CN103804456B - CDB-2914 intermediate and preparation method thereof - Google Patents
CDB-2914 intermediate and preparation method thereof Download PDFInfo
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- CN103804456B CN103804456B CN201210461565.0A CN201210461565A CN103804456B CN 103804456 B CN103804456 B CN 103804456B CN 201210461565 A CN201210461565 A CN 201210461565A CN 103804456 B CN103804456 B CN 103804456B
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- 0 C[C@]1(C(CC2)C(CCC(C3)=C4CCC33OCCO3)C4=CC1)[C@@]2(*)C(OC)=C Chemical compound C[C@]1(C(CC2)C(CCC(C3)=C4CCC33OCCO3)C4=CC1)[C@@]2(*)C(OC)=C 0.000 description 3
- XRICNGBEEDABGB-UHFFFAOYSA-N CC(C)CC(C1)=CCCC11OCCO1 Chemical compound CC(C)CC(C1)=CCCC11OCCO1 XRICNGBEEDABGB-UHFFFAOYSA-N 0.000 description 1
- URRGKLIELUXJDT-BKKSKEKOSA-N CC[C@](CC1)([C@]2(C)C1C(CCC(C1)=C3CCC11OCCO1)C3=CC2)C1(C)OCCO1 Chemical compound CC[C@](CC1)([C@]2(C)C1C(CCC(C1)=C3CCC11OCCO1)C3=CC2)C1(C)OCCO1 URRGKLIELUXJDT-BKKSKEKOSA-N 0.000 description 1
- XUOQKQRMICQUQC-TVPLGVNVSA-N C[C@]1(C(CC2)C(CCC(C3)=C4CCC33OCCO3)C4=CC1)C2=O Chemical compound C[C@]1(C(CC2)C(CCC(C3)=C4CCC33OCCO3)C4=CC1)C2=O XUOQKQRMICQUQC-TVPLGVNVSA-N 0.000 description 1
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Abstract
The present invention relates to CDB-2914 intermediate and preparation method thereof.Specifically, it is used to prepare 3 the invention discloses a variety of, 3,20,20 pairs of norpregnas 5 (10) of (ethylenedioxy) 17 α hydroxyls 19, intermediate of 9 (11) diene (i.e. Formula VII compound) and preparation method thereof, the structure of the intermediate is as shown in this paper Formulas I, Formula II, formula III, formula IV or Formula V.It is used for the method for formula VII compounds using above-mentioned intermediate the invention also discloses a kind of.This method raw material is easy to get, and reaction condition is gentle, and high income, cost is relatively low, and accessory substance is few in course of reaction, and target product purity is high, is adapted to industrialized production.
Description
Technical field
The invention belongs to chemical pharmacy field.Specifically, the invention discloses the centre for preparing CDB-2914
Body and preparation method thereof.
Background technology
CDB-2914 is the progesterone receptor modulator (SPRM) for the selectivity developed by HRA drugmakers, is used for
After unprotect sexual intercourse or contraceptive failure in 5 days (120 hours) emergency contraception.Contraception mechanism is to prevent progesterone and its acceptor knot
Close, thus suppress the normal gene transcription of progesterone excitation, be allowed to that the albumen needed for gestation starts and maintained can not be synthesized, so as to reach
To the effect of contraception.
Double (ethylenedioxy) -17 Alpha-hydroxy -19- norpregnas -5 (10) of 3,3,20,20-, 9 (11)-diene is (hereinafter referred to as
Formula VII compound) it is the key intermediate for synthesizing CDB-2914, shown in the following Formula VII of structural formula.
The primary synthetic methods of current Formula VII compound have：
First, method disclosed in WO9630390：Using three ketals as initiation material, VII compounds are obtained by the reaction of 4 steps, always
Yield is 55%.Process route is as shown in route one.
Route one
This route has used poisonous reagent acetone cyanohydrin, occupational health and ring of the acetone cyanohydrin to producers in the 1st step
There is very big harm in border, and the reaction temperature of the step for -70 DEG C, it is necessary to deep freeze refrigeration plant.Use and arrive in the reaction of the 3rd step
Hazardous agents lithium sand, lithium sand easily explodes.Therefore, the method is not suitable for industrialized production.
2nd, method disclosed in CN101466723：Three ketals equally are used for initiation material, and formula is obtained by the reaction of 5 steps
VII compounds, total recovery is 46%.Process route is as shown in route two.
Route two
This method avoid using acetone cyanohydrin, but the side reaction for often walking reaction is more, and product does not allow easy purification, gained
The purity of product is low.
Therefore, this area still need a kind of low production cost of research and development, it is mild condition, easy to operate, it is safe and effective and suitable
Close double (ethylenedioxy) -17 Alpha-hydroxy -19- norpregnas -5 (10) of industrialized preparation 3,3,20,20-, 9 (11)-diene
Method.
The content of the invention
A purpose of the invention is to provide a kind of low production cost, mild condition, easy to operate, and safely and effectively 3,3,
Double (ethylenedioxy) -17 Alpha-hydroxy -19- norpregnas -5 (10) of 20,20-, 9 (11)-diene (Formula VII compound) preparation side
Method.
Another object of the present invention is to provide intermediate and these midbody compounds for formula VII compounds
Preparation method.
There is provided compound of formula I in first aspect present invention：
Wherein, R is-O- (CHR1)n-O-；Wherein, n is 2-6 integer；R1For H or C1-3Straight chained alkyl；And R1It is different
When be H.
In another preference, R is selected from the group：
a)Wherein, R1For C1-3Linear paraffin；
b)Wherein, R1For C1-3Linear paraffin；Or
c)Wherein, R2For-(CHR1)m-；M is 4-6 integer；R1For H or C1-3Straight chained alkyl.
In another preference, R2In substituent R1It is asynchronously H.
In another preference, R1For methyl.
In another preference, the compound of formula I is selected from the group：
There is provided the preparation method of compound of formula I as described in the first aspect of the invention in second aspect of the present invention, bag
Include step：In ether solvent, in the presence of hydrogen halides/ether solvent, in -20-0 DEG C, by female steroid -4,9- diene -3,17- bis-
Ketone is reacted with diol, derivatives, so as to obtain compound of formula I；
In formula, R is-O- (CHR1)n-O-；Wherein, n is 2-6 integer；R1For H or C1-3Straight chained alkyl；And R1It is different
When be H；
Described ether solvent is selected from the group：Glycol dimethyl ether, ethylene glycol diethyl ether, isopropyl ether, tetrahydrofuran, dioxy
Six rings or its combination；
Described hydrogen halides/ether solvent is selected from the group：Hydrogen chloride/dioxane, hydrogen chloride/tetrahydrofuran, hydrogen bromide/
Tetrahydrofuran.
In another preference, described diol, derivatives are HO- (CHR1)n- OH, R1It is as defined above.
In another preference, described diol, derivatives are 1,2-PD, 1,2- butanediols, 1,2- pentanediols, 2,
3- butanediols, 2,4-PD, 2- methyl-1,3-propanediols, 1,4- pentanediols.
In another preference, the mol ratio of female steroid -4,9- diene -3,17- diketone and diol, derivatives is 1：1-1.2
(it is preferably 1：1.05-1.10).
There is provided Formula II compound in third aspect present invention：
Wherein, R is-O- (CHR1)n-O-；Wherein, n is 2-6 integer；R1For H or C1-3Straight chained alkyl；And R1It is different
When be H.
There is provided formula III compound in fourth aspect present invention：
Wherein, R is-O- (CHR1)n-O-；Wherein, n is 2-6 integer；R1For H or C1-3Straight chained alkyl；And R1It is different
When be H.
