CN102757459B - For the synthesis of the intermediate and preparation method thereof of prostanoid medicine - Google Patents

Abstract

The invention relates to an intermediate for synthesizing prostaglandin drugs and a preparation method thereof. The present invention relates to a kind of intermediate (structural formula I) that is used for synthesizing prostaglandin medicine, and the preparation method of this intermediate, and this intermediate can be used for synthesizing prostaglandin medicine, such as bimatoprost (bimatoprost), travolta prostaglandin, latanoprost, etc. This intermediate can be prepared by Wittig reaction of hemiacetal and its derivatization.

Description

Intermediate for synthesizing prostaglandin drugs and its preparation method

technical field

The invention relates to an intermediate for synthesizing prostaglandin drugs and a preparation method thereof.

Background technique

Prostaglandins are a class of fatty acid derivatives with 20 carbon atoms. Prostaglandins regulate various physiological functions of the human body at the level of hormone concentration, and have regulatory effects on blood pressure, smooth muscle contraction, gastric juice secretion and platelet aggregation. Among them, prostaglandin F-type derivatives are clinically used to treat open-angle glaucoma and ocular hypertension, so as to reduce the intraocular high pressure of patients.

Prostaglandins are trace components widely present in various tissues of humans and animals, and the content is extremely low. In addition, prostaglandin F-type derivatives have excellent therapeutic effects on glaucoma and intraocular hypertension and other diseases. Natural sources of prostaglandins cannot meet the requirements. Clinical drug needs. For this reason, scientists have been working on the total synthesis of prostaglandin derivatives and have achieved fruitful results so far.例如，EP1886992，EP1721894，EP2143712，US2003/187071，US2005/209337，US2008/033176，US2009/259066，US2010/056807，WO90/02553，WO94/06433，WO97/22602，WO200I/010873，WO2002/096898，WO2007/ 041273 and other patent documents describe in detail the use of various prostaglandin F derivatives and their preparation methods.

Contents of the invention

The present invention relates to an intermediate used for synthesizing prostaglandin drugs and a preparation method thereof. Through the intermediate, the synthesis steps of prostaglandin drugs can be shortened, thereby improving the synthesis efficiency of prostaglandin drugs such as bimatoprost, travoprost, and latanoprost.

The object of the present invention is to provide an intermediate for the synthesis of prostaglandin drugs as shown in formula I.

Wherein, each of R ¹ , R ² and R ³ is hydrogen or a hydroxyl protecting group, preferably, each of R ¹ , R ² and R ³ is independently selected from hydrogen, THP, -C(O)R ⁶ or -SiR ⁷ R ⁸ R ⁹ , wherein R ⁶ , R ⁷ , R ⁸ and R ⁹ are each a C _1-10 linear or branched alkyl group, a C _3-8 cyclic alkyl group, or a C _6-10 substituted or Non-substituted aryl; R ⁴ and R ⁵ are each hydrogen, amino, methoxy, C _1-10 straight or branched chain alkyl, C _3-8 cyclic alkyl, or C _6-10 substituted or unsubstituted aryl, R ⁴ and R ⁵ can be independently selected from hydrogen, methyl, ethyl, propyl, butyl, phenyl, amino or methoxy; or R ⁴ , R ⁵ and nitrogen The atoms together form a 5-8 membered heterocyclic ring, preferably a five-membered ring and a six-membered ring, more preferably a five-membered ring. R ⁴ and R ⁵ cannot be amino or methoxy at the same time.

In a preferred embodiment of the present invention, in formula I, R ¹ is THP; R ² is THP; R ³ is TIPS; R ⁴ is ethyl; R ⁵ is hydrogen; or, R ¹ is THP; R2 is THP; ^R3 is TIPS ^; R4 is ^{hydrogen ;} R5 is ethyl.

The object of the present invention is to provide a kind of preparation method of synthesizing the intermediate shown in formula Ia,

It is characterized in that, the hemiacetal of structural formula II and the amide derivative of structural formula III are prepared by Wittig reaction under alkaline conditions as the intermediate shown in formula Ia:

Wherein X in the formula III is a halogen, X can be selected from Cl, Br or I, preferably Br; Ar is a C _6-10 unsubstituted or substituted aryl group, preferably a phenyl group.

According to requirements, the intermediate Ia can be prepared as the intermediate shown in formula I by protecting the hydroxyl group, deprotecting the hydroxyl group, or changing the protecting group of the hydroxyl group.

