase is with anhydrous Na2SO4It dries, filters, vacuum revolving removes solvent, and TLC solvent condition is MeOH:CHCl3=1:3 (V:V), RfValue is 0.36.Residue is purified with RP-HPLC, and the eluant, eluent condition of RP-HPLC purifying is MeOH:H2O=33:77 (V:V), RT= 27.3min obtains light green solid 204.5mg, yield 89.6%.1H NMR(300MHz,CDCl3)δ:9.47(br,4H), 8.34 (br, 2H), 7.42 (d, J=9Hz, 1H), 7.36 (d, J=9Hz, 1H), 7.02 (m, 2H), 6.91 (m, 2H), 6.75 (m, 2H), 6.50 (d, J=15Hz, 1H), 6.40 (d, J=15Hz), 4.56 (m, 1H), 4.33 (m, 1H), 4.23 (m, 1H), 2.18- 1.89(m,4H),1.55-1.46(m,2H)；13C NMR(75MHz,CDCl3)δ:169.3,168.8,148.8(2C),146.7 (2C),142.7,142.9,131.1(2C),128.4(2C),122.3(2C),118.8(2C),118.5(2C),116.6(2C), 115.3(2C),73.5,56.7,51.9,32.0,30.9,20.6；ESI-MS(m/z):453.3[M-H]-,908.1[2M-H]-, 943.4[2M+Cl]-；HRMS-ESI(m/z):calcd for C24H27N2O7 455.1740,found:455.1738[M+H]+。 All data confirm thats substance is the optical isomer intermixture of two coffee amide of 3- hydroxy cyclohexylphenyl -1,2-.
The optical isomer intermixture of obtained two coffee amide of 3- hydroxy cyclohexylphenyl -1,2- is divided using RP-HPLC From purifying: using C18Chromatographic column；Mobile phase A is mutually the water containing isopropanol and oxalic acid, and isopropanol concentration expressed in percentage by volume is 0.6%, concentration of oxalic acid 0.5g/mL；Mobile phase B is mutually the methanol containing isopropanol and oxalic acid, isopropanol concentration expressed in percentage by volume It is 0.6%, concentration of oxalic acid 0.5g/mL；Elution program: 0-5min, 5%B phase；5-10min, 5% → 25%B phase；10- 12min, 25% → 38%B phase；12-35min, 38%B phase；Flow velocity is 0.8mL/min；
Two coffee amide (CLC-H01) of (1S, 2S, 3R) -3- hydroxy cyclohexylphenyl -1,2-: retention time RT=28.3min is collected Fraction, vacuum revolving remove solvent, and residue freeze-drying obtains light green solid 73.4mg.
Two coffee amide (CLC-H02) of (1S, 2R, 3R) -3- hydroxy cyclohexylphenyl -1,2-: retention time RT=27.4min is collected Fraction, vacuum revolving remove solvent, and residue freeze-drying obtains light green solid 43.5mg.
Two coffee amide (CLC-H03) of (1R, 2S, 3R) -3- hydroxy cyclohexylphenyl -1,2-: retention time RT=27.1min is collected Fraction, vacuum revolving remove solvent, and residue freeze-drying obtains light green solid 21.6mg.
Two coffee amide (CLC-H04) of (1R, 2R, 3R) -3- hydroxy cyclohexylphenyl -1,2-: retention time RT=24.7min is collected Fraction, vacuum revolving remove solvent, and residue freeze-drying obtains light green solid 14.2mg.
Two coffee amide (CLC-H05) of (1S, 2S, 3S) -3- hydroxy cyclohexylphenyl -1,2-: retention time RT=23.2min is collected Fraction, vacuum revolving remove solvent, and residue freeze-drying obtains light green solid 15.3mg.
Two coffee amide (CLC-H06) of (1S, 2R, 3S) -3- hydroxy cyclohexylphenyl -1,2-: retention time RT=22.8min is collected Fraction, vacuum revolving remove solvent, and residue freeze-drying obtains light green solid 16.1mg.
Two coffee amide (CLC-H07) of (1R, 2S, 3S) -3- hydroxy cyclohexylphenyl -1,2-: retention time RT=21.4min is collected Fraction, vacuum revolving remove solvent, and residue freeze-drying obtains light green solid 10.7mg.
Two coffee amide (CLC-H08) of (1R, 2R, 3S) -3- hydroxy cyclohexylphenyl -1,2-: retention time RT=20.8min is collected Fraction, vacuum revolving remove solvent, and residue freeze-drying obtains light green solid 9.7mg.
It the preparation of 4 2- hydroxy cyclohexylphenyl -1,3- of embodiment, two coffee amide (CLC-H09~CLC-H16) and isolates and purifies
(1) preparation of (E) -3- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) acrylic acid, according to the step in embodiment 1 (1) it carries out.
(2) preparation of 1,3- diamino hexamethylene -2- benzyl oxide
The preparation of (2a) 2- cyclohexene -1- alcohol is carried out according to (2a) of 3 step of embodiment (2).
The preparation of (2b ') 1,2,3- phloroglucite
2- cyclohexene -1- alcohol (294.4mg, 3mmol) that step (2a) obtains is weighed in dry 100mL round-bottomed flask In, with the mixed solution (CH of appropriate acetonitrile and water3CN:H2O=3:1, V:V) dissolution, and flask is placed under condition of ice bath and is balanced Then 5min is successively slowly added to N-methyl morpholine oxide (421mg, 3.6mmol), potassium osmate 30mg (catalytic amount), carbonic acid Potassium (498mg, 3.6mmol) keeps under condition of ice bath then moving to room temperature after the reaction was continued 30min, continuing to stir 12h.Wait react Finish, reaction solution is moved in separatory funnel, suitable saturated salt solution dilute reaction solution is added, is extracted with DCM (3 × 50mL) It takes, is washed after merging organic phase with saturated salt solution (2 × 100mL), organic phase anhydrous Na2SO4It dries, filters, vacuum revolving Solvent is removed, TLC solvent condition is CHCl3: MeOH=15:1 (V:V), RfValue is 0.25.It is separated through silica gel column chromatography (CHCl3: MeOH=30:1, V:V) obtain colourless oil liquid 355.2mg, yield 89.6%.1H NMR(300MHz,CDCl3) δ:5.86(br,1H),4.35(br,2H),4.07(m,1H),3.91(m,2H),1.83-1.54(m,4H),1.52-1.43(m, 2H)；13C NMR(75MHz,CDCl3)δ:79.4,73.3,72.5,29.3(2C),20.4。
The preparation of (2c ') 2- hydroxy cyclohexylphenyl -1,3- bis-mesylate
Step (2b ') obtains 1,2,3- phloroglucites (317.2mg, 2.4mmol) are weighed to burn in dry 100mL round bottom It in bottle, is dissolved with suitable heavy steaming methylene chloride, and 4- (N, N- diformazan) aminopyridine (37mg, 0.3mmol) is added, then will Flask is placed under condition of ice bath, is added acid binding agent triethylamine (1mL, 7.2mmol), and 5min is balanced.Then to slow in reaction solution It is added dropwise mesyl chloride (0.56mL, 7.2mmol), after keeping condition of ice bath reaction 30min, then moves to room temperature, continue to stir 12h. It is complete wait react, 5mL pure water quenching reaction is slowly added dropwise in condition of ice bath, then moves to reaction solution in separatory funnel, is added Suitable saturated salt solution dilute reaction solution is extracted with DCM (3 × 50mL), uses saturated salt solution (2 after merging organic phase × 100mL) washing, organic phase anhydrous Na2SO4It dries, filters, vacuum revolving removes solvent, and TLC solvent condition is EtOAc:PE=1:2 (V:V), RfValue is 0.28.Pale yellowish oil is obtained through silica gel column chromatography separation (EtOAc:PE=1:5, V:V) Liquid 577.1mg, yield 83.4%.1H NMR(300MHz,CDCl3) δ: 5.84 (br, 1H), 5.06 (q, J=6.0Hz, 1H), 4.86 (t, J=6.0Hz, 1H), 4.21 (m, 1H), 3.07 (s, 3H ,-SO2CH3),3.05(s,3H,-SO2CH3),2.28- 1.63(m,4H),1.56-1.45(m,2H)；13C NMR(75MHz,CDCl3)δ:80.4,79.8,72.5,38.7(2C),27.2 (2C),20.1；ESI-MS(m/z):311.2[M+Na]+。
The preparation of (2d ') 1,3- diazido hexamethylene -2- alcohol
2- hydroxy cyclohexylphenyl -1,3- bis-mesylate (432.5mg, 1.5mmol) that step (2c ') obtains is weighed in dry In 50mL round-bottomed flask, dissolved with the mixed solvent (DMF:HMPA=3:1, V:V) of appropriate DMF and HMPA, and Azide is added Sodium (293mg, 4.5mmol), reacts 12h under the conditions of 70 DEG C of oil bath.It is complete wait react, 5mL is slowly added dropwise under condition of ice bath Pure water quenching reaction, then moves to reaction solution in separatory funnel, and suitable saturated salt solution dilute reaction solution is added, and uses DCM (3 × 50mL) is extracted, and is washed after merging organic phase with saturated salt solution (2 × 100mL), organic phase anhydrous Na2SO4 It dries, filters, vacuum revolving removes low boiling point solvent, TLC solvent condition EtOAc:PE=1:8 (V:V), RfValue is 0.44. Residue is purified with RP-HPLC, and the eluant, eluent condition of RP-HPLC purifying is MeOH:H2O=75:25 (V:V), RT= 25.8min obtains buff grease 200.0mg, yield 73.2%.1H NMR(300MHz,CDCl3)δ:4.83(br,1H), 3.96 (m, 1H), 3.82 (t, J=6.0Hz, 1H), 3.69 (m, 1H), 2.06-1.87 (m, 4H), 1.56-1.48 (m, 2H)；13C NMR(75MHz,CDCl3)δ:73.7,62.9,58.4,28.3,28.1,20.7；ESI-MS(m/z):205.4[M+Na]+,221.6 [M+K]+。
The preparation of (2e ') 1,3- diazido hexamethylene -2- benzyl oxide
1,3- diazido hexamethylene -2- alcohol (728.7mg, 4mmol) that step (2d ') obtains is weighed in dry 100mL It in round-bottomed flask, is dissolved with suitable heavy steaming tetrahydrofuran, and tetrabutylammonium bromide (161mg, 0.5mmol) is added, then will Flask is placed under conditions of low-temp reaction bathes -5 DEG C and balances 5min.Ready to balance is finished, and divides 3 times and is slowly added to sodium hydride into reaction solution (480mg, 20mmol) keeps -5 DEG C of the reaction was continued 10min.Then cylite (0.71mL, 6mmol) is measured to be slowly dropped to instead It answers in system, after keeping cryogenic conditions 30min, then moves to room temperature, continue to stir 5h.It is complete wait react, under condition of ice bath slowly The methanol quenching reaction of 5mL is added dropwise, then reaction solution is moved in separatory funnel, suitable saturated salt solution diluting reaction is added Liquid is extracted with DCM (3 × 50mL), is washed after merging organic phase with saturated salt solution (2 × 100mL), and organic phase is with anhydrous Na2SO4It dries, filters, vacuum revolving removes solvent, and TLC solvent condition is EtOAc:PE=1:8 (V:V), RfValue is 0.51. Residue is purified with RP-HPLC, and the eluant, eluent condition of RP-HPLC purifying is MeOH:H2O=75:25 (V:V), RT= 25.2min obtains buff grease 921.5mg, yield 84.6%.1H NMR(300MHz,CDCl3)δ:7.36-7.25(m, 5H,H-Ph),4.55(s,2H,-CH2- Ph), 3.96 (m, 1H), 3.84 (t, J=6.0Hz, 1H), 3.67 (m, 1H), 2.03- 1.88(m,4H),1.62-1.53(m,2H)；13C NMR(75MHz,CDCl3)δ:137.8,128.7(2C),128.4,128.2 (2C),89.2,81.4,71.8,64.2,38.6,27.8,20.2；ESI-MS(m/z):295.4[M+Na]+,311.5[M+K]+。
The preparation of (2f ') 1,3- diamino hexamethylene -2- benzyl oxide
1,3- diazido hexamethylene -2- benzyl oxide (231.5mg, 0.85mmol) that step (2e ') obtains is weighed in dry In 50mL round-bottomed flask, with the mixed solvent (MeOH:H of proper amount of methanol and water2O=5:1, V:V) dissolution, and triphenylphosphine is added (336mg, 1.275mmol) flows back under the conditions of 68 DEG C of oil bath, reacts 5h.It is complete wait react, suitable distilled water is added Then reaction solution is adjusted to faintly acid with the hydrochloric acid solution of 0.1M, then is extracted with DCM (2 × 50mL) by dilute reaction solution, abandon Organic phase is gone, water phase is retained.Water phase is adjusted to alkalescent with the sodium hydroxide solution of 0.1M, is extracted with DCM (3 × 50mL), It is washed after merging organic phase with saturated salt solution (2 × 100mL), organic phase anhydrous Na2SO4It dries, filters, vacuum revolving is removed Solvent is removed, TLC solvent condition is MeOH:CHCl3=1:5 (V:V), RfValue is 0.63.Since there are two trips in product structure From amino, stability is poor, and is not easy to separate, therefore residue is directly used in and is reacted in next step.
(3) it the preparation of two coffee amide (CLC-H09~CLC-H16) of 2- hydroxy cyclohexylphenyl -1,3- and isolates and purifies.
(3a) weighs (E) -3- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) acrylic acid that step (1) obtains (384.3mg, 2.0mmol) is dissolved in dry 50mL round-bottomed flask with suitable heavy steaming DMF, and is respectively added slowly to EDCI (460mg, 2.4mmol) and HOBt (324mg, 2.4mmol), reacts 30min under room temperature.It is subsequently added into DIPEA (0.42mL, 2.4mmol), and resulting 1, the 3- diamino hexamethylene -2- benzyl oxide (about 0.83mmol) of 2f ' step reaction is used into drying DMF dissolution, be then slowly dropped in reaction system, the reaction was continued at room temperature 12h.It is complete wait react, in ice bath item 5mL pure water quenching reaction is slowly added dropwise under part, then moves to reaction solution in separatory funnel, suitable saturated salt solution is added Dilute reaction solution is extracted with DCM (3 × 50mL), is washed after merging organic phase with saturated salt solution (2 × 100mL), organic Mutually use anhydrous Na2SO4It drying, filtering, vacuum revolving removes solvent, and TLC solvent condition is 1,3- diamino hexamethylene -2- benzyl oxide, RfValue is 0.61.Residue is purified with RP-HPLC, and the eluant, eluent condition of RP-HPLC purifying is MeOH:H2O=60:40, RT= 28.3min obtains white solid 382.8mg, yield 81.1%.1H NMR(300MHz,CDCl3)δ:7.43-7.23(m,7H,H- ), Ph 6.97 (m, 2H), 6.87 (m, 2H), 6.75 (m, 2H), 6.53 (d, J=15Hz, 1H), 6.34 (d, J=15Hz, 1H), 6.09(s,4H),4.63-4.51(m,3H),4.08(m,1H),3.18(m,1H),2.17-1.83(m,4H),1.61-1.48(m, 2H)；13C NMR(75MHz,CDCl3)δ:169.6,168.97,148.7(2C),146.8(2C),142.7,142.6,139.6, 130.3,130.2,129.7(2C),129.4(2C),129.1,128.5,128.4,122.4,122.3,118.7,118.5, 116.7(2C),115.4(2C),102(2C),80.6,72.7,55.3,52.2,29.7,28.4,20.5；ESI-MS(m/z): 567.5[M+H]+.All data confirm thats substance is 2- benzyloxy hexamethylene -1,3- two [3 ', 4 '-dioxy methene] coffee amide Optical isomer intermixture.
