Method for preparing latanoprostene bunoder and intermediates thereof and compositions containing the same

Abstract

The present invention relates to a method for preparing latanoprostene bronuod and an intermediate thereof and a composition containing the same. The present invention particularly relates to a method for preparing latanoprostene bronuod and an intermediate prepared by the method. The present invention also relates to a latanoprostene bronuod composition comprising high-purity latanoprostene bronuod.

Description

Technical Field

[0001] The present invention relates to a method for preparing latanoprostene bunoder, and intermediates and compositions containing the same. Background Art

[0002] Latanoprostene bunod having the following formula I is an active pharmaceutical ingredient (API) of Vyzulta, an ophthalmic solution for open-angle glaucoma or ocular hypertension:

[0003]

[0004] WO 2005 / 068421 and WO 2017 / 093771 both disclose a method for preparing latanoprostene brood by reacting latanoprost with 4-bromobutyl nitrate, as shown in Scheme 1. However, various impurities will be generated during the process, including isomers and by-products from latanoprost acid, such as compound LB-Br and compound LB-I:

[0005] Process 1

[0006]

[0007] WO 2019 / 031774 discloses a method for preparing latanoprostene brood by reacting AgNO3 and a compound LB-Br prepared from latanoprost acid and 1,4-dibromobutane, as shown in Scheme 2:

[0008] Process 2

[0009]

[0010] However, there is always a certain amount of unreacted compound LB-Br in the reaction of LB-Br and AgNO3, even if the reaction is carried out at high temperature for a long time. In addition, 5,6-trans-latanoprostene bron will also be produced by isomerization of latanoprostene bron during the long-term reaction at high temperature. Therefore, the method of WO 2019 / 031774 not only has the problem of impurity compound LB-Br, but also has the problem of 5,6-trans-latanoprostene bron.

[0011] Because latanoprostene brood is in oily form, its impurities cannot be removed by crystallization purification, but may be removed by chromatography. However, since the polarities of compound LB-Br and compound LB-I are very similar to that of latanoprostene brood (TLCΔRf<0.1), and the polarity of 5,6-trans-latanoprostene brood is almost the same as that of latanoprostene brood, it is still very difficult to remove the impurity compounds LB-Br, compound LB-I and 5,6-trans-latanoprostene brood from latanoprostene brood by chromatography, and even if it is possible, the cost will be very high.

[0012] WO 2017 / 093771 discloses the use of gravity silica gel column chromatography with a large amount (100 times the amount) of specific silica gel to purify crude latanoprostene brood. After purification, 5,6-trans latanoprostene brood and other by-products can be partially removed. However, in order to reduce the high cost of purification in industry, it is best to avoid or reduce the generation of impurities that are difficult to remove or separate during the manufacture of latanoprostene brood, such as compound LB-Br, compound LB-I and 5,6-trans latanoprostene brood. Summary of the invention

[0013] One aspect of the present invention is to provide an efficient and economical method for preparing latanoprostene brood without producing the aforementioned compound LB-Br or compound LB-I which is difficult to remove or separate and minimizing 5,6-trans-latanoprostene brood.

[0014] One embodiment of the present invention relates to a novel method for preparing latanoprost brood, which comprises the step of reacting latanoprost acid with 1,4-butanediol dinitrate.

[0015] One embodiment of the present invention relates to a method for purifying crude latanoprostene brood by silylation of all hydroxyl groups in crude latanoprostene brood with a silanizing agent comprising a residue -SiRaRbRc to form a compound of formula LB-3Si,

[0016]

[0017] wherein Ra, Rb and Rc are each independently C 1-8 alkyl, phenyl, benzyl, substituted phenyl or substituted benzyl; and then desilylation of the resulting compound of formula LB-3Si to form latanoprostene branod, which has a higher purity than crude latanoprostene branod.

[0018] One aspect of the present invention provides a novel intermediate of formula LB-3Si as defined above.

[0019] Another aspect of the present invention provides a method comprising esterifying latanoprost acid with 1,4-butanediol dinitrate to form latanoprostene bunode and a compound of formula LB-dimer,

[0020]

[0021] Another aspect of the present invention provides a novel compound of formula LB-dimer,

[0022]

[0023] Another aspect of the present invention provides a crude latanoprostene brood composition, which contains, in addition to residual solvents and 1,4-butanediol dinitrate, a content of greater than 0.1% and less than 5% of the compound LB-dimer as defined above, greater than 0.1% and less than 3.5% of the 5,6-trans isomer of latanoprostene brood, and less than 0.5% of 15S-latanoprostene brood.