In a preferred embodiment of the present invention, hemiacetal (structural formula II, R ² =H, R ³ =TIPS) and amide derivatives (structural formula III, R ⁴ =Et, R ⁵ =H, Ar is benzene group, X is bromine; or, R ⁴ =H, R ⁵ =Et, Ar is phenyl, X is bromine) Wittig reaction to prepare intermediate Ia (structural formula Ia, R ² =H, R ³ =TIPS, R ⁴ = Et, R ⁵ = H; or, R ² = H, R ³ = TIPS, R ⁴ = H, R ⁵ = Et), the preferred reaction conditions are: potassium tert-butoxide as base, tetrahydrofuran as As a solvent, 3A molecular sieve is used as an activator, and the reaction is carried out at a temperature of 20°C.

The present invention further provides a preparation method for bimatoprost,

Wherein R ¹ and R ² are hydroxyl protecting groups, R is C _1-8 alkyl, it is characterized in that, the method comprises the steps:

1) Intermediate I' is oxidized to obtain Intermediate VI,

2) intermediate VI reacts with phosphate ester IX to obtain intermediate VII,

3) intermediate VII is asymmetrically reduced to obtain intermediate VIII,

4) The intermediate VIII is deprotected to obtain bimatoprost.

The hydroxy protecting group of the present invention is a suitable group known in the art for protecting hydroxy, see the hydroxy protecting group in the literature ("Protective Groups in Organic Synthesis", 5 ^Th . Ed. TW Greene & P. GM Wuts). The hydroxyl protecting group can be (C _1-8 alkyl or aryl ₎ silyl, for example: triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyl Diphenylsilyl, etc.; can be C _1-8 alkyl or substituted alkyl, for example: methyl, tert-butyl, allyl, benzyl, methoxymethyl, ethoxyethyl, 2- Tetrahydropyranyl (THP), etc.; can be (C _1-8 alkyl or aryl) acyl, for example: formyl, acetyl, benzoyl, etc.; can be (C _1-6 alkyl or C _{6 -10} aryl) sulfonyl; also (C _1-6 alkoxy or C _6-10 aryloxy) carbonyl.

The substituted aryl group described in the present invention means that the aromatic ring is substituted by one or more residues selected from, for example, halogen, hydroxyl, cyano, nitro, amino, trifluoromethyl, C _1-8 alkane Base, C _1-8 alkoxy, C _2-8 alkanoyloxy, C _6-10 aryl, allyl, etc.

Abbreviation list:

abbreviation full name DHP 3,4-Dihydro(2H)pyran DIBAL-H Diisobutylaluminum hydride PPTS Pyridinium p-toluenesulfonate TBAF Tetrabutylammonium fluoride TBS tert-butyldimethylsilyl TBSOT tert-Butyldimethylsilyl triflate THP 2-tetrahydropyranyl TIPS Triisopropylsilyl

detailed description

The present invention will be explained in detail below in conjunction with specific examples, so that those skilled in the art can understand this patent more comprehensively. The specific examples are only used to illustrate the technical solutions of the present invention, and do not limit the present invention in any way.

The following table is the structural formula of the compound I involved in the examples

Embodiment 1: Preparation of compound Iaa

Compound Iaa is synthesized as follows:

step 1):

Under a nitrogen atmosphere, triethylamine (2.5 mL) was added to a solution of compound IV (1.0 g, purchased from Shanghai Julong Pharmaceutical Research and Development Co., Ltd.) in dichloromethane (50 mL). The reaction system was cooled to -78°C, and a solution of triisopropylsilyl triflate (2.9 g) in dichloromethane (10 mL) was added. After two hours, the cooling bath was removed, and the reaction system was stirred at 20°C for 30 minutes. The reaction system was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain compound Vaa.

¹ HNMR (400MHz, CDCl ₃ ): δ4.94-4.89(m, 1H), 4.18-4.11(m, 1H), 3.84(dd, J=9.6, 5.2Hz, 1H), 3.69(dd, J=10.4 , 7.2Hz, 1H), 2.79(dd, J=18, 10.8Hz, 1H), 2.63-2.60(m, 1H), 2.53-2.45(m, 2H), 2.70(s, 1H), 2.05-1.97( m, 2H), 1.14-1.01 (m, 21H)

Step 2):

A solution of Vaa (1.675 g) in toluene (30 mL) was cooled to -78°C under nitrogen atmosphere. DIBAL-H (1.0M n-hexane solution, 15.3 mL) was added to the reaction system, and the mixture was stirred at -78°C for 2 hours. The reaction was quenched by adding a saturated sodium potassium tartrate aqueous solution (5 mL), and the system gradually returned to 20° C., and continued stirring until the system was clear. The reaction system was extracted with ether, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain compound IIaa.