(3b) weighs step (3a) reaction gained amyl- 1,3- bis- [3 ', 4 '-dioxy methene] coffee amide of 2- benzyloxy basic ring Optical isomer intermixture (284.3mg, 0.5mmol) is in dry 100mL round-bottomed flask, with suitable heavy steaming methylene chloride Dissolution, and under conditions of flask is placed in -10 DEG C, balance 5min.Ready to balance is finished, and boron chloride is slowly added dropwise into reaction solution The concentration of (1.8mL, 1.8mmol) is that the DCM solution of 1M then moves to room temperature after keeping -10 DEG C of conditioned response 30min, is continued Stir 2h.It is complete wait react, 3mL methanol quenching reaction is slowly added dropwise under condition of ice bath, reaction solution is then moved into separatory funnel In, suitable saturated salt solution dilute reaction solution is added, is extracted with DCM (3 × 50mL), is eaten after merging organic phase with saturation Salt water (2 × 100mL) washing, organic phase anhydrous Na2SO4It dries, filters, vacuum revolving removes solvent, TLC solvent condition For MeOH:CHCl3=1:3 (V:V), RfValue is 0.38.Residue is purified with RP-HPLC, the eluant, eluent condition of RP-HPLC purifying For MeOH:H2O=33:77 (V:V), RT=28.2min obtain light green solid 205.9mg, yield 90.6%.1H NMR (300MHz,CDCl3) δ: 9.42 (br, 4H), 7.43 (d, J=9Hz, 1H), 7.38 (d, J=9Hz, 1H), 7.03 (m, 2H), 6.91 (m, 2H), 6.75 (m, 2H), 6.52 (d, J=15Hz, 1H), 6.43 (d, J=15Hz, 1H), 4.57 (m, 3H), 4.35 (m,1H),4.24(m,1H),2.17-1.96(m,4H),1.57-1.45(m,2H)；13C NMR(75MHz,CDCl3)δ:169.6, 168.97,148.6(2C),146.9(2C),142.7,142.6,131.1(2C),128.6(2C),122.5(2C),118.8 (2C),118.5(2C),116.6(2C),115.3(2C),73.5,56.7,51.8,32.1,30.8,20.7；ESI-MS(m/z): 453.4[M-H]-,907.8[2M-H]-,944.5[2M+Cl]-；HRMS-ESI(m/z):calcd forC23H25N2O7 455.1818,found:455.1815[M+H]+.All data confirm thats substance is two coffee amide of 2- hydroxy cyclohexylphenyl -1,3- Optical isomer intermixture.
The optical isomer intermixture of obtained two coffee amide of 2- hydroxy cyclohexylphenyl -1,3- is divided using RP-HPLC From purifying: using C18Chromatographic column；Mobile phase A is mutually the water containing isopropanol and oxalic acid, and isopropanol concentration expressed in percentage by volume is 0.6%, concentration of oxalic acid 0.5g/mL；Mobile phase B is mutually the methanol containing isopropanol and oxalic acid, isopropanol concentration expressed in percentage by volume It is 0.6%, concentration of oxalic acid 0.5g/mL；Elution program: 0-5min, 5%B phase；5-10min, 5% → 25%B phase；10- 12min, 25% → 38%B phase；12-35min, 38%B phase；Flow velocity is 0.8mL/min；
Two coffee amide (CLC-H09) of (1S, 2R, 3R) -2- hydroxy cyclohexylphenyl -1,3-: retention time RT=29.2min is collected Fraction, vacuum revolving remove solvent, and residue freeze-drying obtains light green solid 73.6mg.
Two coffee amide (CLC-H10) of (1R, 2R, 3R) -2- hydroxy cyclohexylphenyl -1,3-: retention time RT=28.1min is collected Fraction, vacuum revolving remove solvent, and residue freeze-drying obtains light green solid 43.4mg.
Two coffee amide (CLC-H11) of (1S, 2R, 3R) -2- hydroxy cyclohexylphenyl -1,3-: retention time RT=27.6min is collected Fraction, vacuum revolving remove solvent, and residue freeze-drying obtains light green solid 26.3mg.
Two coffee amide (CLC-H12) of (1R, 2R, 3S) -2- hydroxy cyclohexylphenyl -1,3-: retention time RT=26.1min is collected Fraction, vacuum revolving remove solvent, and residue freeze-drying obtains light green solid 12.5mg.
Two coffee amide (CLC-H13) of (1S, 2S, 3R) -2- hydroxy cyclohexylphenyl -1,3-: retention time RT=25.6min is collected Fraction, vacuum revolving remove solvent, and residue freeze-drying obtains light green solid 13.6mg.
Two coffee amide (CLC-H14) of (1R, 2S, 3R) -2- hydroxy cyclohexylphenyl -1,3-: retention time RT=24.2min is collected Fraction, vacuum revolving remove solvent, and residue freeze-drying obtains light green solid 14.3mg.
Two coffee amide (CLC-H15) of (1S, 2S, 3S) -2- hydroxy cyclohexylphenyl -1,3-: retention time RT=23.1min is collected Fraction, vacuum revolving remove solvent, and residue freeze-drying obtains light green solid 11.5mg.
Two coffee amide (CLC-H16) of (1R, 2S, 3S) -2- hydroxy cyclohexylphenyl -1,3-: retention time RT=22.7min is collected Fraction, vacuum revolving remove solvent, and residue freeze-drying obtains light green solid 10.7mg.
It the preparation of 5 3- hydroxycyclopent -1,2- of embodiment, two coffee sulfonamide (CLS-P01~CLS-P08) and isolates and purifies
(1) preparation of (E) -2- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) ethylene -1- sulfonic acid
The preparation of (1a-b) piperonal obtains target compound according to (1a) and (1b) in 1 step of embodiment (1).
The preparation of (1c ') (E) -2- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) ethylene -1- sulfonic acid
In 250ml round-bottomed flask, piperonal (12g, 79.9mmol) and methanesulfonic acid acid anhydride that step (1a-b) is obtained (20.9g, 120mmol) is dissolved with 150ml dry THF, and NaH (2.9g, 120mmol) is added portionwise, after reaction solution moved into oil 115 DEG C of bath is heated to reflux about 2 hours.Reaction process is monitored to piperonal with TLC and is completely disappeared, and shows fully reacting.Reaction solution After being cooled to room temperature, reaction solution is slowly poured into 200ml hydrochloric acid solution (2mol/L) under ice bath, there are a large amount of yellowish whites solid Body is precipitated.Obtain faint yellow solid filter cake through filtering, after faint yellow solid filter cake is washed with 400mL water dispersion, then through filtering Yellowish-white solid filter cake is obtained, and repeating above operation to filter cake pH value is neutrality.It is recrystallized with hot water, collects yellowish white It dries under solid filter cake to infrared lamp to constant weight, obtains yellowish-white solid 13.2g, yield 72.2%.1H NMR(300MHz, CDCl3) δ: 7.81 (d, J=16.0Hz, 1H), 7.31 (d, J=6.0Hz, 1H), 7.24 (s, 1H), 7.08 (d, J=16.0Hz, 1H), 6.95 (d, J=6.0Hz, 1H), 6.07 (s, 2H)；13C NMR(75MHz,CDCl3)δ:149.1,148.2,134.6, 128.3,124.6,113.5,108.3,101.6。
The preparation of the amyl- 1- benzyl oxide of (2) 2,3- diamino basic ring obtains target compound according to 1 step of embodiment (2).
(3) it the preparation of bis- coffee sulfonamide (CLS-P01~CLS-P08) of 3- hydroxycyclopent -1,2- and isolates and purifies, by real 1 step of example (3) progress is applied, wherein raw material (E) -3- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) acrylic acid is changed to (E) -2- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) ethylene -1- sulfonic acid (456.4mg, 2.0mmol).
(3a) TLC solvent condition is MeOH:CHCl3=1:5 (V:V), RfValue is 0.51.Residue is pure with RP-HPLC Change, the eluant, eluent condition of RP-HPLC purifying is MeOH:H2O=60:40 (V:V), RT=24.2min obtain white solid 357.5mg, yield 71.3%.1H NMR(300MHz,CDCl3)δ:7.41-7.21(m,7H,H-Ph,2’,2”),7.03(br, 2H), 6.98 (m, 2H), 6.86 (m, 2H), 6.76 (m, 2H), 6.53 (d, J=15Hz, 1H), 6.35 (d, J=15Hz, 1H), 6.09(s,4H),4.64-4.49(m,3H,H-2,-CH2-Ph),4.08(m,1H,H-3),3.19(m,1H,H-1),2.16- 1.83(m,4H,H-4,5)；13C NMR(75MHz,CDCl3)δ:148.8(2C),146.7(2C),142.8,142.6,139.8, 130.3,130.2,129.7(2C),129.3(2C),129.0,128.5,128.4,122.4,122.3,118.7,118.5, 116.6(2C),115.3(2C),102(2C),80.7,72.5,55.2,52.1,29.6,28.5；ESI-MS(m/z):627.6[M +H]+.All data confirm thats substance is the optics of amyl- 1,2- bis- [3 ', 4 '-dioxy methene] the coffee sulfonamide of 3- benzyloxy basic ring Isomer mixture.
Step (3a) is reacted gained amyl- 1,2- bis- [3 ', 4 '-dioxy methene] the coffee sulfonamide of 3- benzyloxy basic ring by (3b) (313.3mg, 0.5mmol) is dissolved in dry 100mL round-bottomed flask with suitable heavy steaming methylene chloride, and flask is set Under conditions of -10 DEG C, 5min is balanced.Ready to balance is finished, and boron chloride (1.8mL, 1.8mmol) is slowly added dropwise into reaction solution Concentration is that the DCM solution of 1M then moves to room temperature after keeping -10 DEG C of conditioned response 30min, continues to stir 2h.It is complete wait react, 3mL methanol quenching reaction is slowly added dropwise under condition of ice bath, then moves to reaction solution in separatory funnel, suitable saturation is added Saline solution dilute reaction solution is extracted with DCM (3 × 50mL), is washed after merging organic phase with saturated salt solution (2 × 100mL) It washs, organic phase anhydrous Na2SO4It dries, filters, vacuum revolving removes solvent, and TLC solvent condition is MeOH:CHCl3=1:3 (V:V), RfValue is 0.31.Residue is purified with RP-HPLC, and the eluant, eluent condition of RP-HPLC purifying is MeOH:H2O=33:77 (V:V), RT=24.2min obtains light green solid 225.3mg, yield 87.9%.1H NMR(300MHz,CDCl3)δ:9.41 (br, 4H), 7.41 (d, J=9Hz, 1H), 7.36 (d, J=9Hz, 1H), 7.04 (br, 2H), 7.00 (m, 2H), 6.90 (m, 2H), 6.74 (m, 2H), 6.50 (d, J=15Hz, 1H), 6.40 (d, J=15Hz, 1H), 4.57 (m, 3H), 4.33 (m, 1H), 4.23(m,1H),2.18-1.89(m,4H)；13C NMR(75MHz,CDCl3)δ:148.8(2C),146.7(2C),142.9, 142.7,131.1(2C),128.6(2C),122.4(2C),118.8(2C),118.5(2C),116.6(2C),115.3(2C), 73.5,56.7,51.9,32.0,30.9；ESI-MS(m/z):511.3[M-H]-；HRMS-ESI(m/z):calcd for C23H25N2O7 513.1001,found:513.0996[M+H]+.All data confirm thats substance is 3- hydroxycyclopent -1,2- two The optical isomer intermixture of coffee sulfonamide.
The optical isomer intermixture of obtained two coffee sulfonamide of 3- hydroxycyclopent -1,2- is carried out using RP-HPLC It isolates and purifies: using C18Chromatographic column；Mobile phase A is mutually the water containing isopropanol and oxalic acid, and isopropanol concentration expressed in percentage by volume is 0.6%, concentration of oxalic acid 0.5g/mL；Mobile phase B is mutually the methanol containing isopropanol and oxalic acid, isopropanol concentration expressed in percentage by volume It is 0.6%, concentration of oxalic acid 0.5g/mL；Elution program: 0-5min, 5%B phase；5-10min, 5% → 25%B phase；10- 12min, 25% → 38%B phase；12-35min, 38%B phase；Flow velocity is 0.8mL/min；
Two coffee sulfonamide (CLS-P01) of (1S, 2S, 3R) -3- hydroxycyclopent -1,2-: retention time RT=is collected 26.5min fraction, vacuum revolving remove solvent, and residue freeze-drying obtains light green solid 75.2mg.
Two coffee sulfonamide (CLS-P02) of (1S, 2R, 3R) -3- hydroxycyclopent -1,2-: retention time RT=is collected 25.1min fraction, vacuum revolving remove solvent, and residue freeze-drying obtains light green solid 44.8mg.
Two coffee sulfonamide (CLS-P03) of (1R, 2S, 3R) -3- hydroxycyclopent -1,2-: retention time RT=is collected 24.3min fraction, vacuum revolving remove solvent, and residue freeze-drying obtains light green solid 28.4mg.
Two coffee sulfonamide (CLS-P04) of (1R, 2R, 3R) -3- hydroxycyclopent -1,2-: retention time RT=is collected 23.1min fraction, vacuum revolving remove solvent, and residue freeze-drying obtains light green solid 12.5mg.
Two coffee sulfonamide (CLS-P05) of (1S, 2S, 3S) -3- hydroxycyclopent -1,2-: retention time RT=is collected 21.8min fraction, vacuum revolving remove solvent, and residue freeze-drying obtains light green solid 14.6mg.
Two coffee sulfonamide (CLS-P06) of (1S, 2R, 3S) -3- hydroxycyclopent -1,2-: retention time RT=is collected 21.2min fraction, vacuum revolving remove solvent, and residue freeze-drying obtains light green solid 15.8mg.