There is provided formula IV compound in fifth aspect present invention：
Wherein, R is-O- (CHR1)n-O-；Wherein, n is 2-6 integer；R1For H or C1-3Straight chained alkyl；And R1It is different
When be H.
There is provided Formula V compound in sixth aspect present invention：
Wherein, R is-O- (CHR1)n-O-；Wherein, n is 2-6 integer；R1For H or C1-3Straight chained alkyl；And R1It is different
When be H.
There is provided the preparation method of the Formula II compound as described in third aspect present invention in seventh aspect present invention,
Including step：Compound of formula I is subjected to ethynylation, so as to obtain Formula II compound；
Wherein, R definition is with described in third aspect present invention.
In another preference, preparation method of the compound of formula I as described in second aspect of the present invention is made.
In another preference, the step is：In atent solvent, in the presence of a base, by compound of formula I and acetylene gas
Ethynylation is carried out, so as to obtain Formula II compound.
There is provided the preparation method of the formula III compound as described in fourth aspect present invention in eighth aspect present invention,
Including step：Formula II compound and benzene time sulfonic acid chloride are subjected to condensation rearrangement reaction, so as to obtain formula III compound；
Wherein, R definition is with described in fourth aspect present invention.
In another preference, the step is：In halogenated hydrocarbon solvent, in the presence of triethylamine and acetic acid, by Formula II
Compound carries out condensation rearrangement reaction with benzene time sulfonic acid chloride, so as to obtain formula III compound；
In another preference, in the step, Formula II compound, phenylsulfenyl chloride, acetic acid, the mol ratio of triethylamine are
1：2-4：1-1.2：3-6.
In another preference, preparation method of the Formula II compound as described in seventh aspect present invention is made.
There is provided the preparation method of the formula IV compound as described in fifth aspect present invention in ninth aspect present invention,
Including step：In the presence of methanol and sodium methoxide, formula III compound is carried out after addition reaction, then is carried out with Trimethyl phosphite
Reaction, so as to obtain formula IV compound；
Wherein, R definition is with described in fifth aspect present invention.
In another preference, preparation method of the formula III compound as described in eighth aspect present invention is made.
There is provided the preparation method of the Formula V compound as described in sixth aspect present invention in tenth aspect present invention, bag
Include step：In the presence of 0.5-2N hydrochloric acid, reaction is hydrolyzed in formula IV compound, so as to obtain Formula V compound；
Wherein, R definition is with described in sixth aspect present invention.
In another preference, preparation method of the formula IV compound as described in ninth aspect present invention is made.
There is provided the preparation method of Formula IV compound, including step in the tenth one side of the invention：
(i) in the presence of 0.5-2N hydrochloric acid, reaction is hydrolyzed in formula IV compound, so as to obtain Formula V compound；
(ii) in the presence of 5-8N hydrochloric acid, reaction is hydrolyzed in Formula V compound, so as to obtain Formula IV compound；
Wherein, R is-O- (CHR1)n-O-；Wherein, n is 2-6 integer；R1For H or C1-3Straight chained alkyl；And R1It is different
When be H.
In another preference, the preparation method of described formula IV compound as described in ninth aspect present invention is made.
There is provided a kind of preparation method of Formula VII compound, including step in the twelfth aspect of the present invention：
(1) compound of formula I is subjected to ethynylation, so as to obtain Formula II compound；
(2) Formula II compound and benzene time sulfonic acid chloride are subjected to condensation rearrangement reaction, so as to obtain formula III compound；
(3) in the presence of methanol and sodium methoxide, formula III compound is carried out after addition reaction, then entered with Trimethyl phosphite
Row reaction, so as to obtain formula IV compound；
(4) in the presence of 0.5-2N hydrochloric acid, reaction is hydrolyzed in formula IV compound, so as to obtain Formula V compound；
(5) in the presence of 5-8N hydrochloric acid, reaction is hydrolyzed in Formula V compound, so as to obtain Formula IV compound；
(6) Formula IV compound and ethylene glycol are reacted, so as to obtain Formula VII compound.
Wherein, R is-O- (CHR1)n-O-；Wherein, n is 2-6 integer；R1For H or C1-3Straight chained alkyl；And R1It is different
When be H.
In another preference, preparation method of the compound of formula I as described in second aspect of the present invention is made.
In another preference, the step (1) is：In atent solvent, in the presence of a base, by compound of formula I and second
Alkynes gas carries out ethynylation, so as to obtain Formula II compound.
In another preference, the reaction temperature of the step (1) is -10-40 DEG C；It is preferred that -10-20 DEG C.
In another preference, the step (2) is：, will in the presence of triethylamine and acetic acid in halogenated hydrocarbon solvent
Formula II compound carries out condensation rearrangement reaction with benzene time sulfonic acid chloride, so as to obtain formula III compound.
In another preference, the reaction temperature of the step (2) is -10-10 DEG C；It is preferred that -10-0 DEG C.
In another preference, in the step (2), Formula II compound, phenylsulfenyl chloride, acetic acid, triethylamine rub
You are than being 1：2-4：1-1.2：3-6.
In another preference, the reaction temperature of the step (3) is 30 DEG C -70 DEG C；It is preferred that 50-70 DEG C.
In another preference, the step (6) is：In the presence of trimethyl orthoformate and to methylbenzenesulfonic acid, by formula
VI compounds are reacted with ethylene glycol, so as to obtain Formula VII compound.
It should be understood that within the scope of the present invention, above-mentioned each technical characteristic of the invention and have in below (eg embodiment)
It can be combined with each other between each technical characteristic of body description, so as to constitute new or preferred technical scheme.As space is limited, exist
This no longer tires out one by one states.
Embodiment
The present inventor's in-depth study by long-term, it has unexpectedly been found that in formula IV preparation of compounds of formula VI compounds
During, use the mode of distribution hydrolysis so that the condition milder of reaction, and efficiently controlled byproduct of reaction (i.e. formula
VIII compounds) content, so as to obtain the Formula IV compound that purity is higher.On this basis, inventor completes this hair
It is bright.
As used herein, described " C1-3Straight chained alkyl " refers to the straight chained alkyl containing 1-3 carbon atom, such as methyl, second
Base, n-propyl.
As used herein, described " hydrogen halides/ether solvent " refers to solution of the hydrogen halide in ether solvent.It is described
The preferred hydrogen chloride gas of hydrogen halide, bromination hydrogen etc..Described ether solvent is to be suitable for preparing halogenation hydrogen
The solvent of liquid solution, such as tetrahydrofuran, dioxane.
Intermediate
The present invention gives the novel midbody compound for being used to prepare CDB-2914 of multiple structures.Its structure point
It is not:Compound of compound, structure of the compound, structure of structure shown in formula I as shown in Formula II as shown in formula III, knot
Compound, structure compound shown as a formula V of the structure as shown in formula IV.
Wherein, R is-O- (CHR1)n-O-；Wherein, n is 2-6 integer；R1For H or C1-3Straight chained alkyl；And R1It is different
When be H.Described " R1Asynchronously should be by following understanding for H "：For example when n is 2, two R1It is asynchronously H；When n is 3, three
Individual R1It is asynchronously H, by that analogy.
Preferably, R is the group being selected from the group：
a)Wherein, R1For C1-3Linear paraffin；
b)Wherein, R1For C1-3Linear paraffin；
c)Wherein, R2For-(CHR1)m-；M is 4-6 integer；R1For H or C1-3Straight chained alkyl.
In another preference, R2In substituent R1It is asynchronously H.
In another preference, R1For methyl.
