CN107098868B - A kind of preparation method of paricalcitol intermediate - Google Patents
A kind of preparation method of paricalcitol intermediate Download PDFInfo
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- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/132—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group
- C07C29/136—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH
- C07C29/147—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH of carboxylic acids or derivatives thereof
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Abstract
The present invention relates to a kind of preparation methods of paricalcitol intermediate, the preparation method of especially a kind of intermediate (shown in formula (I)) for synthesizing paricalcitol (II), the method obtains chiral intermediate shown in formula (V) by the asymmetric aldol reaction of chipal compounds shown in formula (IV) and acetone, then by reduction, it is halogenated and reacted with triphenyl phosphorus shown in formula (I) for synthesizing the intermediate of paricalcitol.The advantages that this method has reaction condition mild, easy to operate, optical purity height and cheap synthesis cost is suitable for large-scale production.
Description
The application is that Chinese Patent Application No. is 201310046160.5, entitled " among a kind of paricalcitol
The preparation method of body ", the divisional application for the Chinese invention patent application that the applying date is on 2 5th, 2013.
Technical field
The present invention relates to a kind of preparation methods of paricalcitol intermediate.
Background technique
Paricalcitol (paricalcitol, II), trade name Zemplar is Abbott Laboratories from winconsin
Research Foundation secures permission and the synthesis of vitamin d analogues developed, be obtained in 1998 FDA approval for preventing and controlling
Treat the drug of adult secondary hyperparathyroidism (SHPT).
Formula (I) compound represented is to synthesize the important intermediate of paricalcitol.Synthetic route as follows is existing
The synthetic method of published formula (I) compound represented.
The synthetic route (Tetrahedron 1992,48,5151) of compound (I)
In said synthesis route, (S)-Roche methyl esters (shown in Formula X) is starting material, however, (S)-Roche methyl esters
It is expensive, and be not easy largely to buy, thus using existing synthetic method largely synthesize formula (I) compound represented there is also
It is many difficult and insufficient, it is necessary to developing low-cost and the method for being suitable for extensive synthesis formula (I) compound represented.
Summary of the invention
For paricalcitol intermediate shown in existing formula (I) synthesis technology there are the shortcomings that, the present invention provides
The variation route of paricalcitol intermediate shown in one synthesis formula (I), the route are with chiral auxiliary (III) cheap and easy to get
Starting material reacts to obtain shown in Formula V by chipal compounds shown in Formula IV with the asymmetric aldol condensation (Aldol) of acetone
Chiral intermediate, then by reduction, it is halogenated and reacted with triphenyl phosphorus shown in Formulas I for synthesizing paricalcitol
Intermediate.The advantages that this method has reaction condition mild, easy to operate, optical purity height and cheap synthesis cost is suitable for big
Large-scale production.
One aspect of the present invention provides formula (V) compound represented and preparation method thereof, and compound shown in formula (V) is to be used for
Paricalcitol intermediate shown in synthesis formula (I),
Wherein, R is substituted or non-substituted C1-10Alkyl or phenyl, preferably R are benzyl.
Formula (V) compound represented can be made according to following preparation method: chipal compounds and acetone shown in formula (IV)
Asymmetric aldol reaction obtain formula (V) compound represented,
Wherein, R is substituted or non-substituted C1-10Alkyl or phenyl.
In yet other embodiments, the R is benzyl.
Asymmetric aldol reaction is a kind of method for commonly preparing chiral alcohol, and for details, reference can be made to documents:
J.Am.Chem.Soc.1979,101,6120.
Chipal compounds shown in formula (IV) can be reacted to obtain by chiral auxiliary (III) with propionyl chloride or propionic acid,
Wherein, R is substituted or non-substituted C1-10Alkyl or phenyl, preferably phenyl.