[0024] Another aspect of the present invention provides a crude latanoprostene brood composition, which contains, in addition to residual solvents and 1,4-butanediol dinitrate, a content of greater than 0.1% and less than 5% of the compound LB-dimer as defined above, greater than 0.01% and less than 0.1% of the 5,6-trans isomer of latanoprostene brood, and less than 0.1% of 15S-latanoprostene brood.

[0025] Another aspect of the present invention provides a purified latanoprostene brood composition, which comprises a content of greater than 0% and less than 0.1% of the compound LB-dimer as defined above, greater than 0.1% and less than 3.5% of the 5,6-trans isomer of latanoprostene brood, and less than 0.5% of 15S-latanoprostene brood.

[0026] Another aspect of the present invention provides a purified latanoprostene bunoder composition, which contains a content of greater than 0% and less than 0.1% of the compound LB-dimer as defined above, greater than 0.01% and less than 0.1% of the 5,6-trans isomer of latanoprostene bunoder, and less than 0.1% of 15S-latanoprostene bunoder. DETAILED DESCRIPTION

[0027] Preparation of Latanoprost Acid

[0028] The present invention provides a method for preparing latanoprostene bunoder, which comprises reacting latanoprost acid with 1,4-butanediol dinitrate.

[0029] In some embodiments, latanoprost acid can be prepared by any conventional method. For example, latanoprost acid can be prepared by hydrolysis of latanoprost or latanoprost 1,9-lactone, as shown in Scheme 3:

[0030] Process 3

[0031]

[0032] In some embodiments, the hydrolysis reaction can be carried out using sodium hydroxide, potassium hydroxide, lithium hydroxide monohydrate or the like, and is particularly preferably carried out using lithium hydroxide monohydrate. In this case, ethanol, methanol, isopropanol, water or a mixed solvent thereof can be used as a reaction solvent, and a mixed solvent of methanol and water is particularly preferred. In some embodiments, the reaction temperature is preferably room temperature, and the reaction time is preferably about 1 to 20 hours.

[0033] In some embodiments, latanoprost acid can be prepared from latanoprost. Generally speaking, commercially available latanoprost that meets USP requirements contains about 3.5% of 5,6-trans isomers and about 0.5% of 15S-isomers. Therefore, latanoprost acid prepared from commercially available latanoprost by hydrolysis also contains about 3.5% of 5,6-trans isomers and about 0.5% of 15S-isomers. The latanoprost acid thus prepared is represented as latanoprost acid-A in this specification.

[0034] In some embodiments, latanoprost acid can be prepared from latanoprost 1,9-lactone. In an embodiment of the present invention, latanoprost 1,9-lactone disclosed in US 9994543 is used and prepared by hydrolysis. The latanoprost acid thus prepared is substantially free of isomers and contains less than 0.1% of 5,6-trans isomers and 0.1% of 15S-isomers, and is represented in this specification as latanoprost acid-B.

[0035] Preparation of Latanoprostene Bunode

[0036] According to the present invention, latanoprostene bunoder is prepared by esterifying latanoprost acid with 1,4-butanediol dinitrate as shown in Scheme 4:

[0037] Process 4

[0038]

[0039] In some embodiments, the reaction may be carried out in the presence of a base. Examples of suitable bases include, but are not limited to, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), sodium hydroxide and potassium carbonate, and 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or potassium carbonate is particularly preferred.

[0040] In some embodiments, the reaction can be carried out in the presence of a solvent. Examples of suitable solvents include, but are not limited to, acetone, dichloromethane, toluene, tetrahydrofuran (THF) and dimethylformamide (DMF), and dimethylformamide is particularly preferred for the reaction.

[0041] In the present invention, the amount of 1,4-butanediol dinitrate is not particularly limited. In some embodiments, 1,4-butanediol dinitrate can be used in an amount ranging from about 1 to 100 parts by weight, preferably about 3 to 30 parts by weight, or about 5 to 15 parts by weight, and more preferably about 5 to 10 parts by weight per part by weight of latanoprost acid.