In another preference, the compound of formula I is the compound being selected from the group：
Preparation method
The invention provides the preparation method of intermediate of the present invention.It should be understood that the intermediate of the present invention can also be by this
The conventional method in field or condition are made.
Preferably, the preparation method of intermediate compound of formula I, including step：In ether solvent, in hydrogen halides/ethers
In the presence of solvent, in -20-0 DEG C, by female steroid -4,9- diene -3,17- diketone and diol, derivatives (HO- (CHR1)n- OH, R1It is fixed
Justice is ibid) reacted, so as to obtain compound of formula I；
In formula, R is as defined above.
Wherein, described ether solvent may be selected from：Glycol dimethyl ether, ethylene glycol diethyl ether, isopropyl ether, tetrahydrofuran,
Dioxane or its combination；Described hydrogen halides/ether solvent may be selected from：The ring of chlorination hydrogen oxygen six, hydrogen chloride/tetrahydrofuran,
Hydrogen bromide/tetrahydrofuran.
In another preference, described diol, derivatives are 1,2-PD, 1,2- butanediols, 1,2- pentanediols, 2,
3- butanediols, 2,4-PD, 2- methyl-1,3-propanediols or 1,4- pentanediols.
In another preference, the mol ratio of female steroid -4,9- diene -3,17- diketone and diol, derivatives is 1：1-1.2；
Preferably 1：1.05-1.10.
Present invention also offers a kind of preparation method of Formula VII compound, it is preferable that the preparation method includes step：
(1) in atent solvent (such as tetrahydrofuran, methyl tertiary butyl ether(MTBE)), deposited in alkali (such as potassium tert-butoxide, hydrogenationization potassium)
Under, in certain temperature (such as -10-40 DEG C；It is preferred that -10-20 DEG C) under, compound of formula I and acetylene gas are subjected to ethinylation anti-
Should, so as to obtain Formula II compound.
(2) in halogenated hydrocarbons (such as dichloromethane, chloroform), in the presence of triethylamine and acetic acid, in certain temperature
(such as -10-10 DEG C；It is preferred that -10-0 DEG C) under, Formula II compound and benzene time sulfonic acid chloride are subjected to condensation rearrangement reaction, so as to obtain
Formula III compound.
In another preference, in step (2), Formula II compound, phenylsulfenyl chloride, acetic acid (or glacial acetic acid), three second
The mol ratio of amine is 1：2-4：1-1.2：3-6.
(3) in (such as 30 DEG C -70 DEG C of certain temperature；It is preferred that 50-70 DEG C) under, in the presence of methanol and sodium methoxide, formula III
Compound is carried out after addition reaction, then reacted with Trimethyl phosphite, so as to obtain formula IV compound；
(4) in (such as 0-20 DEG C of certain temperature；It is preferred that 5-15 DEG C) under, in the presence of 0.5-2N watery hydrochloric acid, by formula IV
Reaction is hydrolyzed in compound, so as to obtain Formula V compound；
(5) in (such as 0-20 DEG C of certain temperature；It is preferred that 5-15 DEG C) under, in the presence of 5-8N concentrated hydrochloric acid, by Formula V compound
Reaction is hydrolyzed, so as to obtain Formula IV compound；
(6) in the presence of trimethyl orthoformate and to methylbenzenesulfonic acid, Formula IV compound and ethylene glycol are reacted, from
And obtain Formula VII compound.
It is above-mentioned it is various in, R is as defined above.
Inventor has found under study for action, if step (4) and step (5) carried out in single step reaction, easily production
Raw 10%-15% open loop impurity, described open loop impurity structure is as shown in Formula VIII.
The open loop impurity with Formula VII compound is extremely difficult separates, cause the purity of Formula VII compound low, and be difficult to improve.
And use after the fractional hydrolysis of the present invention, the content of the open loop impurity significantly reduces (can as little as less than 2%), so that
By simply post-processing, you can obtain the VII compounds of high-purity (purity is up to more than 98%).
Beneficial effects of the present invention are mainly：
1. the present invention provides one kind and prepares double (ethylenedioxy) -17 Alpha-hydroxy -19- norpregnas -5 of 3,3,20,20-
(10), the method for 9 (11)-diene (i.e. Formula VII compound).
First, the blocking group of 3- ketone groups of starting material is studied in detail inventor, it was found that Duo Zhongbao
The compound of formula I of base protection is protected, Formula VII compound can be prepared so that the raw material sources of formula VII compounds are more
Extensively, so as to select the raw material that financial cost is lower, so as to reduce the overall financial cost of technique.
Secondly, during by formula IV preparation of compounds of formula VI compounds, the mode for having used distribution to hydrolyze so that anti-
The condition milder answered, has efficiently controlled the content (caning be controlled in less than 2%) of byproduct of reaction (i.e. Formula VIII compound),
So as to obtain the Formula IV compound of purity higher (more than 95%).Pass through further condensation reaction, it is easy to which ground, which has been made, to be contained
The Formula VII compound of amount more than 98%.
Therefore, preparation method reaction condition of the invention is gentle, and raw material is selectively more and flexible, each raw material and reagent letter
Singly it is easy to get, is adapted to industrialized production.
2. present invention also offers it is multiple be used to synthesizing double (ethylenedioxy) -17 Alpha-hydroxy -19- of 3,3,20,20- go first
Pregnant steroid -5 (10), the intermediate of 9 (11)-diene.
With reference to specific implementation, the present invention is expanded on further.It should be understood that these embodiments be merely to illustrate the present invention and
It is not used in limitation the scope of the present invention.The experimental method of unreceipted actual conditions in the following example, generally according to normal condition,
Or according to the condition proposed by manufacturer.Unless otherwise indicated, otherwise percentage and number are calculated by weight.If without other theorys
Bright, the various raw materials used in the present embodiment are commercially available.Raw material female steroid -4,9- diene -3,17- diketone is purchased from Xianju, Zhejiang monarch
Industry pharmaceutcal corporation, Ltd.
Embodiment 13,3- (2- methyl ethylenedioxy)-female steroid -5 (10), the preparation of 9 (11)-diene -17- ketone (I-1)
Add female steroid -4,9- diene -3,17- diketone (100.0g, 0.37mol) in reaction bulb, glycol dimethyl ether 1l, 1,
2- propane diols (30.0ml, 0.41mol), the dioxane solution (11.0ml) of 1N hydrogen chloride is reacted 4 hours at -20 DEG C.Add
Triethylamine (200ml) terminating reaction, concentration removes solvent.Residue is dissolved in ethyl acetate, water is added and is extracted, point
Layer, organic phase is concentrated to dryness.Residue isopropyl ether crystallization, filtering collects solid and drying, obtains title compound
(89.0g)。
MS(m/z):328.20;1H-NMR(DMSO):δ1.30(3H,18-CH3),3.73-4.07(6H,-O-CH(CH3)
CH2O-),5.50(1H,H-11);13C-NMR:145.4(C-5),136.8(C-9),132.8(C-10),124.1(C-11),
118.0(C-3),81.5(C-17),71.5(-O-CH2-),75.2(-O-CH-)。
Embodiment 23,3- (2- methyl ethylenedioxy)-17 α-beta-hydroxy of acetenyl-17-female steroid-5 (10), 9 (11)-two
The preparation of alkene (II-1)
Tetrahydrofuran (700ml) is added in reaction bulb, potassium tert-butoxide (35.0g, 0.31mol) is cooled to -2-2 DEG C, lead to second
Alkynes gas 15 minutes.I-1 (70.0g, 0.21mol) is added, continues logical acetylene 1 hour.Reaction is complete, is slowly dropped into 25% chlorination
Aqueous ammonium (550ml), control temperature is no more than 25 DEG C, adds ethyl acetate (300ml) and is extracted, is layered, organic layer subtracts
Pressure is concentrated to dryness, and obtains title compound.