¹ HNMR (400MHz, CDCl ₃ ): δ5.68-5.50(m, 1H), 4.67-4.63(m, 1H), 4.16-4.07(m, 1H), 3.85-3.74(m, 1H), 3.65-3.58 (m, 1H), 2.85-2.65(m, 1H), 2.50-1.60(m, 6H), 1.14-1.01(m, 21H)

Step 3):

At 20°C, potassium tert-butoxide (1M tetrahydrofuran solution, 15.1 mL) was added to compound IIIaa (3.56 g, prepared according to reference J. Med. Chem. 1979, 22, 1340), activated 3A molecular sieve powder (2.5 g) and tetrahydrofuran (15 mL) in suspension. A solution of Ilaa (500 mg) in tetrahydrofuran (2 mL) was then added to the orange ylides formed. The reaction system was stirred at 20° C. for 30 minutes, and water was added to quench the reaction. The system was extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to obtain compound Iaa.

¹ H-NMR (400MHz, CDCl ₃ ) δ5.81(br, 1H), 5.41～5.36(m, 2H), 4.18(s, 2H), 3.90～3.86(m, 1H), 3.62～3.58(m, 1H), 3.29～3.23(m, 2H), 3.15～3.11(m, 2H), 2.39～2.37(m, 1H), 2.21～2.12(m, 4H), 2.06～2.03(m, 1H), 1.90～ 1.87(m, 3H), 1.73～1.65(m, 3H), 1.13～1.00(m, 24H)

Embodiment 2: preparation compound Iab

Using a method similar to the synthesis of compound Iaa, compound Iab was synthesized.

¹ H-NMR (400MHz, CDCl ₃ ) δ5.85(s, 1H), 5.41～5.34(m, 2H), 4.16～4.11(m, 2H), 3.77～3.73(m, 1H), 3.49～3.45( m, 1H), 3.29～3.11(m, 4H), 2.39～2.33(m, 1H), 2.19～2.00(m, 5H), 1.89～1.85(m, 3H), 1.73～1.58(m, 3H), 1.13～1.09(m, 3H), 0.89～0.85(m, 9H), 0.07～0.02(m, 6H)

Embodiment 3: preparation compound Iac

Compound lac was synthesized using a method similar to the synthesis of compound Iaa.

¹ H-NMR (400MHz, CDCl ₃ ) δ5.98～5.96(m, 1H), 5.41～5.34(m, 2H), 4.14～4.10(m, 2H), 3.76～3.72(m, 1H), 3.49～ 3.45(m, 1H), 3.34～3.28(m, 2H), 3.22～3.17(m, 2H), 2.40～2.32(m, 1H), 2.18～2.10(m, 4H), 2.05～1.99(m, 1H) ), 1.85～1.83(br, 3H), 1.71～1.58(m, 3H), 1.48～1.40(m, 2H), 1.35～1.28(m, 2H), 0.90～0.85(m, 3H), 0.84～0.83 (m, 9H), 0.05～0.01(m, 6H)

Embodiment 4: preparation compound Iad

Compound Iad was synthesized using a method similar to the synthesis of compound Iaa.

¹ H-NMR (400MHz, CDCl ₃ ) δ5.91～5.77(m, 2H), 5.43～5.36(m, 2H), 4.18～4.13(m, 2H), 3.78～3.75(m, 1H), 3.50～ 3.46(m, 1H), 3.09(br, 2H), 2.43～2.35(m, 1H), 2.25～2.03(m, 5H), 1.88～1.75(m, 3H), 1.75～1.60(m, 3H), 0.87(s, 9H), 0.06～0.03(m, 6H)

Embodiment 5: preparation compound Iae

Compound lae was synthesized using a method similar to the synthesis of compound laa.