Another aspect of the present invention provides a kind of preparation method of formula (I) compound represented,
It includes that the asymmetric aldol reaction of chipal compounds shown in formula (IV) and acetone obtains changing shown in formula (V)
The step of closing object,
Wherein, X is halogen, preferably chlorine, bromine, iodine, and R is substituted or non-substituted C1-10Alkyl or phenyl.
In a preferred embodiment, the X is iodine, and the R is benzyl.
In a preferred embodiment of the present invention, the preparation method of formula (I) compound represented still further comprises
In reducing agent under effect, formula (V) compound represented is reduced the step of obtaining formula (VI) compound represented, and described goes back
Former agent is sodium borohydride, lithium borohydride, potassium borohydride or lithium aluminium hydride reduction, preferably sodium borohydride,
Wherein defined in R formula (V) compound represented.
In another preferred embodiment of the present invention, the preparation method of formula (I) compound represented is also into one
Step includes that formula (V) compound represented obtains formula (IX) compound represented, then in reducing agent under effect, formula after hydrolysis
(IX) compound represented is reduced the step of obtaining formula (VI) compound represented, and the reducing agent is lithium aluminium hydride reduction, boron
Sodium hydride, lithium borohydride or potassium borohydride, preferably lithium aluminium hydride reduction,
Wherein defined in R formula (V) compound represented.
After obtained formula (VI) compound represented, further prepared shown in formula (I) by formula (VI) compound represented
Compound can be carried out by method known in the state of the art, in a preferred embodiment of the present invention, using Tetrahedron
The route provided in 1992,48,5151 carries out, specifically, being obtained shown in formula (VII) by what is reacted with to methylsufonyl chloride
Compound, formula (VIII) compound represented, chemical combination shown in formula (VIII) are obtained after formula (VII) compound represented is halogenated
Compound shown in formula (I) is obtained after the reaction of object triphenyl phosphorus,
In an especially preferred embodiment, X is iodine in compound shown in formula (I), is the chemical combination as shown in (Ia)
Object, the synthetic route that the present invention provides the compound as shown in (Ia) are as follows:
Specifically, this method includes the following steps:
1) chiral auxiliary compound shown in formula (IIIa) reacts to obtain the compound of formula (VIa) with propionyl chloride；
2) the asymmetric aldol reaction of compound (VIa) and acetone obtain chiral intermediate shown in formula (Va) (dr >
99:1)；
3) compound (Va) obtains chipal compounds shown in formula (VI) after sodium borohydride reduction；
4) what compound (VI) was reacted with to methylsufonyl chloride obtains formula (VII) compound represented；
5) compound (VII) obtains formula (VIIIa) compound represented after reacting with lithium iodide；
6) compound (VIIIa) obtains formula (Ia) compound represented after reacting with triphenyl phosphorus.
The invention also discloses the preparation methods of formula (VI) compound represented, can be by chirality shown in formula (V)
The sodium borohydride reduction of mesosome obtains,
Wherein, R is substituted or non-substituted C1-10Alkyl or phenyl, preferably benzyl.
Alternatively, chiral intermediate shown in formula (V) obtains formula (IX) compound represented, compound (IX) warp after hydrolysis
Formula (VI) compound represented is obtained after Lithium aluminum hydride reduction,
Wherein, R is substituted or non-substituted C1-10Alkyl or phenyl, preferably benzyl.
The preparation method of paricalcitol intermediate shown in formula (I) of the present invention has easy to operate, reaction item
The features such as part is mild, and optical purity is high, and combined coefficient is high, and synthesis cost is cheap, is suitble to industrialized production has significant society
Benefit and economic benefit.