[0042] In some embodiments, the reaction temperature is preferably about 20 to 80° C., about 20 to 70° C., about 20 to 60° C., about 20 to 50° C., about 20 to 40° C., or about 20 to 30° C. The reaction time varies depending on the reaction temperature, and it is preferably about 1 to 6 hours, about 1 to 5 hours, about 1 to 4 hours, about 1 to 3 hours, or about 1 to 2 hours.

[0043] As shown in Scheme 4 above, the method for preparing latanoprostene bunoder further comprises the formation of a dimer of formula LB- as a byproduct.

[0044] In some embodiments, using latanoprost acid-A as a starting material in the method of the present invention can provide a crude latanoprostene brood composition A, which includes a content of greater than about 0.1% and less than about 5% of compound LB-dimer, greater than about 0.1% and less than about 3.5% of 5,6-trans isomer of latanoprostene brood, and less than about 0.5% of 15S-latanoprostene brood, except for residual solvents and 1,4-butanediol dinitrate. In some embodiments, 15S-latanoprostene brood and 5,6-trans isomer of latanoprostene brood are produced from 15S-isomer and 5,6-trans isomer in the starting material of latanoprost acid-A, respectively. In some embodiments, the crude latanoprostene brood composition A does not contain any compound LB-Br or compound LB-I.

[0045] In some embodiments, using latanoprost acid-B as a starting material in the method of the present invention can provide a crude latanoprostene brood composition B, which includes a content of greater than about 0.1% and less than about 5% of compound LB-dimer, greater than about 0.01% and less than about 0.1% of 5,6-trans isomer of latanoprostene brood, and less than about 0.1% of 15S-latanoprostene brood, except for residual solvents and 1,4-butanediol dinitrate. In some embodiments, 15S-latanoprostene brood and 5,6-trans isomer of latanoprostene brood are produced from 15S-isomer and 5,6-trans isomer in the starting material of latanoprost acid-B, respectively. In some embodiments, crude latanoprostene brood composition B does not contain any compound LB-Br or compound LB-I.

[0046] In the method of the present invention, although the crude latanoprostene bunode compositions A and B each include an excess of 1,4-butanediol dinitrate as a reaction reagent (TLCΔRf>0.7, 33% hexane / ethyl acetate) and a by-product of compound LB-dimer (TLCΔRf>0.5, 100% ethyl acetate), the excess reaction reagent and by-product can be easily removed by a general or simple chromatography method. However, in the prior art methods, such as the methods disclosed in WO 2005 / 068421, WO 2017 / 093771 and WO 2019 / 031774, impurities with a TLCΔRf of less than 0.1 are generated, such as compound LB-Br (TLCΔRf<0.04, 33% hexane / ethyl acetate), compound LB-I (TLCΔRf<0.07, 33% hexane / ethyl acetate) and 5,6-trans isomer of latanoprostene brood (TLCΔRf<0.01, 33% hexane / ethyl acetate), which are difficult to remove by general chromatography and can only be removed by difficult or complex chromatography. Therefore, the method of the present invention is simpler and more cost-effective than the prior art method.

[0047] In addition to the reaction reagent of excess 1,4-butanediol dinitrate and the byproduct of compound LB-dimer, crude latanoprostene brood further contains a small amount of high polarity non-prostaglandin impurities and low polarity non-prostaglandin impurities generated by the reagent or solvent. In the method of the present invention, only one general chromatography method is needed to purify crude latanoprostene brood, and excess 1,4-butanediol dinitrate, compound LB-dimer, high polarity non-prostaglandin impurities and low polarity non-prostaglandin impurities can be removed simultaneously.

[0048] In some embodiments, all hydroxyl groups of crude latanoprostene brood can be protected by silyl protecting groups to form protected latanoprostene brood with low polarity. Subsequently, the protected latanoprostene brood with low polarity can be purified by general chromatography as appropriate to remove non-prostaglandin impurities of high polarity. Afterwards, the protected latanoprostene brood is desilylated to form crude latanoprostene brood with high polarity, which does not contain any non-prostaglandin impurities of high polarity. Then, the crude latanoprostene brood with high polarity only needs to be further purified using a general chromatography method once to remove non-prostaglandin impurities of low polarity.

[0049] General chromatography suitable for the method of the present invention is a known and widely used method in the art. In the method of the present invention, general chromatography can be used to purify crude latanoprostene bunode or crude protected latanoprostene bunode. For example, column chromatography with low-cost irregular silica gel with a common particle size of 63 μm to 200 μm or 50 μm to 150 μm can be used to effectively remove excess reaction reagents, by-products and non-prostaglandin impurities. In addition, as long as the amount of silica gel is about (or more than) 3 times the content of the substance to be separated, the above impurities can be removed to less than about 0.1%. Preferably, the amount of silica gel is about 5 to 50 times the content of the substance to be separated. More preferably, the amount of silica gel is about 5 to 20 times the content of the substance to be separated.