¹ H-NMR (400MHz, CDCl ₃ ) δ8.12～8.00(m, 1H), 7.56～7.54(m, 2H), 7.32～7.28(m, 2H), 7.11～7.08(m, 1H), 5.80( s, 1H), 5.45～5.37(m, 2H), 4.19～4.18(br, 2H), 3.78～3.46(m, 2H), 3.20(br, 1H), 2.45～2.09(m, 7H), 1.9～ 1.60(m, 5H), 0.89(s, 9H), 0.09～0.02(m, 6H)

Embodiment 6: preparation compound Iaf

Using a method similar to the synthesis of compound Iaa, compound Iaf was synthesized.

¹ H-NMR (400MHz, CDCl ₃ ) δ5.42～5.38(m, 2H), 4.18(s, 2H), 3.90～3.87(m, 1H), 3.63～3.59(m, 1H), 3.18(s, 1H), 3.08～3.06(m, 1H), 2.99(s, 3H), 2.93(s, 3H), 2.42～2.30(m, 4H), 2.24～2.03(m, 1H), 1.92～1.87(m, 4H), 1.71～1.66(m, 3H), 1.11～0.99(m, 21H)

Embodiment 7: preparation compound Iag

Compound Iag was synthesized using a method similar to the synthesis of compound Iaa.

¹ H-NMR (400MHz, CDCl ₃ ) δ5.42～5.39(m, 2H), 4.18～4.16(br, 2H), 3.88～3.87(m, 1H), 3.62～3.59(m, 1H), 3.28～ 3.24(m, 3H), 3.19～3.15(m, 3H), 2.45～1.50(m, 16H), 1.1～1.01(m, 21H), 0.92～0.85(m, 6H)

Example 8: Preparation of Compound Iah

Compound Iah was synthesized using a method similar to the synthesis of compound Iaa.

¹ H-NMR (400MHz, CDCl ₃ ) δ6.32～5.10(m, 3H), 4.20～3.42(m, 8H), 2.25～2.09(m, 5H), 1.89～1.61(m, 7H), 0.90～ 0.88(m, 9H), 0.10～0.01(m, 6H)

Embodiment 9: Preparation of compound Iai

Compound lai was synthesized using a method similar to the synthesis of compound laa.

1H-NMR (400MHz, CDCl ₃ ) δ5.43～5.40(m, 2H), 4.18～4.11(m, 2H), 3.79～3.75(m, 1H), 3.67(s, 3H), 3.51～3.47(m , 1H), 3.17(s, 3H), 2.95(s, 1H), 2.88(s, 1H), 2.46～2.42(m, 3H), 2.19～2.08(m, 3H), 1.90～1.86(m, 3H ), 1.71～1.61(m, 3H), 0.85(s, 9H), 0.06～0.03(m, 6H)

Example 10: Preparation of Compound Iaj

Compound Iaj was synthesized using a method similar to the synthesis of compound Iaa.

¹ H-NMR (400MHz, CDCl ₃ ) δ5.42～5.38(m, 2H), 4.18～4.16(m, 2H), 3.90～3.75(m, 2H), 3.30～3.23(m, 2H), 3.10～ 3.05(m, 4H), 2.34～2.30(m, 2H), 2.20～2.12(m, 2H), 2.05～1.52(m, 13H), 1.05～0.92(m, 18H)

Embodiment 11: preparation compound Iak

Add compound IIIaa (1.05g) and redistilled tetrahydrofuran solvent (30mL) to a dry 100mL single-necked bottle, stir well at room temperature and add potassium tert-butoxide (1.0M tetrahydrofuran solution) (5.37mL), and the reaction solution instantly becomes Deep orange. A solution of compound Hak (200 mg) in THF was then added slowly and the reaction was stirred overnight at room temperature. It was detected that most of the raw materials disappeared, and then quenched by adding 20 mL of water, extracted several times with ether, washed the organic phase with saline several times, and dried over anhydrous sodium sulfate. The crude product was separated by silica gel column chromatography (dichloromethane:methanol=15:1) to obtain Iak.

¹ H-NMR (400MHz, CDCl ₃ ) δ5.94(s, 1H), 5.45～5.33(m, 2H), 4.69～4.66(m, 1H), 4.21～4.08(m, 2H), 3.86～3.62( m, 2H), 3.51～3.35(m, 2H), 3.28～3.21(m, 2H), 2.41～2.37(m, 2H), 2.19～1.48(m, 17H), 1.12～1.08(m, 3H), 0.89(s, 9H), 0.06～0.05(m, 6H)

Embodiment 12: Preparation of compound Ial

Using a method similar to the synthesis of compound Iak, compound Ial was synthesized.