Term used in the present invention has following meaning in addition to having opposite statement:
" alkyl " refers to the aliphatic hydrocarbon group of saturation, and straight chain and branched group including 1 to 10 carbon atom preferably include 1
To 6 carbon atoms.Non-limiting embodiment include but is not limited to methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group,
Tert-butyl, sec-butyl, n-pentyl, 1,1- dimethyl propyl, 1,2- dimethyl propyl, 2,2- dimethyl propyl, 1- ethyl propyl,
2- methyl butyl, 3- methyl butyl, n-hexyl, 1- Ethyl-2-Methyl propyl, 1,1,2- thmethylpropyl, 1,1- dimethyl butyrate
Base, 1,2- dimethylbutyl, 2,2- dimethylbutyl, 1,3- dimethylbutyl, 2- ethyl-butyl, 2- methyl amyl, 3- methyl
Amyl, 4- methyl amyl, 2,3- dimethylbutyl etc..Alkyl can be substituted or unsubstituted, when substituted, substituent group
It can be substituted on any workable tie point, preferably one or more following groups, independently selected from alkyl, alkene
Base, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, mercaptan, hydroxyl, nitro, cyano, naphthenic base, Heterocyclylalkyl, aryl,
Heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, oxo.
" aryl " refers to 6 to 10 yuan of full carbon monocycles or fused polycycle (rings of namely shared adjacent carbon atoms pair) group, tool
There are polycyclic (i.e. its ring for the having phase adjacency pair carbon atom) group of the pi-electron system of conjugation, such as phenyl and naphthalene.Aryl can be with
Be it is substituted or unsubstituted, when substituted, substituent group is preferably one or more following groups, independently selected from alkyl,
Alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, mercaptan, hydroxyl, nitro, cyano, naphthenic base, Heterocyclylalkyl, virtue
Base, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group.
Abbreviations table:
| Abbreviation | Full name |
| Bn | Benzyl |
| Ph | Phenyl |
| Ts | To Methyl benzenesulfonyl base |
Specific embodiment
The present invention is explained in detail below with reference to specific example so that this hair is more fully understood in those skilled in the art
Bright, specific example is only used to illustrate the technical scheme of the present invention, and does not limit the present invention in any way.
Embodiment 1: prepare compound Va
Compound IIIa (177g is purchased from Jiangsu Sen Xuan medication chemistry company) is dissolved in 3L methylene chloride, cools to 0 DEG C,
Triethylamine (162g) and 4-dimethylaminopyridine (12g) is added, propionyl chloride is added dropwise, and (101g reaches auspicious fine chemicals purchased from Shanghai
Co., Ltd), 0 DEG C is reacted 1 hour, and water quenching reaction is added, and methylene chloride phase is collected in liquid separation, and anhydrous sodium sulfate dries, filters,
It is concentrated to give 220g compound IVa, is directly used in next step.
Compound IVa (220g) is dissolved in 2.5L methylene chloride, 0 DEG C of dropwise addition titanium tetrachloride (186g), stirs 15 points
Diisopropyl ethyl amine (133.4g) is added dropwise after clock, is cooled to -20 DEG C, titanium tetrachloride (186g) and acetone is successively added dropwise
(109g) reacts 2 hours.Add water quenching reaction, methylene chloride phase is collected in liquid separation, and anhydrous sodium sulfate is dried, filtered, is concentrated to give
250g solid product Va, two step yields 90%.
Va:1HMNR(400MHz,CDCl3): 7.23-7.34 (m, 5H), 4.72 (m, 1H), 4.12-4.19 (m, 2H),
3.93-3.96 (dd, 1H, J=6.4,14.4Hz), 3.39 (s, 1H), 3.32-3.36 (dd, 1H, J=3.6,13.2Hz),
2.71-2.76 (dd, 1H, J=9.2,14.0Hz), 1.34 (s, 3H), 1.24 (s, 3H), 1.22-1.24 (d, 3H, J=
7.2Hz)。
Embodiment 2: prepare compound VI
Compound Va (200g) is dissolved in 3.6L tetrahydrofuran and 1L water, is added sodium borohydride (148g), it is anti-at 20 DEG C
It answers 24 hours, is extracted with ethyl acetate, merge organic phase, anhydrous sodium sulfate is dry.Concentration, crude product are dense through short silica gel column purification
Contract to obtain 75g compound VI, yield 92%.