[0050] In some embodiments, a two-component mixture of non-polar and polar solvents can be applied as an eluent in various compositions. Examples of non-polar solvents in the two-component mixture include, but are not limited to, hydrocarbons, halogenated aliphatic hydrocarbons, and ether solvents such as pentane, hexane, heptane, cyclohexane, and dichloromethane and diisopropyl ether. Examples of polar solvents in the two-component mixture include, but are not limited to, alcohols, esters, or ketones containing linear or branched alkyl groups.

[0051] In some embodiments, crude buno-latanoprost can be purified by silylation and desilylation. In some embodiments, crude latanoprostene buno-latanoprost can be purified by silylation of all hydroxyl groups in latanoprostene buno-latanoprost with a silanizing agent comprising a residue -SiRaRbRc to form a crude compound of formula LB-3Si:

[0052]

[0053] wherein Ra, Rb and Rc are each independently C 1-8 In some embodiments, the silanizing agent has the formula XSiRaRbRc, wherein X is a halogen such as F, Cl or Br; and Ra, Rb and Rc are each independently C 1-8Alkyl, phenyl, benzyl, substituted phenyl or substituted benzyl. According to one embodiment of the present invention, the silanizing agent suitable for the purification reaction is selected from the group consisting of trimethylsilyl chloride, triethylsilyl chloride, dimethyl (octyl) silane chloride and tertiary butyl dimethyl silane chloride.

[0054] In some embodiments, the crude compound of formula LB-3Si can be purified by general chromatography. Since the compound of formula LB-3Si has very low polarity, impurities with higher polarity (for example, impurities generated from solvents such as DMF and from reagents such as 1,4-butanediol dinitrate) can be easily removed by using simple chromatography. Then, the resulting compound of formula LB-3Si is desilylated to form another crude latanoprostene brood. Thereafter, another crude latanoprostene brood can be purified by general chromatography to form latanoprostene brood with improved purity. In some embodiments, the conditions for carrying out the silylation and desilylation reactions are conditions that are obvious to those skilled in the art.

[0055] In some embodiments, the crude compound of formula LB-3Si can be purified as appropriate. In the method of the present invention, impurities with higher polarity can be reduced to less than 0.1% to meet regulatory requirements, even when only general chromatography is used to purify crude latanoprostene bunode, that is, without purifying the compound of formula LB-3Si. In some embodiments, by additionally purifying the compound of formula LB-3Si by general chromatography, impurities with higher polarity can be reduced to less than 0.1% or even less than the detection limit of high performance liquid chromatography (HPLC).

[0056] In some embodiments, by using latanoprost acid-A as a starting material, a purified latanoprostene brood composition C can be obtained, which includes a content of greater than about 0% and less than about 0.1% of compound LB-dimer, greater than about 0.1% and less than about 3.5% of 5,6-trans isomer of latanoprostene brood, and less than about 0.5% of 15S-latanoprostene brood. In some embodiments, a purified latanoprostene brood composition C can be obtained by purifying a crude latanoprostene brood composition A. In some embodiments, the purified latanoprostene brood composition C does not contain any compound LB-Br or compound LB-I.

[0057] In some embodiments, by using latanoprost acid-B as a starting material, a purified latanoprostene brood composition D can be obtained, which includes a content of greater than about 0% and less than about 0.1% of compound LB-dimer, greater than about 0.01% and less than about 0.1% of 5,6-trans isomer of latanoprostene brood, and less than about 0.1% of 15S-latanoprostene brood. In some embodiments, a purified latanoprostene brood composition D can be obtained by purifying a crude latanoprostene brood composition B. In some embodiments, the purified latanoprostene brood composition D does not contain any compound LB-Br or compound LB-I.

[0058] It should be understood that the specific embodiments described herein are shown by way of illustration and are not intended to be limitations of the present invention. The key features of the present invention may be employed in various embodiments without departing from the scope of the present invention. Those skilled in the art will recognize or be able to ascertain, using no more than routine experimentation, many equivalents to the specific procedures described herein. Such equivalents are considered to be within the scope of the present invention and are covered by the claims.