¹ H-NMR (400MHz, CDCl ₃ ) δ5.85(s, 1H), 5.39～5.30(m, 2H), 4.19～4.05(m, 2H), 3.75～3.60(m, 2H), 3.28～3.21( m, 2H), 2.58～2.49(m, 2H), 2.09～1.45(m, 11H), 1.10～1.05(m, 3H), 0.91～0.88(m, 18H), 0.06～0.05(m, 12H)

Embodiment 13: preparation compound Iam

Compound lam was synthesized using a method similar to the synthesis of compound lak.

¹ H-NMR (400MHz, CDCl ₃ ) δ5.82(s, 1H), 5.52～5.40(m, 2H), 4.25～4.13(m, 2H), 3.70～3.59(m, 2H), 3.21～3.18( m, 2H), 2.60～2.35(m, 2H), 2.30(s, 3H), 2.11～1.52(m, 11H), 1.11～1.08(m, 3H), 0.88(s, 9H), 0.06～0.05( m, 6H)

Example 14: Preparation of Compound Ian

Using a method similar to the synthesis of compound Iaa, compound Ian was synthesized.

¹ H-NMR (400MHz, CDCl ₃ ) δ5.47～5.36(m, 3H), 4.20～4.19(m, 2H), 4.10～4.04(m, 1H), 3.91～3.87(m, 1H), 3.62～ 3.58(m, 1H), 2.93～2.88(br, 2H), 2.44～2.36(m, 1H), 2.21～2.02(m, 5H), 1.95～1.84(m, 3H), 1.77～1.64(m, 3H ), 1.24～1.19(m, 6H), 1.14～0.94(m, 21H).

Embodiment 15: preparation compound Iao

Compound Iao was synthesized using a method similar to the synthesis of compound Iaa.

¹ H-NMR (400MHz, CDCl ₃ ) δ6.16(s, 1H), 5.42～5.32(m, 2H), 4.18(s, 2H), 3.89～3.86(m, 1H), 3.61～3.57(m, 1H), 3.24～3.19(br, 2H), 2.68～2.64(m, 1H), 2.45～2.33(m, 1H), 2.17～1.97(m, 5H), 1.92～1.82(m, 3H), 1.73～ 1.61(m, 3H), 1.17～0.98(m, 21H), 0.73～0.70(m, 2H), 0.48～0.46(m, 2H).

Embodiment 16: preparation compound Iap

Compound lap was synthesized using a method similar to the synthesis of compound laa.

¹ H-NMR (400MHz, CDCl ₃ ) δ5.57～5.37(m, 3H), 4.22～4.17(m, 3H), 3.91～3.87(m, 1H), 3.62～3.58(m, 1H), 2.40～ 2.36(m, 2H), 2.21～1.89(m, 10H), 1.75～1.56(m, 7H), 1.39～1.31(m, 3H), 1.13～0.99(m, 21H).

Embodiment 17: preparation compound Ib

DHP (10 mL) and PPTS (20 mg) were added to a solution of Iaa in dichloroethane (20 mL), and the reaction system was stirred at 20°C for 24 hours and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with saturated Sodium bicarbonate aqueous solution and saturated brine for washing. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by column chromatography to obtain compound Ib.

¹ HNMR (400MHz, CDCl ₃ ): 5.60-5.32(m, 3H), 4.70-4.57(m, 2H), 4.20-3.20(m, 6H), 3.50-3.40(m, 2H), 3.31-3.21(m , 2H), 2.40-2.01(m, 6H), 2.00-1.40(m, 18H), 1.20-1.01(m, 24H)

Example 18: Preparation of Compound Ic

TBAF (4.93mL) was added to a solution of compound Ib (300mg) in dichloromethane, the reaction system was stirred at 20°C for 24 hours and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate and Wash with saturated saline. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by column chromatography to obtain compound Ic.

¹ H-NMR (400MHz, CDCl ₃ ) δ5.40～5.36(m, 3H), 4.73～4.59(m, 2H), 4.15～3.46(m, 8H), 3.30～3.23(m, 2H), 3.00～ 2.85(s, 1H), 2.32～1.50(m, 24H), 1.14～1.10(m, 3H)

Embodiment 19: Preparation of Compound Id

Triethylamine (35.55 mg) and acetyl chloride (20.79 mg) were added to a dichloromethane solution of Compound Ic (80 mg) at 0°C, and stirred at 0°C for 2 hours. After the reaction system was quenched, it was extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to obtain compound Id.