Two coffee sulfonamide (CLS-P07) of (1R, 2S, 3S) -3- hydroxycyclopent -1,2-: retention time RT=is collected 19.5min fraction, vacuum revolving remove solvent, and residue freeze-drying obtains light green solid 11.7mg.
Two coffee sulfonamide (CLS-P08) of (1R, 2R, 3S) -3- hydroxycyclopent -1,2-: retention time RT=is collected 18.4min fraction, vacuum revolving remove solvent, and residue freeze-drying obtains light green solid 10.3mg.
It the preparation of 6 2- hydroxycyclopent -1,3- of embodiment, two coffee sulfonamide (CLS-P09~CLS-P16) and isolates and purifies
(1) preparation of (E) -2- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) ethylene -1- sulfonic acid, according to 5 step of embodiment (1) target compound is obtained,.
The preparation of the amyl- 2- benzyl oxide of (2) 1,3- diamino basic ring obtains target compound according to 2 step of embodiment (2).
(3) it the preparation of bis- coffee sulfonamide (CLS-P09~CLS-P16) of 2- hydroxycyclopent -1,3- and isolates and purifies, by real 5 step of example (3) progress is applied, wherein raw material 2, the amyl- 1- benzyl oxide of 3- diamino basic ring are changed to the amyl- 2- benzyl oxide of 1,3- diamino basic ring.
(3a) TLC solvent condition is MeOH:CHCl3=1:5 (V:V), RfValue is 0.56.Residue is pure with RP-HPLC Change, the eluant, eluent condition of RP-HPLC purifying is MeOH:H2O=60:40 (V:V), RT=26.5min obtain white solid 389.0mg, yield 77.6%.1H NMR(300MHz,CDCl3)δ:7.44-7.23(m,7H,H-Ph),6.97(m,2H), 6.87 (m, 2H), 6.75 (m, 2H), 6.53 (d, J=15Hz, 1H), 6.36 (d, J=15Hz, 1H), 6.07 (s, 4H), 4.62- 4.49(m,3H),4.07(m,1H),3.18(m,1H),2.17-1.85(m,4H)；13C NMR(75MHz,CDCl3)δ:148.7 (2C),146.6(2C),142.7,142.4,139.7,130.2,130.1,129.6(2C),129.3(2C),129.0,128.5, 128.4,122.4,122.3,118.7,118.5,116.6(2C),115.3(2C),102(2C),80.7,72.5,55.2, 52.1,29.7,28.4；ESI-MS(m/z):627.6[M+H]+.All data confirm thats substance is the amyl- 1,3- of 2- benzyloxy basic ring The optical isomer intermixture of two [3 ', 4 '-dioxy methene] coffee sulfonamide.
Step (3a) is reacted gained amyl- 1,3- bis- [3 ', 4 '-dioxy methene] the coffee sulfonamide of 2- benzyloxy basic ring by (3b) (313.3mg, 0.5mmol)；TLC solvent condition is MeOH:CHCl3=1:3 (V:V), RfValue is 0.34.Residue RP- HPLC purifying, the eluant, eluent condition of RP-HPLC purifying are MeOH:H2O=33:77, RT=26.9min obtain light green solid 231.2mg, yield 90.2%.1H NMR(300MHz,CDCl3) δ: 9.36 (br, 4H), 7.43 (d, J=9Hz, 1H), 7.38 (d, J=9Hz, 1H), 7.03 (m, 2H), 6.91 (m, 2H), 6.75 (m, 2H), 6.52 (d, J=15Hz, 1H), 6.43 (d, J= 15Hz,1H),4.56(m,3H),4.33(m,1H),4.23(m,1H),2.17-1.96(m,4H)；13C NMR(75MHz,CDCl3) δ:148.9(2C),146.7(2C),142.9,142.7,131.1(2C),128.6(2C),122.5(2C),118.8(2C), 118.5(2C),116.6(2C),115.3(2C),73.5,56.7,51.8,32.1,30.8；ESI-MS(m/z):511.4[M- H]-；HRMS-ESI(m/z):calcd for C23H25N2O7 513.1001,found:513.0997[M+H]+.All data cards The real substance is the optical isomer intermixture of two coffee sulfonamide of 2- hydroxycyclopent -1,3-.
The optical isomer intermixture of obtained two coffee sulfonamide of 2- hydroxycyclopent -1,3- is carried out using RP-HPLC It isolates and purifies: using C18Chromatographic column；Mobile phase A is mutually the water containing isopropanol and oxalic acid, and isopropanol concentration expressed in percentage by volume is 0.6%, concentration of oxalic acid 0.5g/mL；Mobile phase B is mutually the methanol containing isopropanol and oxalic acid, isopropanol concentration expressed in percentage by volume It is 0.6%, concentration of oxalic acid 0.5g/mL；Elution program: 0-5min, 5%B phase；5-10min, 5% → 25%B phase；10- 12min, 25% → 38%B phase；12-35min, 38%B phase；Flow velocity is 0.8mL/min；
Two coffee sulfonamide (CLS-P09) of (1S, 2S, 3R) -2- hydroxycyclopent -1,3-: retention time RT=is collected 27.6min fraction, vacuum revolving remove solvent, and residue freeze-drying obtains light green solid 79.1mg.
Two coffee sulfonamide (CLS-P10) of (1R, 2S, 3R) -2- hydroxycyclopent -1,3-: retention time RT=is collected 26.4min fraction, vacuum revolving remove solvent, and residue freeze-drying obtains light green solid 48.3mg.
Two coffee sulfonamide (CLS-P11) of (1S, 2S, 3S) -2- hydroxycyclopent -1,3-: retention time RT=is collected 25.2min fraction, vacuum revolving remove solvent, and residue freeze-drying obtains light green solid 30.2mg.
Two coffee sulfonamide (CLS-P12) of (1R, 2S, 3S) -2- hydroxycyclopent -1,3-: retention time RT=is collected 24.3min fraction, vacuum revolving remove solvent, and residue freeze-drying obtains light green solid 17.5mg.
Two coffee sulfonamide (CLS-P13) of (1S, 2S, 3R) -2- hydroxycyclopent -1,3-: retention time RT=is collected 23.1min fraction, vacuum revolving remove solvent, and residue freeze-drying obtains light green solid 15.9mg.
Two coffee sulfonamide (CLS-P14) of (1R, 3R) -2- hydroxycyclopent -1,3-: retention time RT=22.2min is collected Fraction, vacuum revolving remove solvent, and residue freeze-drying obtains light green solid 16.6mg.
Two coffee sulfonamide (CLS-P15) of (1S, 3S) -2- hydroxycyclopent -1,3-: retention time RT=20.9min is collected Fraction, vacuum revolving remove solvent, and residue freeze-drying obtains light green solid 12.2mg.
Two coffee sulfonamide (CLS-P16) of (1R, 2r, 3S) -2- hydroxycyclopent -1,3-: retention time RT=is collected 19.7min fraction, vacuum revolving remove solvent, and residue freeze-drying obtains light green solid 11.4mg.
It the preparation of 7 3- hydroxy cyclohexylphenyl -1,2- of embodiment, two coffee sulfonamide (CLS-H01~CLS-H08) and isolates and purifies
(1) preparation of (E) -2- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) ethylene -1- sulfonic acid, according to 5 step of embodiment (1) target compound is obtained.
The preparation of (2) 2,3- diamino hexamethylene -1- benzyl oxide obtains target compound by 3 step of embodiment (2)
(3) it the preparation of bis- coffee sulfonamide (CLS-H01~CLS-H08) of 3- hydroxy cyclohexylphenyl -1,2- and isolates and purifies, by real 5 step of example (3) progress is applied, wherein raw material 2, the amyl- 1- benzyl oxide of 3- diamino basic ring are changed to 2,3- diamino hexamethylene -1- benzyl oxide.
The 2,3- diamino hexamethylene -1- benzyl oxide 0.82mmol that the step of (3a) is put into (2) obtains；TLC solvent condition is MeOH:CHCl3=1:5 (V:V), RfValue is 0.54.Residue is purified with RP-HPLC, and the eluant, eluent condition of RP-HPLC purifying is MeOH:H2O=60:40 (V:V), RT=25.8min obtain white solid 396.1mg, yield 75.4%.1H NMR(300MHz, CDCl3)δ:8.33(br,2H),7.31-7.26(m,5H,H-Ph),6.99(m,2H),6.87(m,2H),6.75(m,2H), 6.53 (d, J=15Hz), 6.35 (d, J=15Hz, 1H), 6.07 (s, 4H), 4.63-4.48 (m, 3H, H-2 ,-CH2-Ph), 4.08(m,1H),3.18(m,1H),2.18-1.84(m,4H),1.55-1.46(m,2H)；13C NMR(75MHz,CDCl3)δ: 148.6(2C),146.8(2C),142.8,142.4,139.7,130.2,130.1,129.6(2C),129.3(2C),129.0, 128.5,128.4,122.4,122.3,118.7,118.5,116.6(2C),115.3(2C),102(2C),80.7,72.5, 55.2,52.2,29.5,28.4,20.6；ESI-MS(m/z):641.6[M+H]+.All data confirm thats substance is 3- benzyloxy The optical isomer intermixture of hexamethylene -1,2- two [3 ', 4 '-dioxy methene] coffee sulfonamide.
Step (3a) is reacted two [3 ', 4 '-dioxy methene] coffee sulfonamide of gained 3- benzyloxy hexamethylene -1,2- by (3b) (320.4mg, 0.5mmol)；TLC solvent condition is MeOH:CHCl3=1:3 (V:V), RfValue is 0.33.Residue RP- HPLC purifying, the eluant, eluent condition of RP-HPLC purifying are MeOH:H2It is solid to obtain light green color by O=33:77 (V:V), RT=26.5min Body 234.0mg, yield 88.7%.1H NMR(300MHz,CDCl3)δ:9.45(br,4H),8.32(br,2H),7.41(d,J =9Hz, 1H), 7.35 (d, J=9Hz, 1H), 7.03 (m, 2H), 6.91 (m, 2H), 6.75 (m, 2H), 6.50 (d, J=15Hz, 1H), 6.40 (d, J=15Hz), 4.56 (m, 1H), 4.33 (m, 1H), 4.23 (m, 1H), 2.17-1.88 (m, 4H), 1.54- 1.47(m,2H)；13C NMR(75MHz,CDCl3)δ:148.7(2C),146.6(2C),142.5,142.8,131.1(2C), 128.4(2C),122.3(2C),118.8(2C),118.5(2C),116.6(2C),115.3(2C),73.5,56.7,51.9, 32.0,30.8,20.5；ESI-MS(m/z):526.3[M-H]-；HRMS-ESI(m/z):calcd for C24H27N2O7 527.1158,found:527.1155[M+H]+.All data confirm thats substance is two coffee sulfonamide of 3- hydroxy cyclohexylphenyl -1,2- Optical isomer intermixture.
The optical isomer intermixture of obtained two coffee sulfonamide of 3- hydroxy cyclohexylphenyl -1,2- is carried out using RP-HPLC It isolates and purifies: using C18Chromatographic column；Mobile phase A is mutually the water containing isopropanol and oxalic acid, and isopropanol concentration expressed in percentage by volume is 0.6%, concentration of oxalic acid 0.5g/mL；Mobile phase B is mutually the methanol containing isopropanol and oxalic acid, isopropanol concentration expressed in percentage by volume It is 0.6%, concentration of oxalic acid 0.5g/mL；Elution program: 0-5min, 5%B phase；5-10min, 5% → 25%B phase；10- 12min, 25% → 38%B phase；12-35min, 38%B phase；Flow velocity is 0.8mL/min；
Two coffee sulfonamide (CLS-H01) of (1S, 2S, 3R) -3- hydroxy cyclohexylphenyl -1,2-: retention time RT=is collected 27.6min fraction, vacuum revolving remove solvent, and residue freeze-drying obtains light green solid 79.2mg.
Two coffee sulfonamide (CLS-H02) of (1S, 2R, 3R) -3- hydroxy cyclohexylphenyl -1,2-: retention time RT=is collected 26.5min fraction, vacuum revolving remove solvent, and residue freeze-drying obtains light green solid 48.3mg.
Two coffee sulfonamide (CLS-H03) of (1R, 2S, 3R) -3- hydroxy cyclohexylphenyl -1,2-: retention time RT=is collected 26.2min fraction, vacuum revolving remove solvent, and residue freeze-drying obtains light green solid 25.7mg.
Two coffee sulfonamide (CLS-H04) of (1R, 2R, 3R) -3- hydroxy cyclohexylphenyl -1,2-: retention time RT=is collected 24.5min fraction, vacuum revolving remove solvent, and residue freeze-drying obtains light green solid 17.5mg.
Two coffee sulfonamide (CLS-H05) of (1S, 2S, 3S) -3- hydroxy cyclohexylphenyl -1,2-: retention time RT=is collected 22.8min fraction, vacuum revolving remove solvent, and residue freeze-drying obtains light green solid 18.4mg.
Two coffee sulfonamide (CLS-H06) of (1S, 2R, 3S) -3- hydroxy cyclohexylphenyl -1,2-: retention time RT=is collected 22.1min fraction, vacuum revolving remove solvent, and residue freeze-drying obtains light green solid 19.2mg.
Two coffee sulfonamide (CLS-H07) of (1R, 2S, 3S) -3- hydroxy cyclohexylphenyl -1,2-: retention time RT=is collected 20.7min fraction, vacuum revolving remove solvent, and residue freeze-drying obtains light green solid 13.1mg.
Two coffee sulfonamide (CLS-H08) of (1R, 2R, 3S) -3- hydroxy cyclohexylphenyl -1,2-: retention time RT=is collected 19.3min fraction, vacuum revolving remove solvent, and residue freeze-drying obtains light green solid 12.6mg.
It the preparation of 8 2- hydroxy cyclohexylphenyl -1,3- of embodiment, two coffee sulfonamide (CLS-H09~CLS-H16) and isolates and purifies
(1) preparation of (E) -2- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) ethylene -1- sulfonic acid, according to 5 step of embodiment (1) target compound is obtained.
The preparation of (2) 1,3- diamino hexamethylene -2- benzyl oxide obtains target compound according to 4 step of embodiment (2).
(3) it the preparation of bis- coffee sulfonamide (CLS-H09~CLS-H16) of 2- hydroxy cyclohexylphenyl -1,3- and isolates and purifies, by real 5 step of example (3) progress is applied, wherein raw material 2, the amyl- 1- benzyl oxide of 3- diamino basic ring are changed to 1,3- diamino hexamethylene -2- benzyl oxide.