MS(m/z):354.22;1H-NMR(DMSO):δ1.04(3H,18-CH3),3.52(H,20-C≡CH),3.73-
4.07(6H,-O-CH(CH3)CH2O-),5.50(1H,H-11);13C-NMR:145.4(C-5),136.8(C-9),132.8(C-
10),124.1(C-11),118.0(C-3),87.6(C-19),81.5(C-17),74.0(C-20),71.5(-O-CH2-),
75.2(-O-CH-)。
Embodiment 33,3- (2- methyl ethylenedioxy) -21- (phenylsufinyl) -19- norpregnas -5 (10), 9
(11), 17 (20), the preparation of 20- tetraenes (III-1)
Add II-1 obtained above in reaction bulb, dichloromethane (500ml) is stirred 10 minutes at 15-20 DEG C.Mixture
Triethylamine (93.5ml, 0.92mol) is added after dissolved clarification, glacial acetic acid (14.5ml, 0.24mol) is subsequently cooled to -5--10 DEG C, drop
Plus dichloromethane (150ml) solution of phenylsulfenyl chloride (47.0ml, 0.49mol).Insulation reaction 5 hours, into reaction solution
The aqueous solution of methanol is instilled, control temperature is no more than 5 DEG C.Then 25% aqueous ammonium chloride solution (750ml) is added dropwise to, 15 points are stirred
Clock.Layering, organic phase is concentrated to dryness, and residue is recrystallized with methyl tertiary butyl ether(MTBE), and solid is collected by filtration, and obtains title compound
(72.9g)。
MS(m/z):462.22;1H-NMR(DMSO):δ1.23(3H,18-CH3),3.73-4.07(6H,-O-CH(CH3)
CH2O-),5.50(1H, H-11), 4.8 (1H, 20-=CH-S-), 7.56-7.71 (5H, PhH);13C-NMR:204.6 (=C
=), 145.1 (C-5), 136.8 (C-9), 132.8 (C-10), 124.1 (C-11), 118.0 (C-3), 87.6 (C-19), 81.5
(C-17),74.0(C-20),71.5(-O-CH2-),75.2(-O-CH-)。
Embodiment 43,3- (2- methyl ethylenedioxy) -17 alpha-hydroxy-2 0- methoxyl group -19- norpregnas -5 (10), 9
The preparation of (11) -20 triolefins (IV-1)
Addition methanol (500ml) in reaction bulb, sodium methoxide (1.5g), 20-30 DEG C is stirred 30 minutes.Add III-1
(50.0g, 0.11mol), is warming up to 50-55 DEG C and reacts 6 hours.Trimethyl phosphite (10.0ml) is added, 55-60 DEG C is warming up to
Reaction 3.5 hours.Reaction is finished, and reaction solution is cooled to after 15-20 DEG C, and purified water (400ml) is slowly added dropwise into reaction solution, is added dropwise
About 1 hour time.Completion of dropping, is stirred at room temperature 1.5 hours.Then filter, filter cake 100ml points of 2 elution of water, 40-
It is dried in vacuo 12 hours at 45 DEG C, obtains yellow solid (IV-1,40.1g).
MS(m/z):386.25;1H-NMR(DMSO):δ1.04(3H,18-CH3),3.73-4.07(6H,-O-CH(CH3)
CH2O-),5.50(1H, H-11), 4.03-4.06 (2H, 20-=CH2),3.51(3H,-O-CH3);13C-NMR:170.0(C-
19),145.4(C-5),136.8(C-9),132.8(C-10),124.1(C-11),118.0(C-3),93.2(C-17),74.0
(C-20),71.5(-O-CH2-),75.2(-O-CH-),17.3(C-18)。
Embodiment 53,3- (2- methyl ethylenedioxy) -17 Alpha-hydroxy -19- norpregnas -5 (10), 9 (11) diene (V-
1) preparation
Added in reaction bulb under IV-1 (20.0g, 0.052mol), methanol (200ml), stirring and add 1N hydrochloric acid (60ml),
Reacted 1 hour in 13-17 DEG C.Purified water (250ml) is added dropwise into reaction solution, time for adding about 1 hour is warming up to room temperature, stirred
Mix 1 hour.Filtering, filter cake is washed with water to neutrality, obtains yellow powder (V-1,18.6g).
MS(m/z):372.50;1H-NMR(DMSO):δ1.04(3H,18-CH3),3.73-4.07(6H,-O-CH(CH3)
CH2O-),5.50(1H, H-11), 2.13 (3H, 20-C=OCH3),3.65(H,17-OH);13C-NMR:210.1(C-19),
118.0(C-3),145.4(C-5),136.8(C-9),132.8(C-10),124.1(C-11),96.9(C-17),27.3(C-
20),71.5(-O-CH2-),75.2(-O-CH-),16.4(C-18)。
Alpha-hydroxy -19- the norpregnas -4 (5) of embodiment 617, the preparation of 9 (10) diene -3,20- diketone (VI)
Added in reaction bulb under V-1 (10.0g, 0.027mol), methanol (100ml), stirring and add 6N hydrochloric acid (10ml), in
10-15 DEG C is reacted 1 hour.Purified water (120ml), time for adding about 1 hour are added dropwise into reaction solution.Continue to stir 1 hour.Cross
Filter, filter cake is washed with water to neutrality, obtains buff powder (VI, 7.8g), and HPLC purity assays are 96.0%, wherein, Formula VIII
Compound content is 1.5%.
MS(m/z):314.19;1H-NMR(DMSO):δ1.04(3H,18-CH3),5.50(1H,H-11),2.13(3H,20-
C=OCH3),3.65(H,17-OH),2.49(2H,1-CH2);13C-NMR:210.1(C-19),210.0(C-3),141.3(C-
5),136.8(C-9),131.0(C-10),124.1(C-11),96.9(C-17),27.3(C-20),20.0(C-1),16.4(C-
18)。
Double (ethylenedioxy) -17 Alpha-hydroxy -19- norpregnas -5 (10) of embodiment 73,3,20,20-, 9 (11)-diene
(VII) preparation
VI (7.0g, 0.022mol), dichloromethane (80ml), ethylene glycol (5.0ml), orthoformic acid front three are added in reaction bulb
Ester (1.0ml), p-methyl benzenesulfonic acid (1.0g) reacts 4 hours in 15-20 DEG C.Reaction is finished, and unsaturated carbonate is instilled into reaction solution
Hydrogen sodium solution, is stirred 30 minutes.Layering, organic layer is concentrated to dryness, residue methanol crystallization is collected by filtration solid, obtained
Light yellow solid.Crude product is recrystallized with methyl tertiary butyl ether(MTBE), white solid (VII, 6.3g) is obtained, HPLC purity assays are
99.0%。
MS(m/z):402.24,1H-NMR(CDCl3):δ0.80(s,18-CH3),1.38(s,21-CH3),4.0(m,
3.20- acetals), 5.60 (br.s, C-11H).