¹ H-NMR (400MHz, CDCl ₃ ) δ5.68～5.34(m, 3H), 4.72～4.59(m, 2H), 4.21～3.81(m, 6H), 3.49～3.47(m, 2H), 3.31～ 3.24(m, 2H), 2.39～2.05(m, 9H), 1.95～1.45(m, 18H), 1.18～1.15(m, 3H)

Example 20: Preparation of Compound Ie

Compound Id (86 mg) was dissolved in 10 ml of methanol, p-toluenesulfonic acid hydrate (133.9 mg) was added, and the resulting mixture was heated to 40°C and then stirred at this temperature for 1 hour. The reacted mixture was evaporated to dryness, diluted with ethyl acetate, and washed successively with water and saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated, and the residue was purified by column chromatography to obtain compound Ie.

¹ H-NMR (400MHz, CDCl ₃ ) δ5.68(br, 1H), 5.42～5.39(m, 2H), 4.30～4.11(m, 3H), 4.03～3.93(m, 1H), 3.31～3.26( m, 4H), 2.47～2.39(m, 1H), 2.23～2.02(m, 8H), 1.97～1.66(m, 5H), 1.54～1.49(m, 1H), 1.16～1.13(m, 3H)

Example 21: Preparation of Compound If

Compound Ie (30mg) was dissolved in dichloromethane (10mL), the resulting solution was cooled to 0°C, triethylamine (18.18mg) and acetic anhydride (91.88mg) were added, and the mixture was stirred at 20°C for 18 hours. After the reaction system was quenched, it was extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to obtain compound If.

¹ H-NMR (400MHz, CDCl ₃ ) δ5.66～5.58(m, 2H), 5.38～5.30(m, 2H), 5.10～4.97(m, 2H), 4.28～4.15(m, 2H), 3.27～ 3.22(m, 2H), 2.36～1.98(m, 16H), 1.80～1.64(m, 4H), 1.13～1.08(m, 3H)

Example 22: Preparation of Compound Ig

Triethylamine (50.5 mg) and TBSOTf (198 mg) were added to a dichloromethane solution of compound Iab (100 mg) at 0°C, and the reaction solution was stirred at 0°C for 2 hours. After the reaction system was quenched, it was extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to obtain compound Ig.

¹ H-NMR (400MHz, CDCl ₃ ) δ5.43～5.31(m, 3H), 4.09～4.02(m, 2H), 3.68～3.55(m, 2H), 3.31～3.24(m, 2H), 2.17～ 2.03(m, 6H), 1.76～1.54(m, 6H), 1.14～1.10(m, 3H), 0.88～0.84(m, 27H), 0.04～0.00(m, 18H)

Example 23: Preparation of Compound Ih

Compound Ig (50 mg) was dissolved in methanol (5 mL), the resulting solution was cooled to 0°C, p-toluenesulfonic acid hydrate (7.6 mg) was added, and the resulting mixture was stirred at 0°C for 1 hour. The reacted mixture was evaporated to dryness, diluted with ethyl acetate, and washed successively with water and saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated, and the residue was purified by column chromatography to obtain compound Ih.

¹ H-NMR (400MHz, CDCl ₃ ) δ5.56～5.36(m, 3H), 4.12～3.98(m, 2H), 3.77～3.67(m, 2H), 3.30～3.25(m, 2H), 2.63( s, 1H), 2.21～1.91(m, 6H), 1.72～1..51(m, 6H), 1.14～1.06(m, 3H), 0.86～0.82(m, 18H), 0.09～0.05(m, 12H)

Example 24: Preparation of Compound Ii

DHP (70 mg) and PPTS (2 mg) were added to a solution of compound Ih (86 mg) in 1,2-dichloroethane (5 mL), and the reaction solution was stirred at 20° C. for 18 hours. After the reaction system was quenched, it was extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to obtain compound Ii.

¹ H-NMR (400MHz, CDCl ₃ ) δ5.51～5.34(m, 3H), 4.60～4.58(m, 1H), 4.14～4.01(m, 2H), 3.88～3.78(m, 2H), 3.54～ 3.50(m, 2H), 3.43～3.27(m, 2H), 2.24～2.07(m, 6H), 1.93～1.53(m, 12H), 1.17～1.13(m, 3H), 0.89(m, 18H), 0.09～0.06(m,12H)

Example 25: Preparation of Compound Ij

TBAF (1.34 mL) was added to a solution of compound Ii (80 mg) in dichloromethane, and the reaction solution was stirred at 20° C. for 18 hours. After the reaction system was quenched, it was extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to obtain compound Ij.