[0059] All publications and patent applications mentioned in this specification are indicative of the level of skill of those skilled in the art to which the invention pertains. All publications and patent applications are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

[0060] When used in conjunction with the term "comprising" in the claims and / or specification, the use of the words "a" or "an" can mean "one", but it is also consistent with the meaning of "one or more", "at least one", and "one or more than one". Although the present invention supports definitions referring to only alternatives and "and / or", the use of the term "or" in the claims is used to mean "and / or" unless explicitly indicated as referring to only alternatives or that the alternatives are mutually exclusive. Throughout this application, the term "about" is used to indicate that a value includes the inherent deviation of the device, the method used to determine the value, or the deviation that exists among the study subjects.

[0061] As used in this specification and claims, the words "comprising" (and any forms of comprising, such as "comprise" and "comprises"), "having" (and any forms of having, such as "have" and "has"), "including" (and any forms of including, such as "includes" and "include"), or "containing" (and any forms of containing, such as "contains" and "contain") are inclusive or open-ended and do not exclude additional, unrecited elements or method steps.

[0062] Although the word "about" is added before the minimum and maximum values ​​within the range, unless otherwise explicitly indicated, the use of numerical values ​​in the multiple quantitative values ​​specified in this application is stated as approximate values. In this way, slight changes in the numerical values ​​can be used to achieve substantially the same results as the numerical values. In addition, the scope of the present disclosure is intended to be a continuous range, including each numerical value between the minimum and maximum values ​​and any range that can be formed by such numerical values. Also disclosed herein are any and all ratios (and any range of such simulated ratios) that can be formed by dividing the stated numerical values ​​into any other stated numerical values. Accordingly, those skilled in the art will understand that many of the ratios, ranges, and ranges of ratios can be clearly derived from the numerical values ​​proposed herein, and the ratios, ranges, and ranges of ratios described in all examples represent multiple embodiments of the present invention.

[0063] All compounds and / or methods disclosed and claimed herein can be made and performed according to the present invention without undue experimentation. Although the compounds and methods of the present invention have been described according to preferred embodiments, it should be clear to those skilled in the art that changes can be applied to the compositions and / or methods described herein and to the steps or sequence of steps of the methods without departing from the concept, spirit and scope of the present invention. All such similar substitutions and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the present invention as defined by the appended claims.

[0064] Examples

[0065] Example 1

[0066] Preparation of Latanoprost Acid-A

[0067] A solution of latanoprost (containing 2.38% 5,6-trans isomer and 0.05% 15S-isomer) (1.0 g, 2.31 mmol) in isopropanol (8 mL) was treated with 3N aqueous potassium hydroxide solution (3.85 mL). The mixture was stirred at 50 to 55 ° C for 2 hours, cooled, and then adjusted to pH 8.0 to 8.3 with 3N aqueous hydrochloric acid. Subsequently, most of the solvent was removed under reduced pressure. The residue was diluted with saturated aqueous sodium bicarbonate solution (5 mL) and ethyl acetate (2 mL). The mixture was then stirred at room temperature for 5 minutes, and the organic phase and aqueous phase were collected separately. The aqueous layer was adjusted to pH 3.0 to 3.2 with 3N aqueous hydrochloric acid at room temperature and extracted with ethyl acetate (20 mL). The organic layer was dried over magnesium sulfate (3 g) and concentrated under reduced pressure to give 1.1 g of crude latanoprost acid-A. HPLC analysis of the product showed that it contained 2.34% 5,6-trans isomer and 0.05% 15S-isomer.

[0068] Example 2

[0069] Preparation of Latanoprost Acid-B

[0070] A solution of latanoprost 1,9-lactone (30.0 g, 0.08 mol) obtained by the method disclosed in US 9,994,543 was treated with 3N aqueous potassium hydroxide solution (100 mL). The mixture was stirred at 50 to 55 ° C for 2 hours, cooled, and then adjusted to pH 8.0 to 8.3 with 3N aqueous hydrochloric acid. Subsequently, most of the solvent was removed under reduced pressure. The residue was diluted with saturated aqueous sodium bicarbonate solution (150 mL) and ethyl acetate (60 mL). The mixture was then stirred at room temperature for 5 minutes, and the organic phase and aqueous phase were collected separately. The aqueous layer was adjusted to pH 3.0 to 3.2 with 3N aqueous hydrochloric acid at room temperature and extracted with ethyl acetate (500 mL). The organic layer was dried over magnesium sulfate (60 g) and concentrated under reduced pressure to obtain 36.2 g of crude latanoprost acid-B. HPLC analysis of the product showed that no isomers were detected.