Embodiment 83,3- (2,2- dimethyl ethylenedioxy)-female steroid -5 (10), 9 (11)-diene -17- ketone (I-2)
Prepare
Female steroid -4,9- diene -3,17- diketone (50.0g, 0.18mol), glycol dimethyl ether are added in reaction bulb
(600ml), 2,3-butanediol (17.5ml, 0.19mol), the dioxane solution (5.0ml) of 1N hydrogen chloride reacts 6 at -15 DEG C
Hour.Triethylamine (100ml) terminating reaction is added, concentration removes solvent.Residue is dissolved in ethyl acetate, adds water extraction,
Layering, organic phase is concentrated to dryness.Residue isopropyl ether crystallization, is collected by filtration solid and drying, obtains title compound
(43.1g)。
MS(m/z):342.22;1H-NMR(DMSO):δ1.30(3H,18-CH3),4.06(8H,-O-CH(CH3)CH(CH3)
O-),5.50(1H,H-11);13C-NMR:145.4(C-5),136.8(C-9),132.8(C-10),124.1(C-11),115.5
(C-3),220(C-17),80.5(-O-CH(CH3)-)。
Embodiment 93,3- (2,2- dimethyl ethylenedioxy)-17 α-beta-hydroxy of acetenyl-17-female steroid-5 (10), 9
(11) preparation of-diene (II-2)
Tetrahydrofuran (300ml) is added in reaction bulb, potassium tert-butoxide (15.0g, 0.13mol) is cooled to 0-5 DEG C, lead to second
Alkynes gas 15 minutes.I-2 (35.0g, 0.10mol) is added, continues logical acetylene 1 hour.Reaction is complete, is slowly dropped into 25% chlorination
Aqueous ammonium (240ml), control temperature is no more than 25 DEG C, adds ethyl acetate (200ml) extraction, and organic layer is depressurized in layering
It is concentrated to dryness, obtains title compound.
MS(m/z):368.24;1H-NMR(DMSO):δ1.04(3H,18-CH3),3.52(H,20-C≡CH),4.06
(8H,-O-CH(CH3)CH(CH3)O-),5.50(1H,H-11);13C-NMR:145.4(C-5),136.8(C-9),132.8(C-
10),124.1(C-11),115.5(C-3),87.6(C-19),81.5(C-17),74.0(C-20),80.5(-O-CH
(CH3)-)。
Embodiment 103,3- (2,2- dimethyl ethylenedioxy) -21- (phenylsufinyl) -19- norpregnas -5
(10), 9 (11), 17 (20), the preparation of 20- tetraenes (III-2)
Add II-2 obtained above in reaction bulb, dichloromethane (300ml) is stirred 10 minutes at 15-20 DEG C.Mixture
Add triethylamine (51.0ml, 0.50mol) after dissolved clarification, glacial acetic acid (6.5ml, 0.11mol) is subsequently cooled to -5--10 DEG C, dropwise addition
The solution of the dichloromethane (70ml) of phenylsulfenyl chloride (28.0ml, 0.029mol).Insulation reaction 5 hours, into reaction solution
The aqueous solution of methanol is instilled, control temperature is no more than 5 DEG C.Then 25% aqueous ammonium chloride solution (350ml) is added dropwise, stirs 15 minutes.
Layering, organic phase is concentrated to dryness, residue is recrystallized with methyl tertiary butyl ether(MTBE), solid is collected by filtration, obtain title compound
(34.3g)。
MS(m/z):476.24;1H-NMR(DMSO):δ1.23(3H,18-CH3),4.06(8H,-O-CH(CH3)CH(CH3)
O-),5.50(1H, H-11), 4.8 (1H, 20-=CH-S-), 7.56-7.71 (5H, PhH);13C-NMR:204.6 (=C=),
145.1(C-5),136.8(C-9),132.8(C-10),124.1(C-11),115.5(C-3),73(C-19),112.8(C-
17),74.0(C-20),80.5(-O-CH(CH3)-)。
The alpha-hydroxy-2 0- methoxyl group -19- norpregnas -5 of embodiment 113,3- (2,2- dimethyl ethylenedioxy) -17
(10), the preparation of 9 (11) -20 triolefin (IV-2)
Addition methanol (200ml) in reaction bulb, sodium methoxide (0.7g), 20-30 DEG C is stirred 30 minutes.Then III-2 is added
(20.0g, 0.042mol), is warming up to 50-55 DEG C and reacts 6 hours.Then Trimethyl phosphite (4.5ml) is added, 55- is warming up to
60 DEG C are reacted 3.5 hours.Reaction is finished, and reaction solution is cooled into 15-20 DEG C, and purified water (150ml) is slowly added dropwise into reaction solution,
Time for adding about 1 hour.Completion of dropping, is stirred 1.5 hours at room temperature.Filtering, filter cake 50ml points of 2 elution of water, 40-45
It is dried in vacuo 12 hours at DEG C, obtains yellow solid (IV-2,15.0g).
MS(m/z):400.26;1H-NMR(DMSO):δ1.04(3H,18-CH3),4.06(8H,-O-CH(CH3)CH(CH3)
O-),5.50(1H, H-11), 4.03-4.06 (2H, 20-=CH2),3.51(3H,-O-CH3);13C-NMR:170.0(C-19),
145.4(C-5),136.8(C-9),132.8(C-10),124.1(C-11),115.5(C-3),93.2(C-17),74.0(C-
20),80.5(-O-CH(CH3)-),17.3(C-18)。
Embodiment 123,3- (2,2- dimethyl ethylenedioxy) -17 Alpha-hydroxy -19- norpregnas -5 (10), 9 (11) two
The preparation of alkene (V-2)
Added in reaction bulb under IV-2 (15.0g, 0.037mol), methanol (150ml), stirring and add 1N hydrochloric acid (45ml),
Reacted 1 hour in 15-20 DEG C.Purified water (180ml) is added dropwise into reaction solution, time for adding about 1 hour is warming up to room temperature, stirred
Mix 1 hour.Filtering, filter cake is washed with water to neutrality, obtains yellow powder (V-2,13.6g).
MS(m/z):386.25;1H-NMR(DMSO):δ1.04(3H,18-CH3),4.06(8H,-O-CH(CH3)CH(CH3)
O-),5.50(1H, H-11), 2.13 (3H, 20-C=OCH3),3.65(H,17-OH);13C-NMR:210.1(C-19),115.5
(C-3),145.4(C-5),136.8(C-9),132.8(C-10),124.1(C-11),96.9(C-17),27.3(C-20),
80.5(-O-CH(CH3)-),16.4(C-18)。
Alpha-hydroxy -19- the norpregnas -4 (5) of embodiment 1317, the preparation of 9 (10) diene -3,20- diketone (VI)
Added in reaction bulb under V-2 (10.0g, 0.026mol), methanol (100ml), stirring and add 6N hydrochloric acid (10ml), in
10-15 DEG C is reacted 1 hour.Purified water (120ml), time for adding about 1 hour are added dropwise into reaction solution.Continue to stir 1 hour.Cross
Filter, filter cake is washed with water to neutrality, obtains buff powder (VI, 7.6g), and HPLC purity assays are 95.3%, wherein, Formula VIII
Compound content is less than 1.9%.