¹ H-NMR (400MHz, CDCl ₃ ) δ5.82～5.13(m, 3H), 4.61～4.51(m, 3H), 4.20～4.19(br, 2H), 3.91～3.80(m, 2H), 3.65～ 3.49(m, 2H), 3.32～3.24(m, 2H), 2.42～2.31(m, 2H), 2.25～2.14(m, 3H), 2.10～1.91(m, 5H), 1.75～1.51(m, 8H) ), 1.22～1.12(m, 3H)

Example 26: Preparation of bimatoprost

The synthesis process of bimatoprost is as follows:

step 1):

Under a nitrogen atmosphere, a solution of oxalyl chloride (0.28 mL) in dichloromethane (20 mL) was cooled to -78°C. Dimethylsulfoxide (0.47 mL) was added to the reaction system, and the mixture was stirred at -78°C for 10 minutes. A solution of compound Ic (150 mg) in dichloromethane (3 mL) was added to the reaction system. After half an hour, triethylamine (2.8 mL) was added, and the reaction system gradually returned to room temperature. The reaction system was washed with saturated aqueous sodium dihydrogen phosphate (20 mL), saturated brine (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain product VIa. Compound VIa was directly used in the next reaction.

¹ HNMR (400MHz, CDCl ₃ ): 9.77～9.68(m, 1H), 5.75-5.22(m, 3H), 4.80-4.51(m, 2H), 4.20-3.60(m, 4H), 3.59-3.17(m , 4H), 3.10-2.65 (m, 1H), 2.40-1.40 (m, 23H), 1.11 (t, J=7.2Hz, 3H).

Step 2):

Under a nitrogen atmosphere, acetonitrile mixture (10 mL) of 152 mg of compound IXa (prepared according to Bioorg. Med. Chem. Lett 1998, 8, 2849) and lithium chloride (200 mg) was cooled to -15°C. Diisopropylethylamine (0.3 mL) was added to the reaction system, and the mixture was stirred at -15°C for 30 minutes. Acetonitrile (3 mL) solution of compound VIa obtained in step 1 was added to the reaction system. The reaction system was stirred at -15°C for 30 minutes, then gradually returned to room temperature, and stirred overnight. Diethyl ether (50 mL) was added to the system, the solid was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to obtain compound VIIa.

¹ HNMR (400MHz, CDCl ₃ ): 7.45-7.15(m, 5H), 6.72-6.80(m, 1H), 6.26-6.19(m, 1H), 5.85-5.22(m, 3H), 4.80-4.45(m , 2H), 4.25-3.60(m, 4H), 3.51-3.17(m, 4H), 3.10-2.50(m, 5H), 2.40-1.40(m, 23H), 1.11(t, J=7.2Hz, 3H ).

Step 3):

At room temperature, borane (1M solution in tetrahydrofuran, 3.4 mL) and (R)-CBS catalyst (1.0M solution in toluene, 68 uL) were added to tetrahydrofuran (10 mL), and the mixture was stirred for 1 hour. A solution of compound VIIa (200 mg) in tetrahydrofuran (5 mL) was cooled to -10°C, and the above mixture was added to the solution. After 30 minutes, methanol (0.5 mL) was added to quench the reaction. The reaction system was concentrated under reduced pressure to obtain product VIIIa. Compound VIIIa was directly used in the next reaction.

¹ HNMR (400MHz, CDCl ₃ ): 7.39-7.15(m, 5H), 5.78-5.22(m, 4H), 4.80-4.45(m, 2H), 4.25-3.60(m, 5H), 3.51-3.17(m , 4H), 2.80-2.40 (m, 3H), 2.40-1.40 (m, 25H), 1.11 (t, J=7.2Hz, 3H).

Step 4):

Compound VIIIa obtained in step 3 was dissolved in methanol (5 mL), and p-toluenesulfonic acid monohydrate (500 mg) was added. The system was stirred at room temperature for 30 minutes, then concentrated under reduced pressure. The residue was dissolved in ethyl acetate (30 mL), washed with water (30 mL) and saturated brine (30 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by column chromatography to obtain bimatoprost.