The 1,3- diamino hexamethylene -2- benzyl oxide of the step of (3a) is put into (2) is 0.83mmol；TLC solvent condition is MeOH:CHCl3=1:5 (V:V), RfValue is 0.56.Residue is purified with RP-HPLC, and the eluant, eluent condition of RP-HPLC purifying is MeOH:H2O=60:40 (V:V), RT=26.9min obtain white solid 445.1mg, yield 83.7%.1H NMR(300MHz, CDCl3) δ: 7.43-7.23 (m, 7H, H-Ph), 6.96 (m, 2H), 6.88 (m, 2H), 6.75 (m, 2H), 6.56 (d, J=15Hz, 1H), 6.37 (d, J=15Hz, 1H), 6.07 (s, 4H), 4.65-4.53 (m, 3H), 4.08 (m, 1H), 3.17 (m, 1H), 2.17- 1.83(m,4H),1.57-1.46(m,2H)；13C NMR(75MHz,CDCl3)δ:148.5(2C),146.8(2C),142.9, 142.6,139.6,130.3,130.2,129.7(2C),129.4(2C),129.1,128.5,128.4,122.4,122.3, 118.7,118.5,116.7(2C),115.4(2C),102(2C),80.6,72.7,55.4,52.4,29.8,28.6,20.6； ESI-MS(m/z):641.5[M+H]+.All data confirm thats substance is [3 ', the 4 '-dioxy first of 2- benzyloxy hexamethylene -1,3- two Fork] coffee sulfonamide optical isomer intermixture.
Step (3a) is reacted two [3 ', 4 '-dioxy methene] coffee sulfonamide of gained 2- benzyloxy hexamethylene -1,3- by (3b) (320.4mg, 0.5mmol)；TLC solvent condition is MeOH:CHCl3=1:3 (V:V), RfValue is 0.36.Residue RP- HPLC purifying, the eluant, eluent condition of RP-HPLC purifying are MeOH:H2It is solid to obtain light green color by O=33:77 (V:V), RT=27.7min Body 236.1mg, yield 89.5%.1H NMR(300MHz,CDCl3) δ: 9.42 (br, 4H), 7.43 (d, J=9Hz, 1H), 7.38 (d, J=9Hz, 1H), 7.03 (m, 2H), 6.91 (m, 2H), 6.76 (m, 2H), 6.53 (d, J=15Hz, 1H), 6.45 (d, J=15Hz, 1H), 4.56 (m, 3H), 4.37 (m, 1H), 4.25 (m, 1H), 2.18-1.97 (m, 4H), 1.56-1.46 (m, 2H) ；13C NMR(75MHz,CDCl3)δ:148.5(2C),146.8(2C),142.8,142.5,131.2(2C),128.5(2C), 122.6(2C),118.7(2C),118.5(2C),116.6(2C),115.3(2C),73.5,56.7,51.8,32.1,30.8, 20.7；ESI-MS(m/z):526.5[M-H]-；HRMS-ESI(m/z):calcd for C23H25N2O7 527.1158,found: 527.1156[M+H]+.All data confirm thats substance is that the optical isomer of two coffee sulfonamide of 2- hydroxy cyclohexylphenyl -1,3- is mixed Close object.
The optical isomer intermixture of obtained two coffee sulfonamide of 2- hydroxy cyclohexylphenyl -1,3- is carried out using RP-HPLC It isolates and purifies: using C18Chromatographic column；Mobile phase A is mutually the water containing isopropanol and oxalic acid, and isopropanol concentration expressed in percentage by volume is 0.6%, concentration of oxalic acid 0.5g/mL；Mobile phase B is mutually the methanol containing isopropanol and oxalic acid, isopropanol concentration expressed in percentage by volume It is 0.6%, concentration of oxalic acid 0.5g/mL；Elution program: 0-5min, 5%B phase；5-10min, 5% → 25%B phase；10- 12min, 25% → 38%B phase；12-35min, 38%B phase；Flow velocity is 0.8mL/min；
Two coffee sulfonamide (CLS-H09) of (1S, 2r, 3R) -2- hydroxy cyclohexylphenyl -1,3-: retention time RT=is collected 28.6min fraction, vacuum revolving remove solvent, and residue freeze-drying obtains light green solid 81.5mg.
Two coffee sulfonamide (CLS-H10) of (1R, 3R) -2- hydroxy cyclohexylphenyl -1,3-: retention time RT=27.4min is collected Fraction, vacuum revolving remove solvent, and residue freeze-drying obtains light green solid 52.3mg.
Two coffee sulfonamide (CLS-H11) of (1S, 3S) -2- hydroxy cyclohexylphenyl -1,3-: retention time RT=26.9min is collected Fraction, vacuum revolving remove solvent, and residue freeze-drying obtains light green solid 31.2mg.
Two coffee sulfonamide (CLS-H12) of (1R, 2S, 3S) -2- hydroxy cyclohexylphenyl -1,3-: retention time RT=is collected 25.8min fraction, vacuum revolving remove solvent, and residue freeze-drying obtains light green solid 15.6mg.
Two coffee sulfonamide (CLS-H13) of (1S, 2S, 3R) -2- hydroxy cyclohexylphenyl -1,3-: retention time RT=is collected 25.2min fraction, vacuum revolving remove solvent, and residue freeze-drying obtains light green solid 14.2mg.
Two coffee sulfonamide (CLS-H14) of (1R, 3R) -2- hydroxy cyclohexylphenyl -1,3-: retention time RT=24.0min is collected Fraction, vacuum revolving remove solvent, and residue freeze-drying obtains light green solid 16.5mg.
Two coffee sulfonamide (CLS-H15) of (1S, 3S) -2- hydroxy cyclohexylphenyl -1,3-: retention time RT=22.6min is collected Fraction, vacuum revolving remove solvent, and residue freeze-drying obtains light green solid 13.2mg.
Two coffee sulfonamide (CLS-H16) of (1R, 2r, 3S) -2- hydroxy cyclohexylphenyl -1,3-: retention time RT=is collected 21.3min fraction, vacuum revolving remove solvent, and residue freeze-drying obtains light green solid 11.6mg.
The preparation of 9 3- hydroxycyclopent -1,2- of embodiment, two coffee phosphine (mono-methyl) amide (CLP-P01~CLP-P08) and It isolates and purifies
(1) preparation of (E) -2- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) ethylene -1- phosphonic acids mono-methyl
The preparation of (1a-b) piperonal, according to (1a) and (1b) method acquisition target chemical combination in 1 step of embodiment (1) Object.
The preparation of (1c ") (E) -2- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) ethylene -1- dimethyl phosphonate
In 250mL round-bottomed flask, by piperonal (12g, 79.9mmol) and methylphosphine dimethyl phthalate (14.9g, 120mmol) Dissolved with 150mL dry THF, NaH (2.9g, 120mmol) be added portionwise, after reaction solution moved to 115 DEG C of oil bath be heated to reflux About 2 hours.Reaction process is monitored to piperonal with TLC and is completely disappeared, and shows fully reacting.After reaction solution is cooled to room temperature, in Reaction solution is slowly poured into 200mL hydrochloric acid solution (2mol/L) under ice bath, ethyl acetate extracts 3 times, the anhydrous sulphur of organic layer Sour sodium is dry, vacuum rotary steam removing ethyl acetate, silica gel column chromatography separating purification (petroleum ether: ethyl acetate=10:1, V:V), Obtain light yellow viscous liquid 14.1g, yield 68.5%.1H NMR(300MHz,CDCl3) δ: 7.32 (d, J=6.0Hz, 1H), 7.23 (s, 1H), 6.95 (d, J=6.0Hz, 1H), 6.91 (d, J=17.0Hz, 1H), 5.63 (d, J=17.0Hz, 1H), 6.06 (s,2H),4.23(s,6H)；13C NMR(75MHz,CDCl3)δ:150.1,147.9,147.8,128.5,123.5,111.5, 111.2,109.2,101.2,61.9(2)；31P NMR(162MHz,CDCl3)δP:20.0。
The preparation of (1d ") (E) -2- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) ethylene -1- phosphonic acids mono-methyl
In 100mL round-bottomed flask, by (E) -2- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) ethylene -1- phosphonic acids diformazan Ester (1.28g, 5mmol) 30mL dry THF dissolves, and under nitrogen protection, 3 solution of LiBH (s-Bu) of 1.0M is added dropwise in room temperature (6.0mL, 6.0mmol), TLC tracking is until hydrolysis is complete.Then, reaction solution is slowly poured into 50mL hydrochloric acid under ice bath In solution (2mol/L), there are a large amount of yellowish-white solids to be precipitated.Obtain faint yellow solid filter cake through filtering, after by faint yellow solid Filter cake is washed with 100mL water dispersion, then obtains yellowish-white solid filter cake through filtering, and repeat above operation to filter cake pH value and be It is neutral.It is recrystallized with hot water, collects and dry under yellowish-white solid filter cake to infrared lamp to constant weight, obtain yellowish-white solid 1.13g, yield 93.2%.1H NMR(300MHz,CDCl3) δ: 7.34 (d, J=6.0Hz, 1H), 7.235 (s, 1H), 6.96 (d, J=6.0Hz, 1H), 6.92 (d, J=17.0Hz, 1H), 5.64 (d, J=17.0Hz, 1H), 6.07 (s, 2H), 4.25 (s, 3H) ；13C NMR(75MHz,CDCl3)δ:150.2,147.8,147.7,128.6,123.4,111.6,111.3,109.3,101.2, 61.8；31P NMR(162MHz,CDCl3)δP:34.8。
The preparation of the amyl- 1- benzyl oxide of (2) 2,3- diamino basic ring obtains target compound according to 1 step of embodiment (2).
(3) preparation and separation of two coffee phosphine (mono-methyl) amide (CLP-P01~CLP-P08) of 3- hydroxycyclopent -1,2- Purifying is carried out by 1 step of embodiment (3), wherein raw material (E) -3- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) acrylic acid replacement Obtained for step (1) (E) -2- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) ethylene -1- phosphonic acids mono-methyl (484.3mg, 2.0mmol)。
(3a) TLC solvent condition is MeOH:CHCl3=1:5 (V:V), RfValue is 0.52.Residue is pure with RP-HPLC Change, the eluant, eluent condition of RP-HPLC purifying is MeOH:H2O=60:40 (V:V), RT=25.4min obtain white solid 370.8mg, yield 70.8%.1H NMR(300MHz,CDCl3)δ:7.42-7.22(m,7H,H-Ph,2’,2”),7.04(br, 2H), 6.98 (m, 2H), 6.86 (m, 2H), 6.76 (m, 2H), 6.53 (d, J=15Hz, 1H), 6.35 (d, J=15Hz, 1H), 6.09(s,4H),4.64-4.49(m,3H,H-2,-CH2-Ph),4.08(m,1H),3.92(s,6H),3.19(m,1H),2.16- 1.83(m,4H)；13C NMR(75MHz,CDCl3)δ:148.7(2C),146.8(2C),142.8,142.5,139.7,130.3, 130.2,129.7(2C),129.3(2C),129.0,128.5,128.4,122.4,122.3,118.7,118.5,116.6 (2C),115.3(2C),102(2C),80.7,72.5,55.2,54.6(2),52.1,29.6,28.5；31P NMR(162MHz, CDCl3)δP:25.8；ESI-MS(m/z):655.4[M+H]+.All data confirm thats substance is the amyl- 1,2- bis- of 3- benzyloxy basic ring The optical isomer intermixture of [3 ', 4 '-dioxy methene] coffee phosphine (mono-methyl) amide.
Step (3a) is reacted gained amyl- 1,2- bis- [3 ', 4 '-dioxy methene] coffee phosphine (the single first of 3- benzyloxy basic ring by (3b) Ester) amide (327.3mg, 0.5mmol)；TLC solvent condition is VMeOH:VCHCl3=MeOH:CHCl3=1:3 (V:V), RfValue is 0.32.Residue is purified with RP-HPLC, and the eluant, eluent condition of RP-HPLC purifying is MeOH:H2O=33:77 (V:V), RT= 25.8min obtains light green solid 230.5mg, yield 85.3%.1H NMR(300MHz,CD3OD)δ:9.53(s,4H),7.55 (d, J=16.0Hz, 2H), 7.47 (s, 1H), 7.32 (d, J=16.0Hz, 2H), 7.05 (s, 2H), 7.03 (s, 2H), 6.87 (d, J=2.5Hz, 1H), 6.85 (d, J=2.5Hz, 1H), 6.63 (d, J=2.5Hz, 2H), 6.78 (dd, J=8.0,2.5Hz, 2H), 5.36 (br, 1H), 4.63 (br, 1H), 4.22 (dd, J=7.5,3.0Hz, 1H), 4.16 (m, 2H), 3.92 (s, 6H), 2.19-2.13(m,2H),1.92-1.87(m,2H)；13C NMR(75MHz,CD3OD)δ:148.8(2),146.7(2),142.6, 142.5,134.4(2C),128.5(2C),124.4(2C),118.8(2C),118.5(2C),116.6(2C),115.3(2C), 80.5,73.5,56.7,54.6(2),51.9,29.5,28.6；31P NMR(162MHz,CDCl3)δP:25.7；HRMS-ESI(m/ z):calcd for C23H25N2O7 541.1505,found:541.1502[M+H]+.All data confirm thats substance is 3- hydroxyl The optical isomer intermixture of amyl- 1,2- bis- coffee phosphine (mono-methyl) amide of basic ring.
The optical isomer intermixture of obtained 3- hydroxycyclopent -1,2- two coffee phosphine (mono-methyl) amide is utilized into RP- HPLC is isolated and purified: using C18Chromatographic column；Mobile phase A is mutually the water containing isopropanol and oxalic acid, isopropanol volume basis Concentration is 0.6%, concentration of oxalic acid 0.5g/mL；Mobile phase B is mutually the methanol containing isopropanol and oxalic acid, isopropanol volume hundred Dividing concentration is 0.6%, concentration of oxalic acid 0.5g/mL；Elution program: 0-5min, 5%B phase；5-10min, 5% → 25%B phase； 10-12min, 25% → 38%B phase；12-35min, 38%B phase；Flow velocity is 0.8mL/min；
(1S, 2S, 3R) -3- hydroxycyclopent -1,2- two coffee phosphine (mono-methyl) amide (CLP-P01): retention time is collected RT=27.1min fraction, vacuum revolving remove solvent, and residue freeze-drying obtains light green solid 78.1mg.
(1S, 2R, 3R) -3- hydroxycyclopent -1,2- two coffee phosphine (mono-methyl) amide (CLP-P02): retention time is collected RT=26.5min fraction, vacuum revolving remove solvent, and residue freeze-drying obtains light green solid 47.6mg.
(1R, 2S, 3R) -3- hydroxycyclopent -1,2- two coffee phosphine (mono-methyl) amide (CLP-P03): retention time is collected RT=25.8min fraction, vacuum revolving remove solvent, and residue freeze-drying obtains light green solid 30.8mg.
(1R, 2R, 3R) -3- hydroxycyclopent -1,2- two coffee phosphine (mono-methyl) amide (CLP-P04): retention time is collected RT=24.2min fraction, vacuum revolving remove solvent, and residue freeze-drying obtains light green solid 15.2mg.