VI:1HMNR(400MHz,CDCl3):3.68-3.76(m,2H),1.80-1.84(m,1H),1.27(s,3H),1.19
(s,3H),0.87(d,3H)。
Embodiment 3: prepare compound VI
Compound Va (120g) is dissolved in 2L tetrahydrofuran, and 500ml water is added, and system cools to 0 DEG C, and 30% peroxide is added
Change hydrogen (313ml) and Lithium hydroxide monohydrate (35g), stirring, 0 DEG C is reacted 6 hours, and methyl tertiary butyl ether(MTBE) extracts organic phase, water phase
With dilute hydrochloric acid tune pH value=2, extraction is proposed with ethyl acetate, extract liquor is dried, filtered with anhydrous sodium sulfate, is concentrated to give 50g chemical combination
Object IX yield: 91%.
IX:1HMNR(400MHz,CDCl3): 2.54-2.59 (m, 1H), 1.32 (s, 3H), 1.25-1.27 (m, 6H).
Lithium aluminium hydride reduction (36g) is dissolved in 3L anhydrous tetrahydro furan, cools to -20 DEG C, the four of compound IX (50g) are added
Hydrogen tetrahydrofuran solution (100ml) after 1 hour, is warming up to 20 DEG C naturally, reacts 15 hours at 20 DEG C.Excessive hydrogenation is quenched with water
Aluminium lithium is added dropwise 20%HCl and adjusts pH=2, is extracted with ethyl acetate, and combined ethyl acetate phase, anhydrous sodium sulfate dries, filters,
Concentration, obtains 39g compound VI, yield: 88%.
VI:1HMNR(400MHz,CDCl3):3.68-3.76(m,2H),1.80-1.84(m,1H),1.27(s,3H),1.19
(s,3H),0.87(d,3H)。
Embodiment 4: prepare compound Ia
Compound VI (37g) is dissolved in 350mL pyridine, cools to -15 DEG C, be added p-methyl benzene sulfonic chloride (65.5g,
0.345mol), it reacted 12 hours for -15 DEG C.Reaction is quenched with water, methyl tertiary butyl ether(MTBE) extraction merges methyl tertiary butyl ether(MTBE) phase,
15% hydrochloric acid is washed till acidity, and anhydrous sodium sulfate is dry, and concentration obtains 80g compound VII, 99.5%ee, yield: 93%.
VII:1HMNR:7.79(d,2H),7.35(d,2H),4.24(m,1H),3.93(m,1H),2.45(s,3H),1.85
(m,1H),1.19(s,3H),1.12(s,3H),0.96(d,3H)。
Compound VII (57g) is dissolved in 400mL anhydrous tetrahydro furan, is added anhydrous lithium iodide (35g), is warming up to 65
DEG C, it reacts 1 hour, reaction is quenched with water, is extracted with ethyl acetate, merge organic phase, anhydrous sodium sulfate dries, filters, and is concentrated
Obtain 45g compound VIIIa, yield: 93%.
VIIIa:1H-NMR(400MHz,CDCl3):3.68(dd,1H),2.92(dd,1H),1.86(m,1H),1.26(s,
3H),1.17(s,3H),1.11(d,3H)。
Compound VIIIa (41g) is dissolved in 1L acetonitrile, is added triphenylphosphine (330g), nitrogen protection is heated to reflux down
Reaction 48 hours.It is concentrated under reduced pressure, 600mL anhydrous ether is added, stir, filtering obtains 75g solid product Ia, yield after drying:
85%.
Ia:1HNMR(400MHz,CDCl3):7.97-7.69(m,15H),4.47(m,1H),2.88-2.78(m,1H),
2.11(m,1H),1.37(s,3H),1.28(s,3H),0.53(d,3H)。
Due to describing the present invention according to its specific embodiment, certain modifications and equivalent variations are for being proficient in this neck
The technical staff in domain is obvious and is included within the scope of the invention.