¹ HNMR (400MHz, CD ₃ OD): 7.27-7.14 (m, 5H), 5.61-5.30 (m, 4H), 4.15-4.00 (m, 2H), 3.87-3.81 (m, 1H), 3.20-3.12 ( m, 2H), 2.70-2.65 (m, 2H), 2.41-2.00 (m, 8H), 1.89-1.46 (m, 6H), 1.09 (t, J=7.2Hz, 3H).

Since this invention has been described in terms of specific embodiments thereof, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be encompassed within the scope of this invention.

Claims (13)

1. a kind of intermediate for preparing prostaglandin medicine as shown in structural formula (I), described prostaglandin medicine is bimatoprost, Among them, R ¹ and R ² are hydrogen, R ³ is a hydroxyl protecting group; R ⁴ and R ⁵ are each hydrogen, amino, methoxy, C _1-10 straight or branched chain alkyl, C _{3- 8} cyclic alkyl group, or C _6-10 substituted or unsubstituted aryl group; or R ⁴ , R ⁵ and nitrogen atom together form a 5-8 membered heterocyclic ring; R ⁴ and R ⁵ cannot be amino or methyl at the same time Oxygen. 2. The intermediate according to claim 1, wherein R ⁴ , R ⁵ and the nitrogen atom together form a five-membered ring or a six-membered ring. 3. The intermediate according to claim 1, wherein the hydroxyl protecting group is selected from THP, -C(O)R ⁶ or -SiR ⁷ R ⁸ R ⁹ , wherein R ⁶ , R ⁷ , R ⁸ and R ⁹ are each a C _1-10 linear or branched alkyl group, a C _3-8 cyclic alkyl group, or a C _6-10 substituted or unsubstituted aryl group. 4. The intermediate according to any one of claims ¹ to ³ , wherein R and R are each independently selected from hydrogen, methyl, ethyl, propyl, butyl, phenyl, amino or methoxy ; R ⁴ and R ⁵ cannot be amino or methoxy at the same time. 5. The intermediate according to claim 4, wherein R ⁴ is ethyl and R ⁵ is hydrogen; or R ⁴ is hydrogen and R ⁵ is ethyl. 6. A method for preparing an intermediate shown in structural formula (Ia), It is characterized in that the hemiacetal of structural formula (II) and the amide derivative of structural formula (III) are prepared by Wittig reaction under alkaline conditions as the intermediate shown in formula (Ia): Wherein in formula (Ia) and formula (II) R ² is hydrogen, R ³ is a hydroxyl protecting group; In formula (Ia) and formula (III) R ⁴ and R ⁵ are respectively hydrogen, amino, methoxy, C _1-10 straight chain or branched chain alkyl, C _3-8 cyclic alkyl, or C _6-10 substituted or unsubstituted aryl; or R ⁴ , R ⁵ and nitrogen atom together form 5-8 membered heterocycle; R ⁴ and R ⁵ cannot be amino or methoxy at the same time; X in formula (III) is halogen, and Ar is C _6-10 substituted or unsubstituted aryl. 7. the method for preparing the intermediate shown in structural formula (Ia) according to claim 6, wherein in formula (Ia) and formula (III) R ⁴ , R ⁵ and nitrogen atom form five-membered ring or six-membered ring together ring. 8. The preparation method according to claim 6 or 7, wherein the hydroxyl protecting group is selected from THP, -C(O)R ⁶ or -SiR ⁷ R ⁸ R ⁹ , wherein R ⁶ , R ⁷ , R ⁸ and R ⁹ are each a C _1-10 linear or branched alkyl group, a C _3-8 cyclic alkyl group, or a C _6-10 substituted or unsubstituted aryl group. 9. The preparation method according to claim 6 or 7, wherein R ² is hydrogen, and R ³ is TIPS. 10. The preparation method according to claim 6 or 7, wherein R ⁴ and R ⁵ are each selected from hydrogen, methyl, ethyl, propyl, butyl, phenyl, amino or methoxy; R ⁴ and ^R5 cannot be amino or methoxy at the same time. 11. The preparation method according to claim 10, wherein R ⁴ is ethyl and R ⁵ is hydrogen; or R ⁴ is hydrogen and R ⁵ is ethyl. 12. The preparation method according to claim 6 or 7, X is selected from Cl, Br or I. 13. The preparation method according to claim 6 or 7, wherein Ar is phenyl.