(1S, 2S, 3S) -3- hydroxycyclopent -1,2- two coffee phosphine (mono-methyl) amide (CLP-P05): retention time is collected RT=23.5min fraction, vacuum revolving remove solvent, and residue freeze-drying obtains light green solid 17.2mg.
(1S, 2R, 3S) -3- hydroxycyclopent -1,2- two coffee phosphine (mono-methyl) amide (CLP-P06): retention time is collected RT=22.4min fraction, vacuum revolving remove solvent, and residue freeze-drying obtains light green solid 16.1mg.
(1R, 2S, 3S) -3- hydroxycyclopent -1,2- two coffee phosphine (mono-methyl) amide (CLP-P07): retention time is collected RT=21.3min fraction, vacuum revolving remove solvent, and residue freeze-drying obtains light green solid 13.2mg.
(1R, 2R, 3S) -3- hydroxycyclopent -1,2- two coffee phosphine (mono-methyl) amide (CLP-P08): retention time is collected RT=20.2min fraction, vacuum revolving remove solvent, and residue freeze-drying obtains light green solid 12.3mg.
The preparation of 10 2- hydroxycyclopent -1,3- of embodiment, two coffee phosphine (mono-methyl) amide (CLP-P09~CLP-P16) And it isolates and purifies
(1) preparation of (E) -2- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) ethylene -1- phosphonic acids mono-methyl, according to implementation Target compound is obtained in 9 step of example (1).
The preparation of the amyl- 2- benzyl oxide of (2) 1,3- diamino basic ring obtains target compound according to 2 step of embodiment (2).
(3) preparation and separation of two coffee phosphine (mono-methyl) amide (CLP-P09~CLP-P16) of 2- hydroxycyclopent -1,3- Purifying is carried out by 9 step of embodiment (3), and wherein raw material 2, the amyl- 1- benzyl oxide of 3- diamino basic ring are changed to step (2) obtains 1,3- The amyl- 2- benzyl oxide of diamino basic ring.
The amyl- 2- benzyl oxide of 1,3- diamino basic ring that step (2) input by (3a) obtains is 0.8mmol；TLC solvent condition For MeOH:CHCl3=1:5 (V:V), RfValue is 0.57.Residue is purified with RP-HPLC, the eluant, eluent condition of RP-HPLC purifying For MeOH:H2O=60:40 (V:V), RT=27.2min obtain white solid 399.0mg, yield 76.2%.1H NMR (300MHz,CDCl3)δ:7.45-7.24(m,7H,H-Ph),6.96(m,2H),6.86(m,2H),6.74(m,2H),6.54(d, J=15Hz, 1H), 6.37 (d, J=15Hz, 1H), 6.08 (s, 4H), 4.62-4.49 (m, 3H), 4.07 (m, 1H), 3.92 (s, 6H),3.18(m,1H),2.17-1.85(m,4H)；13C NMR(75MHz,CDCl3)δ:148.6(2C),146.5(2C), 142.7,142.4,139.7,130.2,130.1,129.6(2C),129.3(2C),129.0,128.5,128.4,122.4, 122.3,118.7,118.5,116.6(2C),115.3(2C),102(2C),80.7,72.5,55.2,54.5(2C),52.1, 29.6,28.5；31P NMR(162MHz,CDCl3)δP:25.8；ESI-MS(m/z):655.4[M+H]+.All data confirm thats object Matter is the optical isomer intermixture of amyl- 1,3- bis- [3 ', 4 '-dioxy methene] coffee phosphine (mono-methyl) amide of 2- benzyloxy basic ring.
Step (3a) is reacted gained amyl- 1,3- bis- [3 ', 4 '-dioxy methene] coffee phosphine (the single first of 2- benzyloxy basic ring by (3b) Ester) amide (327.3mg, 0.5mmol)；TLC solvent condition is MeOH:CHCl3=1:3 (V:V), RfValue is 0.35.Residue Purified with RP-HPLC, the eluant, eluent condition of RP-HPLC purifying is MeOH:H2O=33:77 (V:V), RT=27.4min are obtained shallowly Green solid 244.0mg, yield 90.3%.1H NMR(300MHz,CDCl3) δ: 9.37 (br, 4H), 7.45 (d, J=9Hz, 1H), 7.39 (d, J=9Hz, 1H), 7.03 (m, 2H), 6.91 (m, 2H), 6.75 (m, 2H), 6.52 (d, J=15Hz, 1H), 6.43 (d, J=15Hz, 1H), 4.56 (m, 3H), 4.33 (m, 1H), 4.23 (m, 1H), 3.94 (s, 6H), 2.17-1.96 (m, 4H)；13C NMR(75MHz,CDCl3)δ:148.8(2C),146.6(2C),142.8,142.7,131.1(2C),128.6(2C), 122.5(2C),118.8(2C),118.5(2C),116.6(2C),115.3(2C),73.5,56.7,54.6(2C),51.7, 32.2,30.7；31P NMR(162MHz,CDCl3)δP:25.9；ESI-MS(m/z):539.4[M-H]-；HRMS-ESI(m/z): calcd for C23H25N2O7 541.1505,found:541.1503[M+H]+All data confirm thats substance is 2- hydroxyl ring The optical isomer intermixture of amyl- 1,3- bis- coffee phosphine (mono-methyl) amide.
The optical isomer intermixture of obtained 2- hydroxycyclopent -1,3- two coffee phosphine (mono-methyl) amide is utilized into RP- HPLC is isolated and purified: using C18Chromatographic column；Mobile phase A is mutually the water containing isopropanol and oxalic acid, isopropanol volume basis Concentration is 0.6%, concentration of oxalic acid 0.5g/mL；Mobile phase B is mutually the methanol containing isopropanol and oxalic acid, isopropanol volume hundred Dividing concentration is 0.6%, concentration of oxalic acid 0.5g/mL；Elution program: 0-5min, 5%B phase；5-10min, 5% → 25%B phase； 10-12min, 25% → 38%B phase；12-35min, 38%B phase；Flow velocity is 0.8mL/min；
(1S, 2r, 3R) -2- hydroxycyclopent -1,3- two coffee phosphine (mono-methyl) amide (CLP-P09): retention time is collected RT=28.3min fraction, vacuum revolving remove solvent, and residue freeze-drying obtains light green solid 81.2mg.
(1R, 3R) -2- hydroxycyclopent -1,3- two coffee phosphine (mono-methyl) amide (CLP-P10): retention time RT=is collected 27.5min fraction, vacuum revolving remove solvent, and residue freeze-drying obtains light green solid 50.6mg.
(1S, 3S) -2- hydroxycyclopent -1,3- two coffee phosphine (mono-methyl) amide (CLP-P11): retention time RT=is collected 26.6min fraction, vacuum revolving remove solvent, and residue freeze-drying obtains light green solid 31.3mg.
(1R, 2S, 3S) -2- hydroxycyclopent -1,3- two coffee phosphine (mono-methyl) amide (CLP-P12): retention time is collected RT=25.9min fraction, vacuum revolving remove solvent, and residue freeze-drying obtains light green solid 19.2mg.
(1S, 2S, 3R) -2- hydroxycyclopent -1,3- two coffee phosphine (mono-methyl) amide (CLP-P13): retention time is collected RT=24.2min fraction, vacuum revolving remove solvent, and residue freeze-drying obtains light green solid 18.1mg.
(1R, 3R) -2- hydroxycyclopent -1,3- two coffee phosphine (mono-methyl) amide (CLP-P14): retention time RT=is collected 23.7min fraction, vacuum revolving remove solvent, and residue freeze-drying obtains light green solid 17.2mg.
(1S, 3S) -2- hydroxycyclopent -1,3- two coffee phosphine (mono-methyl) amide (CLP-P15): retention time RT=is collected 22.3min fraction, vacuum revolving remove solvent, and residue freeze-drying obtains light green solid 14.1mg.
(1R, 2r, 3S) -2- hydroxycyclopent -1,3- two coffee phosphine (mono-methyl) amide (CLP-P16): retention time is collected RT=20.2min fraction, vacuum revolving remove solvent, and residue freeze-drying obtains light green solid 12.3mg.
The preparation of 11 3- hydroxy cyclohexylphenyl -1,2- of embodiment, two coffee phosphine (mono-methyl) amide (CLP-H01~CLP-H08) And it isolates and purifies
(1) preparation of (E) -2- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) ethylene -1- phosphonic acids mono-methyl, according to implementation Target compound is obtained in 9 step of example (1).
The preparation of (2) 2,3- diamino hexamethylene -1- benzyl oxide obtains target compound by 3 step of embodiment (2)
(3) preparation and separation of two coffee phosphine (mono-methyl) amide (CLP-H01~CLP-H08) of 3- hydroxy cyclohexylphenyl -1,2- Purifying is carried out by 5 step of embodiment (3), and wherein raw material 2, the amyl- 1- benzyl oxide of 3- diamino basic ring are changed to 2,3- diamino hexamethylene- 1- benzyl oxide.
The 2,3- diamino hexamethylene -1- benzyl oxide 0.82mmol that step (2) input by (3a) obtains；TLC solvent condition For MeOH:CHCl3=1:5, RfValue is 0.55.Residue is purified with RP-HPLC, and the eluant, eluent condition of RP-HPLC purifying is MeOH:H2O=60:40 (V:V), RT=26.2min obtain white solid 410.1mg, yield 74.8%.1H NMR(300MHz, CDCl3)δ:8.31(br,2H),7.32-7.27(m,5H,H-Ph),6.98(m,2H),6.86(m,2H),6.76(m,2H), 6.54 (d, J=15Hz), 6.36 (d, J=15Hz, 1H), 6.08 (s, 4H), 4.63-4.48 (m, 3H, H-2 ,-CH2-Ph), 4.08(m,1H),3.93(s,6H),3.18(m,1H),2.18-1.84(m,4H),1.56-1.47(m,2H)；13C NMR (75MHz,CDCl3)δ:148.5(2C),146.7(2C),142.6,142.5,139.7,130.2,130.1,129.6(2C), 129.3(2C),129.0,128.5,128.4,122.4,122.3,118.7,118.5,116.6(2C),115.3(2C),102 (2C),80.7,72.5,55.2,54.7(2C),52.2,29.5,28.4,20.6；31P NMR(162MHz,CDCl3)δP:25.6； ESI-MS(m/z):669.5[M+H]+.All data confirm thats substance is [3 ', the 4 '-dioxy first of 3- benzyloxy hexamethylene -1,2- two Fork] coffee phosphine (mono-methyl) amide optical isomer intermixture.
Step (3a) is reacted two [3 ', 4 '-dioxy methene] coffee phosphine (single first of gained 3- benzyloxy hexamethylene -1,2- by (3b) Ester) amide (334.3mg, 0.5mmol)；TLC solvent condition is MeOH:CHCl3=1:3 (V:V), RfValue is 0.34.Residue Purified with RP-HPLC, the eluant, eluent condition of RP-HPLC purifying is MeOH:H2O=33:77 (V:V), RT=27.2min are obtained shallowly Green solid 247.3mg, yield 89.2%.1H NMR(300MHz,CDCl3)δ:9.47(br,4H),8.33(br,2H), 7.42 (d, J=9Hz, 1H), 7.36 (d, J=9Hz, 1H), 7.04 (m, 2H), 6.91 (m, 2H), 6.75 (m, 2H), 6.50 (d, J =15Hz, 1H), 6.40 (d, J=15Hz), 4.56 (m, 1H), 4.33 (m, 1H), 4.23 (m, 1H), 3.95 (s, 6H), 2.17- 1.88(m,4H),1.54-1.47(m,2H)；13C NMR(75MHz,CDCl3)δ:148.7(2C),146.6(2C),142.5, 142.8,131.1(2C),128.4(2C),122.3(2C),118.8(2C),118.5(2C),116.6(2C),115.3(2C), 73.5,56.7,54.7(2C),51.8,32.2,30.7,20.6；31P NMR(162MHz,CDCl3)δP:25.8；ESI-MS(m/ z):526.3[M-H]-；HRMS-ESI(m/z):calcd for C24H27N2O7 555.1661,found:555.1658[M+H]+。 All data confirm thats substance is the optical isomer intermixture of 3- hydroxy cyclohexylphenyl -1,2- two coffee phosphine (mono-methyl) amide.
The optical isomer intermixture of obtained 3- hydroxy cyclohexylphenyl -1,2- two coffee phosphine (mono-methyl) amide is utilized into RP- HPLC is isolated and purified: using C18Chromatographic column；Mobile phase A is mutually the water containing isopropanol and oxalic acid, isopropanol volume basis Concentration is 0.6%, concentration of oxalic acid 0.5g/mL；Mobile phase B is mutually the methanol containing isopropanol and oxalic acid, isopropanol volume hundred Dividing concentration is 0.6%, concentration of oxalic acid 0.5g/mL；Elution program: 0-5min, 5%B phase；5-10min, 5% → 25%B phase； 10-12min, 25% → 38%B phase；12-35min, 38%B phase；Flow velocity is 0.8mL/min；
(1S, 2S, 3R) -3- hydroxy cyclohexylphenyl -1,2- two coffee phosphine (mono-methyl) amide (CLP-H01): retention time is collected RT=28.3min fraction, vacuum revolving remove solvent, and residue freeze-drying obtains light green solid 80.5mg.
(1S, 2R, 3R) -3- hydroxy cyclohexylphenyl -1,2- two coffee phosphine (mono-methyl) amide (CLP-H02): retention time is collected RT=27.5min fraction, vacuum revolving remove solvent, and residue freeze-drying obtains light green solid 50.4mg.
(1R, 2S, 3R) -3- hydroxy cyclohexylphenyl -1,2- two coffee phosphine (mono-methyl) amide (CLP-H03): retention time is collected RT=26.9min fraction, vacuum revolving remove solvent, and residue freeze-drying obtains light green solid 26.6mg.
(1R, 2R, 3R) -3- hydroxy cyclohexylphenyl -1,2- two coffee phosphine (mono-methyl) amide (CLP-H04): retention time is collected RT=25.7min fraction, vacuum revolving remove solvent, and residue freeze-drying obtains light green solid 19.8mg.
(1S, 2S, 3S) -3- hydroxy cyclohexylphenyl -1,2- two coffee phosphine (mono-methyl) amide (CLP-H05): retention time is collected RT=24.1min fraction, vacuum revolving remove solvent, and residue freeze-drying obtains light green solid 18.6mg.
(1S, 2R, 3S) -3- hydroxy cyclohexylphenyl -1,2- two coffee phosphine (mono-methyl) amide (CLP-H06): retention time is collected RT=23.5min fraction, vacuum revolving remove solvent, and residue freeze-drying obtains light green solid 21.3mg.
(1R, 2S, 3S) -3- hydroxy cyclohexylphenyl -1,2- two coffee phosphine (mono-methyl) amide (CLP-H07): retention time is collected RT=22.3min fraction, vacuum revolving remove solvent, and residue freeze-drying obtains light green solid 15.6mg.