MS(m/z):314.19;1H-NMR(DMSO):δ1.04(3H,18-CH3),5.50(1H,H-11),2.13(3H,20-
C=OCH3),3.65(H,17-OH),2.49(2H,1-CH2);13C-NMR:210.1(C-19),210.0(C-3),141.3(C-
5),136.8(C-9),131.0(C-10),124.1(C-11),96.9(C-17),27.3(C-20),20.0(C-1),16.4(C-
18)。
Embodiment 143,3- (1,3- dimethyl sub- the third two epoxide)-female steroid -5 (10), 9 (11)-diene -17- ketone (I-3)
Prepare
Female steroid -4,9- diene -3,17- diketone (50.0g, 0.18mol), glycol dimethyl ether are added in reaction bulb
600ml), 2,4- pentanediols (20.0ml, 0.19mol), the tetrahydrofuran solution (6.0ml) of 1N hydrogen bromides reacts 5 at -15 DEG C
Hour.Triethylamine (100ml) terminating reaction is added, concentration removes solvent.Residue is dissolved in ethyl acetate, adds water extraction,
Layering, organic phase is concentrated to dryness.Residue isopropyl ether crystallization, filtering collects solid and drying, obtains title compound
(47.3g)。
MS(m/z):356.24;1H-NMR(DMSO):δ1.30(3H,18-CH3),1.18-3.97(10H,-O-CH(CH3)
CH2CH(CH3)O-),5.50(1H,H-11);13C-NMR:145.4(C-5),136.8(C-9),132.8(C-10),124.1(C-
11),110.0(C-3),220(C-17),69.5(-O-CH(CH3)-)。
Embodiment 153,3- (1,3- dimethyl sub- the third two epoxide)-17 α-beta-hydroxy of acetenyl-17-female steroid-5 (10), 9
(11) preparation of-diene (II-3)
Tetrahydrofuran (300ml) is added in reaction bulb, potassium tert-butoxide (17.5g, 0.15mol) is cooled to 0-5 DEG C, lead to second
Alkynes gas 15 minutes.I-3 (35.0g, 0.10mol) is added, continues logical acetylene 1 hour.Reaction is complete, is slowly dropped into 25% chlorination
Aqueous ammonium (300ml), control temperature is no more than 20 DEG C, adds ethyl acetate (200ml) extraction, and layering concentrates organic layer
To dry, title compound is obtained.
MS(m/z):382.25;1H-NMR(DMSO):δ1.04(3H,18-CH3),3.52(H,20-C≡CH),1.18-
3.97(10H,-O-CH(CH3)CH2CH(CH3)O-),5.50(1H,H-11);13C-NMR:145.4(C-5),136.8(C-9),
132.8(C-10),124.1(C-11),110.0(C-3),87.6(C-19),81.5(C-17),74.0(C-20),69.5(-O-
CH(CH3)-)。
Embodiment 163,3- (1,3- dimethyl sub- the third two epoxide) -21- (phenylsufinyl) -19- norpregnas -5
(10), 9 (11), 17 (20), the preparation of 20- tetraenes (III-3)
Add II-3 obtained above in reaction bulb, dichloromethane (300ml) is stirred 10 minutes at 15-20 DEG C.Mixture
Add triethylamine (45.0ml, 0.44mol) after dissolved clarification, glacial acetic acid (6.5ml, 0.11mol) is subsequently cooled to -5-0 DEG C, benzene is added dropwise
The solution of the dichloromethane (70ml) of base time sulfonic acid chloride (25.0ml, 0.026mol).Insulation reaction 5 hours, drips into reaction solution
Enter the aqueous solution of methanol, control temperature is no more than 5 DEG C.Then 25% aqueous ammonium chloride solution (300ml) is added dropwise to, is stirred 30 minutes.
Layering, organic phase is concentrated to dryness, residue is recrystallized with methyl tertiary butyl ether(MTBE), solid is collected by filtration, obtain title compound
(34.5g)。
MS(m/z):490.25;1H-NMR(DMSO):δ1.23(3H,18-CH3),1.18-3.97(10H,-O-CH(CH3)
CH2CH(CH3)O-),5.50(1H, H-11), 4.8 (1H, 20-=CH-S-), 7.56-7.71 (5H, PhH);13C-NMR:204.6
(=C=), 145.1 (C-5), 136.8 (C-9), 132.8 (C-10), 124.1 (C-11), 110.0 (C-3), 73 (C-19),
112.8(C-17),74.0(C-20),69.5(-O-CH(CH3)-)。
Embodiment 173,3- (1,3- dimethyl sub- the third two epoxide) -17 alpha-hydroxy-2 0- methoxyl group -19- norpregnas -5
(10), the preparation of 9 (11) -20 triolefin (IV-3)
Addition methanol (200ml) in reaction bulb, sodium methoxide (0.6g), 20-30 DEG C is stirred 30 minutes.Then III-3 is added
(20.0g, 0.041mol), is warming up to 55-60 DEG C and reacts 5 hours.Trimethyl phosphite (5.0ml) is added, 60-65 is warming up to
DEG C reaction 5 hours.Reaction is finished, and is cooled to 15-20 DEG C, and purified water (150ml), time for adding about 1 are slowly added dropwise into reaction solution
Hour.Completion of dropping, is stirred 2 hours at room temperature.Filtering, filter cake water 60ml, which divides at 2 elution, 40-45 DEG C, is dried in vacuo 12
Hour, obtain yellow solid (IV-3,15.5g).
MS(m/z):414.28;1H-NMR(DMSO):δ1.04(3H,18-CH3),1.18-3.97(10H,-O-CH(CH3)
CH2CH(CH3)O-),5.50(1H, H-11), 4.03-4.06 (2H, 20-=CH2),3.51(3H,-O-CH3);13C-NMR:
170.0(C-19),145.4(C-5),136.8(C-9),132.8(C-10),124.1(C-11),110.0(C-3),93.2(C-
17),74.0(C-20),69.5(-O-CH(CH3)-),17.3(C-18)。
Embodiment 183,3- (1,3- dimethyl sub- the third two epoxide) -17 Alpha-hydroxy -19- norpregnas -5 (10), 9 (11) two
The preparation of alkene (V-3)
Added in reaction bulb under IV-3 (10.0g, 0.026mol), methanol (100ml), stirring and add 1N hydrochloric acid (30ml),
Reacted 1 hour in 15-20 DEG C.Purified water (200ml) is added dropwise into reaction solution, time for adding about 1 hour is warming up to room temperature, stirred
Mix 1 hour.Filtering, filter cake is washed with water to neutrality, obtains yellow powder (V-3,9.8g).
MS(m/z):400.26;1H-NMR(DMSO):δ1.04(3H,18-CH3),1.18-3.97(10H,-O-CH(CH3)
CH2CH(CH3)O-),5.50(1H, H-11), 2.13 (3H, 20-C=OCH3),3.65(H,17-OH);13C-NMR:210.1(C-
19),110.0(C-3),145.4(C-5),136.8(C-9),132.8(C-10),124.1(C-11),96.9(C-17),27.3
(C-20),69.5(-O-CH(CH3)-),16.4(C-18)。
Alpha-hydroxy -19- the norpregnas -4 (5) of embodiment 1917, the preparation of 9 (10) diene -3,20- diketone (VI)
V-3 (8.0g, 0.022mol), methanol 80ml are added in reaction bulb), stirring is lower to add 6N hydrochloric acid (7.5ml), in 5-
10 DEG C are reacted 1.5 hours.Purified water (100ml), time for adding about 1 hour are added dropwise into reaction solution.Continue to stir 1 hour.Cross
Filter, filter cake is washed with water to neutrality, obtains yellow powder (VI, 6.3g), and HPLC purity assays are 95.5%, wherein, Formula VIII chemical combination
Thing content is less than 1.8%.
MS(m/z):314.19;1H-NMR(DMSO):δ1.04(3H,18-CH3),5.50(1H,H-11),2.13(3H,20-
C=OCH3),3.65(H,17-OH),2.49(2H,1-CH2);13C-NMR:210.1(C-19),210.0(C-3),141.3(C-
5),136.8(C-9),131.0(C-10),124.1(C-11),96.9(C-17),27.3(C-20),20.0(C-1),16.4(C-
18)。
Embodiment 203,3- (3- methyl sub- the third two epoxide)-female steroid -5 (10), the preparation of 9 (11)-diene -17- ketone (I-4)
Female steroid -4,9- diene -3,17- diketone (50.0g, 0.18mol), ethylene glycol diethyl ether are added in reaction bulb
(500ml), 2- methyl isophthalic acids, ammediol (20.0ml, 0.19mol), the dioxane solution (5.0ml) of 1N hydrogen chloride, -10 DEG C
Lower reaction 4 hours.Triethylamine (100ml) terminating reaction is added, concentration removes solvent.Residue is dissolved in ethyl acetate, adds
Water extracts decontamination, and organic phase is concentrated to dryness by layering.Residue isopropyl ether crystallization, filtering is collected solid and drying, obtained
To title compound (42.3g).