Claims (5)
1. a kind of method for preparing compound shown in formula (VI), which is characterized in that the method includes the chiralitys as shown in formula (IV)
The asymmetric aldol reaction of compound and acetone obtains the step of compound shown in formula (V),
Further include the steps that compound shown in formula (V) is reduced to obtain compound shown in formula (VI),
The reducing agent of the reduction reaction is selected from sodium borohydride, lithium borohydride, potassium borohydride or lithium aluminium hydride reduction；
Or compound shown in formula (V) obtains compound shown in formula (IX) after hydrolysis, and then under reducing agent effect, formula (IX) institute
Show that compound is reduced the step of obtaining compound shown in formula (VI),
The reducing agent is selected from lithium aluminium hydride reduction, sodium borohydride, lithium borohydride or potassium borohydride；Wherein R is benzyl.
2. the method as described in claim 1, which is characterized in that compound shown in formula (V) is reduced to obtain formula (VI) shownization
The reducing agent of the step of closing object, the reduction reaction is selected from sodium borohydride.
3. the method as described in claim 1, which is characterized in that compound shown in formula (V) is obtained after hydrolysis shown in formula (IX)
Compound, then under reducing agent effect, compound shown in formula (IX) is reduced the step of obtaining compound shown in formula (VI), institute
It states reducing agent and is selected from lithium aluminium hydride reduction.
4. the method as described in claim 1, which is characterized in that the method also includes compound and propionyl shown in formula (III)
Chlorine or propionic acid react the step of obtaining chiral intermediate (IV),
Wherein, it is defined in R such as claim 1.
5. method as claimed in claim 4, which is characterized in that the method includes compound shown in formula (VI) and to methyl sulphur
Acyl chloride reaction obtains compound shown in formula (VII), and chemical combination shown in formula (VIII) is obtained after compound shown in formula (VII) is halogenated
Object, compound shown in formula (VIII) obtain compound shown in formula (I) after reacting with triphenyl phosphorus,
Wherein defined in R such as claim 1；
X is selected from chlorine, bromine or iodine.
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| CN102131773A (en) * | 2008-07-22 | 2011-07-20 | Azad药物成分股份公司 | Process for producing paricalcitol |
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| US5691381A (en) * | 1995-04-18 | 1997-11-25 | The Dupont Merck Pharmaceutical Company | Hydroxamic and carbocyclic acids as metalloprotease inhibitors |
| WO2007011951A2 (en) * | 2005-07-18 | 2007-01-25 | Teva Pharmaceutical Industries Ltd. | Purification of paricalcitol |
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| CN102131773A (en) * | 2008-07-22 | 2011-07-20 | Azad药物成分股份公司 | Process for producing paricalcitol |
Non-Patent Citations (2)
| Title |
|---|
| Preparation and biological activity of 24-epi-26,26,26,27,27,27-hexafluoro-1α,25-Dihydroxyvitamin D2;Katsuhiko Iseki et al.;《Chem. Pharm. Bull.》;19951130;第43卷(第11期);第1897-1901页 |
| Preparation of Chiral Oxazolidin-2-ones and Vicinal Amino Alcohols;James M. Takacs, et al;《J. Org. Chem.》;19980319;第63卷(第8期);第2742-2748页 |
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Effective date of registration: 20210119 Address after: 222047 No. 7 Kunlun Shan Road, Lianyungang economic and Technological Development Zone, Jiangsu Patentee after: JIANGSU HENGRUI MEDICINE Co.,Ltd. Address before: 222069 No.22, Jinqiao Road, Dapu Industrial Zone, Lianyungang Economic and Technological Development Zone, Jiangsu Province Patentee before: Jiangsu Shengdi Pharmaceutical Co.,Ltd. |