(1R, 2R, 3S) -3- hydroxy cyclohexylphenyl -1,2- two coffee phosphine (mono-methyl) amide (CLP-H08): retention time is collected RT=21.2min fraction, vacuum revolving remove solvent, and residue freeze-drying obtains light green solid 14.5mg.
The preparation of 12 2- hydroxy cyclohexylphenyl -1,3- of embodiment, two coffee phosphine (mono-methyl) amide (CLP-H09~CLP-H16) And it isolates and purifies
(1) preparation of (E) -2- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) ethylene -1- phosphonic acids mono-methyl, according to implementation Target compound is obtained in 9 step of example (1).
The preparation of (2) 1,3- diamino hexamethylene -2- benzyl oxide obtains target compound according to 4 step of embodiment (2).
(3) preparation and separation of two coffee phosphine (mono-methyl) amide (CLP-H09~CLP-H16) of 2- hydroxy cyclohexylphenyl -1,3- Purifying is carried out by 9 step of embodiment (3), and wherein raw material 2, the amyl- 1- benzyl oxide of 3- diamino basic ring are changed to step (2) obtains 1,3- Diamino hexamethylene -2- benzyl oxide.
The amyl- 2- benzyl oxide of 1,3- diamino basic ring that step input by (3a) (2) obtains is 0.83mmol；TLC solvent condition For MeOH:CHCl=1:5 (V:V), RfValue is 0.57.Residue is purified with RP-HPLC, the eluant, eluent condition of RP-HPLC purifying For MeOH:H2O=60:40 (V:V), RT=27.5min obtain white solid 466.7mg, yield 84.1%.1H NMR (300MHz,CDCl3)δ:7.45-7.25(m,7H,H-Ph),6.97(m,2H),6.89(m,2H),6.76(m,2H),6.57(d, J=15Hz, 1H), 6.37 (d, J=15Hz, 1H), 6.07 (s, 4H), 4.65-4.53 (m, 3H), 4.08 (m, 1H), 3.96 (s, 6H),3.17(m,1H),2.18-1.85(m,4H),1.58-1.47(m,2H)；13C NMR(75MHz,CDCl3)δ:148.6 (2C),146.9(2C),142.8,142.5,139.6,130.3,130.2,129.7(2C),129.4(2C),129.1,128.5, 128.4,122.4,122.3,118.7,118.5,116.7(2C),115.4(2C),102(2C),80.6,72.7,55.4,54.6 (2C),52.5,29.8,28.7,20.7；31P NMR(162MHz,CDCl3)δP:25.8；ESI-MS(m/z):669.5[M+H]+。 All data confirm thats substance is the light of 2- benzyloxy hexamethylene -1,3- two [3 ', 4 '-dioxy methene] coffee phosphine (mono-methyl) amide Learn isomer mixture.
Step (3a) is reacted two [3 ', 4 '-dioxy methene] coffee phosphine (single first of gained 2- benzyloxy hexamethylene -1,3- by (3b) Ester) amide (334.3mg, 0.5mmol)；TLC solvent condition is MeOH:CHCl3=1:3 (V:V), RfValue is 0.37.Residue Purified with RP-HPLC, the eluant, eluent condition of RP-HPLC purifying is MeOH:H2O=33:77 (V:V), RT=28.4min are obtained shallowly Green solid 246.5mg, yield 88.9%.1H NMR(300MHz,CDCl3) δ: 9.43 (br, 4H), 7.45 (d, J=9Hz, 1H), 7.39 (d, J=9Hz, 1H), 7.04 (m, 2H), 6.92 (m, 2H), 6.75 (m, 2H), 6.54 (d, J=15Hz, 1H), 6.45 (d, J=15Hz, 1H), 4.56 (m, 3H), 4.37 (m, 1H), 4.25 (m, 1H), 3.94 (s, 6H), 2.17-1.95 (m, 4H),1.54-1.43(m,2H)；13C NMR(75MHz,CDCl3)δ:148.6(2C),146.7(2C),142.8,142.5, 131.2(2C),128.5(2C),122.6(2C),118.7(2C),118.5(2C),116.6(2C),115.3(2C),73.5, 56.7,54.8(2C),51.8,32.2,30.9,20.8；31P NMR(162MHz,CDCl3)δP:25.8；ESI-MS(m/z): 553.5[M-H]-；HRMS-ESI(m/z):calcd for C23H25N2O7 555.1661,found:555.1659[M+H]+Institute Having the data confirm that substance is the optical isomer intermixture of 2- hydroxy cyclohexylphenyl -1,3- two coffee phosphine (mono-methyl) amide.
The optical isomer intermixture of obtained 2- hydroxy cyclohexylphenyl -1,3- two coffee phosphine (mono-methyl) amide is utilized into RP- HPLC is isolated and purified: using C18Chromatographic column；Mobile phase A is mutually the water containing isopropanol and oxalic acid, isopropanol volume basis Concentration is 0.6%, concentration of oxalic acid 0.5g/mL；Mobile phase B is mutually the methanol containing isopropanol and oxalic acid, isopropanol volume hundred Dividing concentration is 0.6%, concentration of oxalic acid 0.5g/mL；Elution program: 0-5min, 5%B phase；5-10min, 5% → 25%B phase； 10-12min, 25% → 38%B phase；12-35min, 38%B phase；Flow velocity is 0.8mL/min；
(1S, 2r, 3R) -2- hydroxy cyclohexylphenyl -1,3- two coffee phosphine (mono-methyl) amide (CLP-H09): retention time is collected RT=28.9min fraction, vacuum revolving remove solvent, and residue freeze-drying obtains light green solid 83.6mg.
(1R, 3R) -2- hydroxy cyclohexylphenyl -1,3- two coffee phosphine (mono-methyl) amide (CLP-H10): retention time RT=is collected 27.6min fraction, vacuum revolving remove solvent, and residue freeze-drying obtains light green solid 52.5mg.
(1S, 3S) -2- hydroxy cyclohexylphenyl -1,3- two coffee phosphine (mono-methyl) amide (CLP-H11): retention time RT=is collected 27.2min fraction, vacuum revolving remove solvent, and residue freeze-drying obtains light green solid 33.2mg.
(1R, 2S, 3S) -2- hydroxy cyclohexylphenyl -1,3- two coffee phosphine (mono-methyl) amide (CLP-H12): retention time is collected RT=26.3min fraction, vacuum revolving remove solvent, and residue freeze-drying obtains light green solid 17.3mg.
(1S, 2S, 3R) -2- hydroxy cyclohexylphenyl -1,3- two coffee phosphine (mono-methyl) amide (CLP-H13): retention time is collected RT=25.8min fraction, vacuum revolving remove solvent, and residue freeze-drying obtains light green solid 15.6mg.
(1R, 3R) -2- hydroxy cyclohexylphenyl -1,3- two coffee phosphine (mono-methyl) amide (CLP-H14): retention time RT=is collected 24.6min fraction, vacuum revolving remove solvent, and residue freeze-drying obtains light green solid 16.9mg.
(1S, 3S) -2- hydroxy cyclohexylphenyl -1,3- two coffee phosphine (mono-methyl) amide (CLP-H15): retention time RT=is collected 23.2min fraction, vacuum revolving remove solvent, and residue freeze-drying obtains light green solid 14.7mg.
(1R, 2r, 3S) -2- hydroxy cyclohexylphenyl -1,3- two coffee phosphine (mono-methyl) amide (CLP-H16): retention time is collected RT=21.7min fraction, vacuum revolving remove solvent, and residue freeze-drying obtains light green solid 12.7mg.
The preventing respiratory viruses Activity determination of 13 ring triol derivates of embodiment
Virus, host cell material: selecting Respiratory Syncytial Virus(RSV) (RSV), and host cell is laryngeal cancer cell (HEp-2). Viral RSV and cell HEp-2 is purchased from medicinal institute of viruses, Wuhan University.
Cell growth medium is the MEM culture medium containing the calf serum (FBS) that concentration is percent by volume 10%, cell dimension Holding liquid is the MEM culture medium containing percent by volume 1%FBS.
Positive control drug is Ribavirin, natural products 1 α from elephants-foot, 2 bis- amyl- 3 β-of caffeoyl ring of β-O, O- Alcohol.
Tetrazolium salts (MMT) solution is prepared: being configured to 5mg/mL solution with buffer PBS (0.1M, pH7.4).
Sample solution is prepared: ring triol derivates prepared by embodiment 1~12 and Ribavirin are maintained using cell Liquid is made into the sample solution of 200 μ g/mL and 100 μ g/mL respectively.
(1) it uses the cytotoxicity of MMT method detection compound: HEp-2 cell and mdck cell is inoculated in 96 holes respectively In plate, inoculum density is 1 × 104A/hole, after waiting cell monolayers to grow well, it is molten that addition cell maintenance medium dilutes the sample prepared Liquid is to series of concentrations (3.1~200 μ g/mL), in 37 DEG C, 5% CO2It is cultivated 3 days in incubator, the MTT that 10 μ L are prepared is added Solution continues to cultivate 4h.Sample solution is sucked out, 100 μ L dimethyl sulfoxides (DMSO) is added, 96 orifice plates is placed in micro- sky at room temperature 10min is shaken in the plate oscillator of hole, then with the OD value at microplate reader detection 570nm, calculates separately HEp-2 cell and MDCK is thin Born of the same parents' survival rate；Every group sets 4 balance holes, is repeated 3 times.Calculated result draws curve, finds out half toxic concentration (CC50), detection It the results are shown in Table 1~3.
(2) antiviral activity is measured to the inhibition level of cytopathic effect by observation sample: by HEp-2 cell and Mdck cell is cultivated respectively in 96 plate holes, wait cell monolayers grow it is good after, 100 times of halves that addition has been diluted with cell maintenance medium Infective dose (100TCID50) RSV, PIV3 and FluA H1N1 virus liquid, add with cell maintenance medium dilution prepare sample Solution is to series of concentrations (0.4~100.0 μ g/mL), in 37 DEG C, 5% CO2It is cultivated 3~4 days in incubator.Daily in inversion The degree of microscopically observation cytopathic effect (CPE), and record.Indicate no CPE；+ indicate that 0~25% cell has CPE；2+ indicates that 25~50% cell has CPE；3+ indicates that 50~70% cell has CPE；4+ indicates 75~100% cell There is CPE.Finally estimate half-inhibitory concentration (IC50).Selectivity index (SI)=CC50/IC50.Experimental result is shown in Table 1~3.
The anti respiratory syncytial virus of 1 ring triol derivates of table and positive control activity
Table 1 statistics indicate that, with positive control drug Ribavirin and the native compound from elephants-foot 1 α, 2 β-O, O- The amyl- 3 β -ol of two caffeoyl rings is compared, cytotoxicity, preventing respiratory born of the same parents' combination of syndromes cytotoxic activity and the selectivity of ring triol derivates Index more preferably than Ribavirin, wherein especially with CLC-P07, CLC-H15, CLS-P07, CLS-H15, CLP-P07 and CLP-H15 Overall merit is best.
Stability of the 14 part ring triol derivates of embodiment in fetal calf serum
Experimental material: calf serum (FBS) and culture medium DMEM are purchased from GIBCO company.
Experimentation: 1) standard working curve of test sample using high-efficient liquid phase technique is established；2) it configures final concentration of The sample solution of 20mM adds the fetal calf serum of 200 μ L sample solution and 1.8mL in 6 orifice plates, 37 DEG C incubation, 0.25h, 0.5h, 1h, 2h, 4h, 8h, 12h, 10 μ L mixing samples are taken respectively for 24 hours, 90 μ L 20% (v/v) Thyronorman's alcoholic solutions are added, Oscillation stands 30min after mixing, 10000rpm is centrifuged 5min.Supernatant HPLC is taken to analyze.With when the mapping of m- concentration, obtain to Half-life period of the sample in fetal calf serum, it the results are shown in Table 2.
Stability of the 2 ring triol derivates of table in fetal calf serum
Sample t1/2(h)
1 α, 2 bis- amyl- 3 β -ol of caffeoyl ring of β-O, O- 0.2
CLC-P07 4.8
CLC-H15 4.3
CLS-P07 5.3
CLS-H15 5.6
CLP-P07 5.2
CLP-H15 5.4
As seen from Table 4, natural products 1 α from elephants-foot, 2 β-O, O- bis- the amyl- 3 β -ol of caffeoyl ring half-life period very It is short, respectively 0.2h；And ring triol derivates CLC-P07, CLC-H15, CLS-P07, CLS-H15, CLP-P07 and CLP-H15 Half-life period be respectively 4.8h, 4.3h, 5.3h, 5.6h, 5.2h and 5.4h, have raising by a relatively large margin.
Embodiment 15 utilizes Biacore method study portion ring triol derivates and RSV pre-fusion F protein phase interaction With
Directly be coupled using amino method (K.Hiroaki, E.Tomohiro, O.Noriko, N.Hiromasa, I.Mariko, U.Haruhisa, J.Pharm.And Biomed.Analysis, 2010,54 (1), 258-263) RSV is merged Before (pre-fusion) F protein be coupled to CM-5 sensing chip, ring triol derivates (50 μM, 25 μ of various concentration gradient are set M, 12.5 μM, 6.25 μM and 3.125 μM), positive controls 3,4-O, O- dicaffeoylquinic acid methyl esters and 1 α, 2 β-O, O- bis- The amyl- 3 β -ol concentration gradient of caffeoyl ring be 100nM, 50nM, 25nM, 12.5nM, 6.25nM, 3.125nM and 1.0625nM, together When experiment start and every group of experiment between setting solvent correct to eliminate DMSO changes of contents bring curve offset.To gained reality Data are tested using the affinity and kinetic constant between Biacore analysis software acquisition point mutation albumen and DH.It the results are shown in Table 3。
The interaction of table 3 ring triol derivates and RSV pre-fusion F protein
Sample Kd(nM)
3,4-O, O- dicaffeoylquinic acid methyl esters 2.5±0.1
1 α, 2 bis- amyl- 3 β -ol of caffeoyl ring of β-O, O- 2.3±0.2
CLC-P07 1.8±0.1
CLC-H15 1.4±0.2
CLS-P07 1.6±0.3
CLS-H15 1.2±0.1
CLP-P07 1.5±0.3
CLP-H15 1.1±0.1
As seen from Table 3, ring triol derivates CLC-P07, CLC-H15, CLS-P07, CLS-H15, CLP-P07 and CLP- H15 can be in conjunction with F protein, and the affinity combined is than the natural products 3,4-O from elephants-foot, bis- caffeoyl Kui of O- Peaceful acid methyl esters and 1 α, the 2 bis- amyl- 3 β -ol of caffeoyl ring of β-O, O- are stronger.