MS(m/z):342.22;1H-NMR(DMSO):δ1.30(3H,18-CH3),0.96-3.88(8H,-O-CH2CH(CH3)
CH2-O-),5.50(1H,H-11);13C-NMR:145.4(C-5),136.8(C-9),132.8(C-10),124.1(C-11),
115.3(C-3),220(C-17),71.5(-O-CH2CH(CH3)-)。
Embodiment 213,3- (3- methyl sub- the third two epoxide)-17 α-beta-hydroxy of acetenyl-17-female steroid-5 (10), 9 (11)-
The preparation of diene (II-4)
Tetrahydrofuran (300ml) is added in reaction bulb, potassium tert-butoxide (16.0g, 0.14mol) is cooled to 0-5 DEG C, lead to second
Alkynes gas 15 minutes.I-4 (35.0g, 0.10mol) is added, continues logical acetylene 1 hour.Reaction is complete, is slowly dropped into 25% chlorination
Aqueous ammonium (300ml), control temperature is no more than 20 DEG C, adds ethyl acetate (200ml) extraction, and layering concentrates organic layer
To dry, title compound is obtained.
MS(m/z):368.24;1H-NMR(DMSO):δ1.04(3H,18-CH3),3.52(H,20-C≡CH),0.96-
3.88(8H,-O-CH2CH(CH3)CH2-O-),5.50(1H,H-11);13C-NMR:145.4(C-5),136.8(C-9),132.8
(C-10),124.1(C-11),115.3(C-3),87.6(C-19),81.5(C-17),74.0(C-20),71.5(-O-CH2CH
(CH3)-)。
Embodiment 223,3- (3- methyl sub- the third two epoxide) -21- (phenylsufinyl) -19- norpregnas -5 (10), 9
(11), 17 (20), the preparation of 20- tetraenes (III-4)
Add II-4 obtained above in reaction bulb, dichloromethane (300ml) is stirred 10 minutes at 15-20 DEG C.Mixture
Triethylamine (36.0ml, 0.35mol) is added after dissolved clarification, glacial acetic acid (6.0ml, 0.10mol) is subsequently cooled to -5-0 DEG C, dropwise addition
The solution of the dichloromethane (70ml) of phenylsulfenyl chloride (22.0ml, 0.023mol).Insulation reaction 5 hours, into reaction solution
The aqueous solution of methanol is instilled, control temperature is no more than 5 DEG C.Then 25% aqueous ammonium chloride solution (300ml) is added dropwise to, 30 points are stirred
Clock.Layering, organic phase is concentrated to dryness, residue is recrystallized with methyl tertiary butyl ether(MTBE), solid is collected by filtration, obtain title compound
Thing (33.3g).
MS(m/z):476.24;1H-NMR(DMSO):δ1.23(3H,18-CH3),0.96-3.88(8H,-O-CH2CH(CH3)
CH2-O-),5.50(1H, H-11), 4.8 (1H, 20-=CH-S-), 7.56-7.71 (5H, PhH);13C-NMR:204.6 (=C
=), 145.1 (C-5), 136.8 (C-9), 132.8 (C-10), 124.1 (C-11), 115.3 (C-3), 73 (C-19), 112.8
(C-17),74.0(C-20),71.5(-O-CH2CH(CH3)-)。
Embodiment 233,3- (3- methyl sub- the third two epoxide) -17 alpha-hydroxy-2 0- methoxyl group -19- norpregnas -5 (10), 9
The preparation of (11) -20 triolefins (IV-4)
Addition methanol (200ml) in reaction bulb, sodium methoxide (0.6g), 20-30 DEG C is stirred 30 minutes.Then III-4 is added
(20.0g, 0.041mol), is warming up to 55-60 DEG C and reacts 5 hours.Trimethyl phosphite (5.0ml) is added, 60-65 is warming up to
DEG C reaction 5 hours.Reaction is finished, and reaction solution is cooled into 15-20 DEG C, and purified water (150ml) is slowly added dropwise into reaction solution, is added dropwise
About 1 hour time.Completion of dropping, is filtered after stirring 2 hours at room temperature, filter cake 60ml points of 2 elution of water, true at 40-45 DEG C
Sky is dried 12 hours, obtains yellow solid (IV-4,14.9g).
MS(m/z):400.26;1H-NMR(DMSO):δ1.04(3H,18-CH3),0.96-3.88(8H,-O-CH2CH(CH3)
CH2-O-),5.50(1H, H-11), 4.03-4.06 (2H, 20-=CH2),3.51(3H,-O-CH3);13C-NMR:170.0(C-
19),145.4(C-5),136.8(C-9),132.8(C-10),124.1(C-11),115.3(C-3),93.2(C-17),74.0
(C-20),71.5(-O-CH2CH(CH3)-),17.3(C-18)。
Embodiment 243,3- (3- methyl sub- the third two epoxide) -17 Alpha-hydroxy -19- norpregnas -5 (10), 9 (11) diene
(V-4) preparation
Added in reaction bulb under IV-4 (10.0g, 0.025mol), methanol (100ml), stirring and add 1N hydrochloric acid (25ml),
Reacted 1.5 hours in 15-20 DEG C.Purified water (150ml) is added dropwise into reaction solution, time for adding about 1 hour is warming up to room temperature,
Stirring 1 hour.Filtering, filter cake is washed with water to neutrality, obtains yellow powder (V-4,9.0g).
MS(m/z):386.25;1H-NMR(DMSO):δ1.04(3H,18-CH3),0.96-3.88(8H,-O-CH2CH(CH3)
CH2-O-),5.50(1H, H-11), 2.13 (3H, 20-C=OCH3),3.65(H,17-OH);13C-NMR:210.1(C-19),
115.3(C-3),145.4(C-5),136.8(C-9),132.8(C-10),124.1(C-11),96.9(C-17),27.3(C-
20),71.5(-O-CH2CH(CH3)-),16.4(C-18)。
Alpha-hydroxy -19- the norpregnas -4 (5) of embodiment 2517, the preparation of 9 (10) diene -3,20- diketone (VI)
Added in reaction bulb under V-4 (7.0g, 0.018mol), methanol (70ml), stirring and add 6N hydrochloric acid (6.0ml), in
5-10 DEG C is reacted 1.5 hours.Purified water (80ml), time for adding about 1 hour are added dropwise into reaction solution.Continue to stir 1 hour.Cross
Filter, filter cake is washed with water to neutrality, obtains yellow powder (VI, 5.3g), and HPLC purity assays are 96.3%, wherein, Formula VIII chemical combination
Thing content is less than 1.3%.