The above embodiment is a preferred embodiment of the present invention, but embodiments of the present invention are not by above-described embodiment Limitation, other any changes, modifications, substitutions, combinations, simplifications made without departing from the spirit and principles of the present invention, It should be equivalent substitute mode, be included within the scope of the present invention.

Claims (10)

1. a kind of ring triol derivates, it is characterised in that have the structure as shown in general formula I:
In general formula I, R1、R2、R3For OH or AcNH；Wherein, R1=OH, R2=R3=AcNH or R2=OH, R1=R3=AcNH or Person R3=OH, R1=R2=AcNH；* R configuration or S configuration are indicated；
The Ac indicates coffee acyl CAc or its derivative coffee sulfonyl SAc, coffee (mono-methyl) phosphono PAc, Structure is as follows:
2. ring triol derivates according to claim 1, it is characterised in that: the ring triol derivates are compound CLC-P01~CLC-P08, CLC-P09~CLC-P16, CLC-H01~CLC-H08, CLC-H09~CLC-H16, CLS-P01~ CLS-P08, CLS-P09~CLS-P16, CLS-H01~CLS-H08, CLS-H09~CLS-H16, CLP-P01~CLP-P08, CLP-P09~CLP-P16, CLP-H01~CLP-H08, CLP-H09~CLP-H16, structure are as follows:
3. the preparation method of the described in any item ring triol derivates of claim 1~2, it is characterised in that include the following steps:
The synthesis of (1a) benzene a pair of horses going side by side [d] [1,3] dioxolen:
Using catechol as starting material, it is dissolved in n,N-Dimethylformamide, adds reagent a and sodium bicarbonate, is reacted, Obtain parallel [d] [1,3] dioxolen of benzene；
The synthesis of (1b) 3,4- dioxymethylene benzaldehyde:
Parallel [d] [1, the 3] dioxolen of benzene obtained in step (1a) is added dissolved in the isopropanol of catalyst, reagent b is added, Reaction, obtains 3,4-methylenedioxy benzaldehyde；
The synthesis of (1c) (E) -3- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) acrylic acid:
3,4-methylenedioxy benzaldehyde and reagent c that step (1b) obtains are dissolved in alkali, reacted, (E) -3- (benzene a pair of horses going side by side [d] is obtained [1,3] dioxolen -5- base) acrylic acid；
The synthesis of (1c ') (E) -2- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) ethylene -1- sulfonic acid:
3,4-methylenedioxy benzaldehyde and Loprazolam acid anhydride that step (1b) obtains are dissolved in dry tetrahydrofuran, hydrogen is added Change sodium, reaction obtains (E) -2- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) ethylene -1- sulfonic acid；
The synthesis of (1c ") (E) -2- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) vinyl phosphonic dimethyl phthalate:
3,4-methylenedioxy benzaldehyde and dimethyl methyl phosphonate that step (1b) obtains are dissolved in dry tetrahydrofuran, added Enter sodium hydride, react, obtains (E) -2- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) vinyl phosphonic dimethyl phthalate；
The synthesis of (1d ") (E) -2- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) ethylene -1- phosphonic acids mono-methyl:
(E) -2- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) vinyl phosphonic dimethyl phthalate that step (1c ") obtains is dissolved in dry Reagent d " is added in dry tetrahydrofuran, obtains (E) -2- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) ethylene -1- phosphonic acids list first Ester；
The synthesis of (2a) 2- cyclopentene -1- alcohol:
Using 2- cyclopentene-1-one as raw material, it is dissolved in methanol, cerous chloride is added, sodium borohydride is added in reaction, and reaction obtains To 2- cyclopentene -1- alcohol；
The synthesis of (2b) 2- cyclopentene -1- benzyl oxide:
2- cyclopentene -1- alcohol obtained in step (2a) is dissolved in and steams tetrahydrofuran again, tetrabutylammonium bromide is added, adds after balance Enter sodium hydride, react, cylite is added dropwise, reaction obtains 2- cyclopentene -1- benzyl oxide；
The synthesis of the amyl- 1- benzyl oxide of (2c) 2,3- dihydroxy basic ring:
2- cyclopentene -1- benzyl oxide obtained in step (2b) is dissolved in acetonitrile solution, reagent 2c is added after balance, reaction obtains The amyl- 1- benzyl oxide of 2,3- dihydroxy basic ring；
The synthesis of the amyl- 1,2- bis-mesylate of (2d) 3- benzyloxy basic ring:
The amyl- 1- benzyl oxide of 2,3- dihydroxy basic ring obtained in step (2c) is dissolved in and steams methylene chloride again, 4- (N, N- diformazan is added Base) aminopyridine, triethylamine is added, reagent 2d is added dropwise again after balance, reacts, obtains amyl- 1,2-, bis- methanesulfonic acid of 3- benzyloxy basic ring Ester；
The synthesis of the amyl- 1- benzyl oxide of (2e) 2,3- diazido ring:
The amyl- 1,2- bis-mesylate of 3- benzyloxy basic ring obtained in step (2d) is dissolved in N,N-dimethylformamide and hexamethyl The mixed solvent of phosphoric triamide, is added sodium azide, and reaction obtains the amyl- 2- methanesulfonates of 1- benzyloxy -3- nitrine ring；
The obtained amyl- 2- methanesulfonates of 1- benzyloxy -3- nitrine ring is dissolved in N,N-dimethylformamide and hexamethyl phosphinylidyne three The mixed solvent of amine, is added sodium azide, and reaction obtains the amyl- 1- benzyl oxide of 2,3- diazido ring；
The synthesis of the amyl- 1- benzyl oxide of (2f) 2,3- diamino basic ring:
The amyl- 1- benzyl oxide of 2,3- diazido ring obtained in step (2e) is dissolved in methanol solution, triphenylphosphine is added, is reacted, Obtain the residue containing the amyl- 1- benzyl oxide of 2,3- diamino basic ring；
The synthesis of penta triol of (2b ') 1,2,3- ring:
2- cyclopentene -1- the alcohol that step (2a) is obtained is according to step (2c), using identical reagent/auxiliary agent/solvent and respectively Molar ratio between substance is synthesized, and 1,2,3- ring, penta triol is obtained；
The synthesis of (2c ') 2- hydroxycyclopent -1,3- bis-mesylate:
1 that step (2b ') is obtained, 2,3- ring, penta triol according to step (2d), using identical reagent/auxiliary agent/solvent and Molar ratio between each substance is synthesized, and 2- hydroxycyclopent -1,3- bis-mesylate is obtained；
The synthesis of the amyl- 2- alcohol of (2d ') 1,3- diazido ring:
2- hydroxycyclopent -1,3- bis-mesylate that step (2c ') is obtained is according to step (2e), using identical reagent/help Molar ratio between agent/solvent and each substance is synthesized, and the amyl- 2- alcohol of 1,3- diazido ring is obtained；
The synthesis of the amyl- 2- benzyl oxide of (2e ') 1,3- diazido ring:
The amyl- 2- alcohol of 1,3- diazido ring that step (2d ') is obtained is according to step (2b), using identical reagent/auxiliary agent/molten Molar ratio between agent and each substance is synthesized, and the amyl- 2- benzyl oxide of 1,3- diazido ring is obtained；
The synthesis of the amyl- 2- benzyl oxide of (2f ') 1,3- diamino basic ring:
The amyl- 2- benzyl oxide of 1,3- diazido ring that step (2e ') is obtained according to step (2f), using identical reagent/auxiliary agent/ Molar ratio between solvent and each substance is synthesized, and the residue of the amyl- 2- benzyl oxide of 1,3- diamino basic ring is obtained；
(E) -3- obtained in step (1c) (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) acrylic acid is dissolved in and steams N again by (3a), N- Dimethylformamide, is added condensing agent and 1- hydroxy benzenes a pair of horses going side by side triazole, and n,N-diisopropylethylamine is added, by step (2f) in reaction Obtained in the amyl- 1- benzyl oxide of 2,3- diamino basic ring residue be dissolved in n,N-Dimethylformamide after be added dropwise into reaction system, Reaction, obtains the optical isomer intermixture of amyl- 1,2- bis- [3 ', 4 '-dioxy methene] the coffee amide of 3- benzyloxy basic ring；
The optical siomerism of amyl- 1,2- bis- [3 ', 4 '-dioxy methene] the coffee amide of the 3- benzyloxy basic ring that (3b) obtains step (3a) Body mixture is dissolved in and steams methylene chloride again, and deprotection agent is added dropwise after balance, and reaction obtains bis- caffeoyl of 3- hydroxycyclopent -1,2- Optical isomer intermixture CLC-P01~CLC-P08 of amine；
Reagent a described in step (1a) is formaldehyde, CH2Cl2、CH2Br2And CH2I2One of；
Catalyst described in step (1b) is one of phosphorus oxychloride, nitric acid and acetic anhydride；
Reagent b described in step (1b) is one of N,N-dimethylformamide, glyoxalic acid and methenamine；
Reagent c described in step (1c) is one of acetic anhydride and malonic acid；
Alkali described in step (1c) be respective acids sodium salt or sylvite, piperidines/pyridine, sodium hydride, lithium diisopropylamine and One of potassium tert-butoxide；
Reagent d described in step (1d ") " it is one of lithium hydroxide, lithium carbonate and tri butyl boron lithium hydride；
Reagent 2c described in step (2c) be potassium osmate/N-methyl morpholine oxide/potassium carbonate, Peracetic acid, hydrogen peroxide, At least one of metachloroperbenzoic acid；
Reagent 2d described in step (2d) is at least one of mesyl chloride and paratoluensulfonyl chloride；
Condensing agent described in step (3a) is N, N'- diisopropylcarbodiimide, 1- (3- dimethylamino-propyl) -3- ethyl carbon One of diimmonium salt hydrochlorate and ethyl chloroformate；
Deprotection agent described in step (3b) is BCl3And BBr3One of；
The preparation process of 2,3- diamino hexamethylene -1- benzyl oxides is carried out by step (2a)~(2f), and wherein starting material is by 2- ring penta Alkene -1- ketone is changed to 2- cyclohexene -1- ketone, and the molar ratio between other reagents, auxiliary agent and solvent type and each substance is identical；
The preparation process of 1,3- diamino hexamethylene -2- benzyl oxide by step (2a), (2b ')~(2f ') carry out, wherein starting material by 2- cyclopentene-1-one is changed to 2- cyclohexene -1- ketone, mole between other reagents, auxiliary agent and solvent type and each substance Than identical；
The preparation process of two coffee amide (CLC-P09~CLC-P16) of 2- hydroxycyclopent -1,3- according to step (3a) and (3b) into Row, the amyl- 1- benzyl oxide of 2,3- diamino basic ring that wherein starting material is obtained by step (2f) are changed to step (2f ') obtains 1,3- The amyl- 2- benzyl oxide of diamino basic ring, the molar ratio between other reagents, auxiliary agent and solvent type and each substance are identical；
The preparation of bis- coffee amide (CLC-H01~CLC-H08) of 3- hydroxy cyclohexylphenyl -1,2- is carried out by step (3a) and (3b), The amyl- 1- benzyl oxide of 2,3- diamino basic ring that middle starting material is obtained by step (2f) is changed to the 2,3- diamino hexamethylene -1- Benzyl oxide, the molar ratio between other reagents, auxiliary agent and solvent type and each substance are identical；
The preparation process of two coffee amide (CLC-H09~CLC-H16) of 2- hydroxy cyclohexylphenyl -1,3- according to step (3a) and (3b) into Row, the amyl- 1- benzyl oxide of 2,3- diamino basic ring that wherein starting material is obtained by step (2f) are changed to 2, the 3- diamino basic ring Hex- 1- benzyl oxide, the molar ratio between other reagents, auxiliary agent and solvent type and each substance are identical；
The preparation process of two coffee sulfonamide (CLS-P01~CLS-P08) of 3- hydroxycyclopent -1,2- is according to step (3a) and (3b) It carries out, (E) -3- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) acrylic acid replacement that wherein starting material is obtained by step (1c) (E) -2- (benzene a pair of horses going side by side [d] [1, the 3] dioxolen -5- base) ethylene -1- sulfonic acid obtained for step (1c '), other reagents, auxiliary agent and Molar ratio between solvent type and each substance is identical；
The preparation process of two coffee sulfonamide (CLS-P09~CLS-P16) of 2- hydroxycyclopent -1,3- is according to step (3a) and (3b) It carries out, (E) -3- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) acrylic acid replacement that wherein starting material is obtained by step (1c) (E) -2- (benzene a pair of horses going side by side [d] [1, the 3] dioxolen -5- base) ethylene -1- sulfonic acid obtained for step (1c '), step (2f) obtain The amyl- 1- benzyl oxide of 2,3- diamino basic rings is changed to the amyl- 2- benzyl oxide of 1,3- diamino basic ring that step (2f ') obtains, other reagents, auxiliary agent Molar ratio between solvent type and each substance is identical；
The preparation process of two coffee sulfonamide (CLS-H01~CLS-H08) of 3- hydroxy cyclohexylphenyl -1,2- is according to step (3a) and (3b) It carries out, (E) -3- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) acrylic acid replacement that wherein starting material is obtained by step (1c) (E) -2- (benzene a pair of horses going side by side [d] [1, the 3] dioxolen -5- base) ethylene -1- sulfonic acid obtained for step (1c '), step (2f) obtain The amyl- 1- benzyl oxide of 2,3- diamino basic rings is changed to 2, the 3- diamino hexamethylene -1- benzyl oxide, other reagents, auxiliary agent and solvent kind Molar ratio between class and each substance is identical；
The preparation process of two coffee sulfonamide (CLS-H09~CLS-H16) of 2- hydroxy cyclohexylphenyl -1,3- is according to step (3a) and (3b) It carries out, (E) -3- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) acrylic acid replacement that wherein starting material is obtained by step (1c) (E) -2- (benzene a pair of horses going side by side [d] [1, the 3] dioxolen -5- base) ethylene -1- sulfonic acid obtained for step (1c '), step (2f) obtain The amyl- 1- benzyl oxide of 2,3- diamino basic rings is changed to 1, the 3- diamino hexamethylene -2- benzyl oxide, other reagents, auxiliary agent and solvent kind Molar ratio between class and each substance is identical；
The preparation process of two coffee phosphine (mono-methyl) amide (CLP-P01~CLP-P08) of 3- hydroxycyclopent -1,2- is according to step (3a) and (3b) is carried out, (E) -3- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) that wherein starting material is obtained by step (1c) Acrylic acid is changed to (E) -2- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) ethylene -1- phosphonic acids list first that step (1d ") obtains Ester, the molar ratio between other reagents, auxiliary agent and solvent type and each substance are identical；
The preparation process of two coffee phosphine (mono-methyl) amide (CLP-P09~CLP-P16) of 2- hydroxycyclopent -1,3- is according to step (3a) and (3b) is carried out, (E) -3- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) that wherein starting material is obtained by step (1c) Acrylic acid is changed to (E) -2- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) ethylene -1- phosphonic acids list first that step (1d ") obtains Ester, the amyl- 1- benzyl oxide of 2,3- diamino basic ring that step (2f) obtains are changed to the amyl- 2- of 1,3- diamino basic ring that step (2f ') obtains Benzyl oxide, the molar ratio between other reagents, auxiliary agent and solvent type and each substance are identical；
The preparation process of two coffee phosphine (mono-methyl) amide (CLP-H01~CLP-H08) of 3- hydroxy cyclohexylphenyl -1,2- is according to step (3a) and (3b) is carried out, (E) -3- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) that wherein starting material is obtained by step (1c) Acrylic acid is changed to (E) -2- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) ethylene -1- phosphonic acids list first that step (1d ") obtains Ester, the amyl- 1- benzyl oxide of 2,3- diamino basic ring that step (2f) obtains are changed to 2, the 3- diamino hexamethylene -1- benzyl oxide, other Molar ratio between reagent, auxiliary agent and solvent type and each substance is identical；
The preparation process of two coffee phosphine (mono-methyl) amide (CLP-H09~CLP-H16) of 2- hydroxy cyclohexylphenyl -1,3- is according to step (3a) and (3b) is carried out, (E) -3- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) that wherein starting material is obtained by step (1c) Acrylic acid is changed to (E) -2- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) ethylene -1- phosphonic acids list first that step (1d ") obtains Ester, the amyl- 1- benzyl oxide of 2,3- diamino basic ring that step (2f) obtains are changed to 1, the 3- diamino hexamethylene -2- benzyl oxide, other Molar ratio between reagent, auxiliary agent and solvent type and each substance is identical.