MS(m/z):314.19;1H-NMR(DMSO):δ1.04(3H,18-CH3),5.50(1H,H-11),2.13(3H,20-
C=OCH3),3.65(H,17-OH),2.49(2H,1-CH2);13C-NMR:210.1(C-19),210.0(C-3),141.3(C-
5),136.8(C-9),131.0(C-10),124.1(C-11),96.9(C-17),27.3(C-20),20.0(C-1),16.4(C-
18)。
Alpha-hydroxy -19- the norpregnas -4 (5) of comparative example 17, the preparation of 9 (10) diene -3,20- diketone (VI)
Added in reaction bulb under IV-1 (1.0g, 2.6mmol), methanol (20ml), stirring and add 3N hydrochloric acid (3.0ml), in
10-15 DEG C is reacted 3 hours.Purified water (30ml), time for adding about 30 minutes are added dropwise into reaction solution.Continue to stir 30 minutes.
Filtering, filter cake is washed with water to neutrality, obtains yellow powder (VI, 0.6g), and HPLC purity assays are 85.6%, Formula VIII compound
Have 12.3%.
In summary, using the preparation method of the present invention, wherein employing open loop in the method for fractional hydrolysis, course of reaction
The content of accessory substance is significantly reduced, and is conducive to being further used for preparing CDB-2914.
All documents referred in the present invention are all incorporated as reference in this application, independent just as each document
It is incorporated as with reference to such.In addition, it is to be understood that after the above-mentioned instruction content of the present invention has been read, those skilled in the art can
To be made various changes or modifications to the present invention, these equivalent form of values equally fall within the model that the application appended claims are limited
Enclose.
Claims (10)
1. a kind of preparation method of Formula IV compound, it is characterised in that including step：
(i) in the presence of 0.5-2N hydrochloric acid, reaction is hydrolyzed in formula IV compound, so as to obtain Formula V compound；
(ii) in the presence of 5-8N hydrochloric acid, reaction is hydrolyzed in Formula V compound, so as to obtain Formula IV compound；
Wherein, R is selected from the group：
a)Wherein, R1For C1-3Linear paraffin；
b)Wherein, R1For C1-3Linear paraffin；Or
c)Wherein, R2For-(CHR1)m-；M is 4-6 integer；R1For H or C1-3Straight chained alkyl.
2. a kind of preparation method of Formula VII compound, it is characterised in that including step：
(1) compound of formula I is subjected to ethynylation, so as to obtain Formula II compound；
(2) Formula II compound and benzene time sulfonic acid chloride are subjected to condensation rearrangement reaction, so as to obtain formula III compound；
(3) in the presence of methanol and sodium methoxide, formula III compound is carried out after addition reaction, then is carried out instead with Trimethyl phosphite
Should, so as to obtain formula IV compound；
(4) in the presence of 0.5-2N hydrochloric acid, reaction is hydrolyzed in formula IV compound, so as to obtain Formula V compound；
(5) in the presence of 5-8N hydrochloric acid, reaction is hydrolyzed in Formula V compound, so as to obtain Formula IV compound；
(6) Formula IV compound and ethylene glycol are reacted, so as to obtain Formula VII compound；
Wherein, R definition is as described in the appended claim 1.
3. the method as described in claim 1, it is characterised in that R is selected from the group：
a)Wherein, R1For C1-3Linear paraffin；
b)Wherein, R1For C1-3Linear paraffin.
4. method as claimed in claim 2, it is characterised in that the compound of formula I is selected from the group：
5. a kind of the method as described in claim 1, it is characterised in that including step：In the presence of methanol and sodium methoxide, formula
III compounds are carried out after addition reaction, then reacted with Trimethyl phosphite, so as to obtain formula IV compound；
Wherein, R definition is with described in claim 1.
6. method as claimed in claim 5, it is characterised in that including step：Formula II compound and benzene time sulfonic acid chloride are carried out
Rearrangement reaction is condensed, so as to obtain formula III compound；
Wherein, R definition is with described in claim 1.
7. method as claimed in claim 6, it is characterised in that including step：Compound of formula I is subjected to ethynylation, from
And obtain Formula II compound；
Wherein, R definition is with described in claim 6.
8. method as claimed in claim 7, it is characterised in that methods described also includes step：In ether solvent, in halogenation
In the presence of hydrogen/ether solvent, in -20-0 DEG C, female steroid -4,9- diene -3,17- diketone and diol, derivatives are reacted, from
And obtain compound of formula I；
In formula, R definition is as described in the appended claim 1；
Described ether solvent is selected from the group：Glycol dimethyl ether, ethylene glycol diethyl ether, isopropyl ether, tetrahydrofuran, dioxy six
Ring or its combination；
Described hydrogen halides/ether solvent is selected from the group：Hydrogen chloride/dioxane, hydrogen chloride/tetrahydrofuran, hydrogen bromide/tetrahydrochysene
Furans.
9. preparation method as claimed in claim 8, it is characterised in that female steroid -4,9- diene -3,17- diketone derives with glycol
The mol ratio of thing is 1：1-1.2.
10. preparation method as claimed in claim 1, it is characterised in that the step (i) includes：
(i) at 0-20 DEG C, in the presence of 0.5-2N watery hydrochloric acid, reaction is hydrolyzed in formula IV compound, so as to obtain Formula V
Compound；
And described step (ii) includes：
(ii) at 0-20 DEG C, in the presence of 5-8N concentrated hydrochloric acid, reaction is hydrolyzed in Formula V compound, so as to obtain Formula IV
Compound；
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| CN106986911B (en) * | 2017-03-23 | 2019-05-10 | 湖南玉新药业有限公司 | The preparation method of dexamethasone key intermediate connection alkene sulfoxide object |
| CN106986908B (en) * | 2017-03-23 | 2019-05-10 | 湖南玉新药业有限公司 | The preparation method of betamethasone |
| CN107629107B (en) * | 2017-11-10 | 2020-06-09 | 广州市桐晖药业有限公司 | Synthetic method of ulipristal acetate |
| CN108084238A (en) * | 2017-12-28 | 2018-05-29 | 广西万德药业有限公司 | A kind of preparation method of canrenone intermediate |
| CN115521352B (en) * | 2022-11-01 | 2024-05-14 | 湖南新合新生物医药有限公司 | Preparation method of methyl dehydropregnenolone |
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| WO2004078709A2 (en) * | 2003-02-28 | 2004-09-16 | The Government Of The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | METHOD FOR PREPARING 17 α-ACETOXY-11β-(4-N,N-DIMETHYLAMINOPHENYL)-19-NORPREGNA-4,9-DIENE-3,20-DIONE, INTERMEDIATES THEREOF, AND METHODS FOR THE PREPARATION OF SUCH INTERMEDIATES |
| CN101466723A (en) * | 2006-06-14 | 2009-06-24 | 吉瑞工厂 | Industrial process for the synthesis of 17a-acetoxy-11ss-[4-(n,n-dimethyl-amino)- phenyl]-19-norpregna-4,9-diene-3,20-dione and new intermediates of the process |
| CN102617692A (en) * | 2011-01-31 | 2012-08-01 | 北京紫竹药业有限公司 | Steroid compound, preparation method and use thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004078709A2 (en) * | 2003-02-28 | 2004-09-16 | The Government Of The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | METHOD FOR PREPARING 17 α-ACETOXY-11β-(4-N,N-DIMETHYLAMINOPHENYL)-19-NORPREGNA-4,9-DIENE-3,20-DIONE, INTERMEDIATES THEREOF, AND METHODS FOR THE PREPARATION OF SUCH INTERMEDIATES |
| CN101466723A (en) * | 2006-06-14 | 2009-06-24 | 吉瑞工厂 | Industrial process for the synthesis of 17a-acetoxy-11ss-[4-(n,n-dimethyl-amino)- phenyl]-19-norpregna-4,9-diene-3,20-dione and new intermediates of the process |
| CN102617692A (en) * | 2011-01-31 | 2012-08-01 | 北京紫竹药业有限公司 | Steroid compound, preparation method and use thereof |
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