4. the preparation method of ring triol derivates according to claim 3, it is characterised in that:
Reagent a described in step (1a) is CH2I2；
Catalyst described in step (1b) is acetic anhydride；
Reagent b described in step (1b) is methenamine；
Reagent c described in step (1c) is malonic acid；
Alkali described in step (1c) is piperidines/pyridine；
Reagent d described in step (1d ") " it is tri butyl boron lithium hydride；
Condensing agent described in step (3a) is 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride；
Deprotecting regent described in step (3b) is BCl3；
It further include by described eight kinds of optical isomers of CLC-P01~CLC-P08 in step (3b) using column chromatography, efficient liquid phase One of method and recrystallization method or at least two the step of isolating and purifying.
5. the preparation method of ring triol derivates according to claim 3, it is characterised in that:
The temperature of reaction described in step (1a) is 70~100 DEG C；
The time of reaction described in step (1a) is 5~20h；
A pair of horses going side by side [d] [1, the 3] dioxolen of benzene described in step (1b) is to be added dropwise to the isopropyl dissolved with catalyst under the conditions of 55 DEG C In alcohol, drip within 0.5 hour；
The temperature of reaction described in step (1b) is 80~120 DEG C；
The time of reaction described in step (1b) is 0.5~3h；
Reaction described in step (1c), (1c ') and (1c ") is to be heated to reflux 4~1h at 90~130 DEG C of oil bath；
Addition reagent d described in step (1d ") " it is to be added dropwise under nitrogen protection；
In step (2a), the reaction after the cerous chloride is added reacts 0.2~2h under the conditions of being -20~0 DEG C；
In step (2a), the reaction after the sodium borohydride is added reacts 1~5h under the conditions of being -20~0 DEG C；
Cerous chloride described in step (2a) is added in three times；
In step (2b), the reaction after the sodium hydride is added reacts 5~30min under the conditions of being -15~0 DEG C；
In step (2b), the reaction after the cylite is added dropwise be prior to -15~0 DEG C under the conditions of react 20~50min, then move To 3~6h of reaction is stirred at room temperature；
Sodium hydride described in step (2b) is added in three times；
Reaction described in step (2c) is 20~50min to be reacted under condition of ice bath, then 10~20h of reaction is stirred at room temperature；
Reaction described in step (2d) is 20~50min to be reacted under condition of ice bath, then 5~20h of reaction is stirred at room temperature；
Addition triethylamine described in step (2d) is that triethylamine is added under condition of ice bath；
In step (2e), first set reaction is 5~20h of reaction under the conditions of 50~100 DEG C of oil baths；
In step (2e), the second secondary response is 10~30h of reaction under the conditions of 100~150 DEG C of oil baths；
Reaction described in step (2f) is 3~10h of back flow reaction under the conditions of 50~80 DEG C of oil baths；
In step (3a), the time of the reaction after the condensing agent and 1- hydroxy benzenes a pair of horses going side by side triazole is added is 20min~50min；
In step (3a), the residue of the amyl- 1- benzyl oxide of 2,3- diamino basic ring is added dropwise after being dissolved in n,N-Dimethylformamide Into in reaction system, the time reacted later is 5~20h；
Reaction in step (3b) reacts 15~45min under the conditions of being 0~-20 DEG C, then moves to and 1~5h of reaction is stirred at room temperature；
The dosage of reagent a described in step (1a) is that 1.0~1.5:1.0 matches by the molar ratio of itself and the catechol Than；
The dosage of reagent b described in step (1b) is 400 by the molar ratio of itself and parallel [d] [1,3] dioxolen of the benzene ~700:1.0 proportion；
The dosage of reagent c described in step (1c) is 1.0 by the molar ratio of itself and the 3,4- dioxymethylene benzaldehyde ~2.0:1.0 proportion；
The dosage of 3,4- dioxymethylene benzaldehyde described in step (1c '), Loprazolam acid anhydride and sodium hydride is according to molar ratio The proportion of 1.0:1.0~2.0:1.5~3.0 calculates；
The dosage of 3,4- dioxymethylene benzaldehyde, dimethyl methyl phosphonate and sodium hydride described in step (1c ") is according to rubbing You match than 1.0:1.0~2.0:1.5~3.0 and calculate；
The dosage of cerous chloride, sodium borohydride and 2- cyclopentene-1-one described in step (2a) according to 1~2:1 of molar ratio~ 2:1 proportion calculates；
Tetrabutylammonium bromide described in step (2b), sodium hydride, cylite and 2- cyclopentene -1- alcohol molar ratio be 1:30~ 50:8~15:5~15；
Acetonitrile solution described in step (2c) is that 3:1 matches to obtain by volume for acetonitrile and water；
The reagent 2c be potassium osmate/N-methyl morpholine oxide/potassium carbonate when, N-methyl morpholine oxide, potassium carbonate and The dosage of 2- cyclopentene -1- benzyl oxide is calculated according to 0.8~1.5:0.8 of molar ratio~1.5:1 proportion；
The dosage of reagent 2d described in step (2d) is 1 by the molar ratio of itself and the amyl- 1- benzyl oxide of 2,3- dihydroxy basic ring ~5:1 proportion calculates；
N,N-dimethylformamide described in step (2e) and the mixed solvent of hexamethylphosphoramide are by by N, N- bis- Methylformamide and hexamethylphosphoramide match to obtain according to volume ratio 3:1；
In step (2e), the dosage for the sodium azide being added for the first time presses itself and amyl- 1,2-, bis- methylsulphur of 3- benzyloxy basic ring The molar ratio of acid esters is that 1~5:1 proportion calculates；
In step (2e), the dosage of second of sodium azide being added presses itself and the amyl- 2- first of 1- benzyloxy -3- nitrine ring The molar ratio of sulphonic acid ester is that 2~8:1 proportion calculates；
Methanol solution described in step (2f) is that first alcohol and water matches to obtain according to volume ratio 5:1；
The dosage of triphenylphosphine described in step (2f) presses the molar ratio of itself and the amyl- 1- benzyl oxide of 2,3- diazido ring It matches and calculates for 0.5~2:1；
The dosage of condensing agent described in step (3a) is by itself and described (the E) -3- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) The molar ratio of acrylic acid is that 0.5~2:1 proportion calculates；
The dosage of deprotection agent described in step (3b) presses itself and amyl- bis- [3 ', the 4 '-dioxies of 1,2- of 3- benzyloxy basic ring Methene] coffee amide optical isomer intermixture molar ratio be 1~5:1 proportion calculate.
6. the preparation method of ring triol derivates according to claim 5, it is characterised in that:
The temperature of reaction described in step (1a) is 80 DEG C；
The time of reaction described in step (1a) is 12h；
The temperature of reaction described in step (1b) is 110 DEG C；
The time of reaction described in step (1b) is 1h；
Being heated to reflux described in step (1c), (1c ') and (1c ") is to be heated to reflux 2h at 115 DEG C of oil bath；
In step (2a), the reaction after the cerous chloride is added reacts 0.5h under the conditions of being -10 DEG C；
In step (2a), the reaction after the sodium borohydride is added reacts 2h under the conditions of being -10 DEG C；
In step (2b), the reaction after the sodium hydride is added reacts 10min under the conditions of being -5 DEG C；
In step (2b), the reaction after the cylite is added dropwise be prior to -5 DEG C under the conditions of react 30min, then move to room temperature and stir Mix reaction 5h；
Reaction described in step (2c) is to react 30min under condition of ice bath, then reaction 12h is stirred at room temperature；
Reaction described in step (2d) is that reaction 12h is stirred at room temperature in reaction 30min again under condition of ice bath；
In step (2e), first set reaction be 70 DEG C of oil baths under the conditions of react 12h；
In step (2e), the second secondary response be 125 DEG C of oil baths under the conditions of react for 24 hours；
Back flow reaction described in step (2f) is back flow reaction 5h under the conditions of 68 DEG C of oil baths；
In step (3a), the time of the reaction after the condensing agent and 1- hydroxy benzenes a pair of horses going side by side triazole is added is 30min；
In step (3a), the residue of the amyl- 1- benzyl oxide of 2,3- diamino basic ring is added dropwise after being dissolved in n,N-Dimethylformamide Into in reaction system, the time reacted later is 12h；
Reaction in step (3b) reacts 30min under the conditions of being -10 DEG C, then moves to and reaction 2h is stirred at room temperature；
The dosage of reagent a described in step (1a) is 1.2:1.0 proportion by the molar ratio of itself and the catechol；
The dosage of reagent b described in step (1b) is 660 by the molar ratio of itself and parallel [d] [1,3] dioxolen of the benzene: 1.0 proportion；
The dosage of reagent c described in step (1c) is 2:1 by the molar ratio of itself and the 3,4- dioxymethylene benzaldehyde Proportion；
The dosage of 3,4- dioxymethylene benzaldehyde described in step (1c '), Loprazolam acid anhydride and sodium hydride is according to molar ratio 1.0:1.5:1.5 proportion calculates；
The dosage of 3,4- dioxymethylene benzaldehyde, dimethyl methyl phosphonate and sodium hydride described in step (1c ") is according to rubbing You match than 1.0:1.5:1.5 and calculate；
The dosage of cerous chloride, sodium borohydride and 2- cyclopentene-1-one described in step (2a) is according to molar ratio 1.2:1.2:1 Proportion calculates；
Tetrabutylammonium bromide described in step (2b), sodium hydride, cylite and 2- cyclopentene -1- alcohol molar ratio be 1:40: 12:8；
The reagent 2c be potassium osmate/N-methyl morpholine oxide/potassium carbonate when, N-methyl morpholine oxide, potassium carbonate and The dosage of 2- cyclopentene -1- benzyl oxide is matched according to molar ratio 1.2:1.2:1 and is calculated；
The dosage of reagent 2d described in step (2d) is 3 by the molar ratio of itself and the amyl- 1- benzyl oxide of 2,3- dihydroxy basic ring: 1 proportion calculates；
In step (2e), the dosage for the sodium azide being added for the first time presses itself and amyl- 1,2-, bis- methylsulphur of 3- benzyloxy basic ring The molar ratio of acid esters is that 3:1 proportion calculates；
In step (2e), the dosage of second of sodium azide being added presses itself and the amyl- 2- first of 1- benzyloxy -3- nitrine ring The molar ratio of sulphonic acid ester is that 5:1 proportion calculates；
The dosage of triphenylphosphine described in step (2f) presses the molar ratio of itself and the amyl- 1- benzyl oxide of 2,3- diazido ring It matches and calculates for 1.5:1；
The dosage of condensing agent described in step (3a) is by itself and described (the E) -3- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) The molar ratio of acrylic acid is that 1.2:1 proportion calculates；
The dosage of deprotection agent described in step (3b) presses itself and amyl- bis- [3 ', the 4 '-dioxies of 1,2- of 3- benzyloxy basic ring Methene] coffee amide optical isomer intermixture molar ratio be 2.5:1 proportion calculate.
7. the preparation method of ring triol derivates according to claim 3, it is characterised in that:
Described in (E) -3- described in step (1c) (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) acrylic acid, step (1c ') (E) (E) -2- (benzene a pair of horses going side by side [d] described in -2- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) ethylene -1- sulfonic acid and step (1d ") [1,3] dioxolen -5- base) vinyl phosphonic acid mono-methyl synthetic route as shown in approach 1:
It is the amyl- 1- benzyl oxide of 2,3- diamino basic ring described in the 2,3- diamino hexamethylene -1- benzyl oxide step and (2f), described The synthetic route such as approach of the amyl- 2- benzyl oxide of 1,3- diamino basic ring described in 1,3- diamino hexamethylene -2- benzyl oxide and step (2f ') 2, shown in approach 3:
Described in (E) -3- described in step (1c) (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) acrylic acid, step (1c ') (E) (E) -2- (benzene a pair of horses going side by side [d] described in -2- (benzene a pair of horses going side by side [d] [1,3] dioxolen -5- base) ethylene -1- sulfonic acid and step (1d ") [1,3] dioxolen -5- base) vinyl phosphonic acid mono-methyl respectively with the amyl- 1- benzyl of 2,3- diamino basic ring described in step (2f) The amyl- 2- benzyl oxide of 1,3- diamino basic ring described in ether, (2f '), the 2,3- diamino hexamethylene -1- benzyl oxide, the 1,3- Benzyl is sloughed after the condensation of diamino hexamethylene -2- benzyl oxide, obtains the route of ring triol derivates as shown in approach 4:
8. application of the described in any item ring triol derivates of claim 1~7 in preparation antiviral drugs, feature exist In: the virus is Respiratory Syncytial Virus(RSV).
9. a kind of antiviral drugs, including 1~7 described in any item ring triol derivates.
10. antiviral drugs according to claim 9, it is characterised in that:
The antiviral drugs can also contain a kind of or at least two pharmaceutically acceptable carrier or auxiliary materials；
The auxiliary material is preferably sustained release agent, excipient, filler, adhesive, wetting agent, disintegrating agent, sorbefacient, absorption Carrier, surfactant or lubricant etc.；
The carrier is at least one of micro-capsule, microballoon, nanoparticle and liposome；
Various dosage forms can be further made in the antiviral drugs, and the drug of various dosage forms can be according to the normal of pharmaceutical field Rule method is prepared.
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