[0071] 1H-NMR (400MHz, CDCl3): δ7.253-7.282(m,2H),7.157-7.194(m,3H),5.455 -5.506(m,1H),5.342-5.394(m,1H),4.142-4.152(m,1H),3.936(m,1H),3 .664-3.711(m,1H),2.754-2.813(m,1H),2.618-2.678(m,1H),2.327(t,2 H),2.241(t,2H),2.133(q,2H),1.496-1.892(m,10H),1.307-1.382(m,2H)

[0072] 13 C-NMR (100MHz, CDCl3): δ177.395,142.122,129.454,129.416,128.392,128.376,125.788,78.386,74. 234,71.509,52.139,51.433,42.461,38.749,35.228,33.201,32.070,29.049,26.575,26.408,24.662

[0073] Comparative Example 3

[0074] Synthesis of latanoprostene brood from latanoprost acid-B and 4-bromobutyl nitrate

[0075] A solution of crude latanoprost acid-B (213 mg, 0.54 mmol) in DMF (5 mL) was treated with K2CO3 (206 mg, 1.49 mmol), KI (77 mg, 0.46 mmol) and 4-bromobutyl nitrate (805 mg, 25% w / w, in dichloromethane, 1.02 mmol). The mixture was then stirred at 45 to 50°C under a nitrogen atmosphere for 2 hours (TLC monitoring). The mixture was diluted with ethyl acetate (100 mL), washed with brine (2×50 mL), dried over magnesium sulfate, and concentrated under reduced pressure to give 0.43 g of crude latanoprostene brood. HPLC analysis of crude latanoprostene brood showed that it contained 4.59% compound LB-Br and 0.91% compound LB-I, and 5,6-trans latanoprostene brood and 15S-latanoprostene brood were not detected.

[0076] Latanoprostene Bunode:

[0077] TLC: Rf 0.205 (33% hexane / ethyl acetate); Rf 0.705 (100% ethyl acetate)

[0078] 1 H-NMR (400MHz, CDCl3): δ7.245-7.281(m,2H),7.146-7.192(m,3H),5.445- 5.490(m,1H),5.331-5.427(m,1H),4.451(t,2H),4.130(m,1H),4.078(t,2H ),3.927(m,1H),3.637(m,1H),3.073(s,1H),2.613-2.781(m,3H),2.263-2. 341(m,3H),2.027-2.208(m,4H),1.495-1.862(m,14H),1.294-1.391(m,2H)

[0079] 13 C-NMR (100MHz, CDCl3): δ173.877,142.113,129.514,129.331,128.390,125.810,78.676,74.592,72.619,71.298, 63.473,52.733,51.799,42.494,39.025,35.762,33.583,32.103,29.583,26.889,26.600,24.938,24.824,23.617

[0080] Compound LB-Br:

[0081] TLC: Rf 0.239 (33% hexane / ethyl acetate)

[0082] 1 H-NMR (400MHz, CDCl3): δ7.162-7.298(m,5H),5.351-5.478(m,2H),4.158(m,1H),4.091(t,2H),3.946(m,1H),3.664(m,1H) ),3.422(t,2H),2.634-2.829(m,3H),2.299-2.361(m,4H),2.091-2.227(m,3H),1.510-2.227(m,15H),1.252-1.419(m,2H)

[0083] 13C-NMR (100MHz, CDCl3): δ173.877,142.052,129.468,129.430,128.413,128.390,125.832,78.797,74.744,71.313,63. 442,52.907,51.883,42.532,39.063,35.784,33.614,33.052,32.111,29.629,29.287,27.299,26.942,26.631,24.839

[0084] Compound LB-I:

[0085] TLC: Rf 0.273 (33% hexane / ethyl acetate)

[0086] 1 H-NMR (400MHz, CDCl3): δ7.150-7.286(m,5H),5.355-5.474(m,2H),4.136(m,1H),4.069(t,2H),3.930(m,1H),3.644-3.661(m ,1H),3.185(t,2H),2.619-2.805(m,3H),2.268-2.324(m,3H),2.808-2.214(m,4H),1.501-1.910(m,15H),1.350-1.373(m,2H)

[0087] 13 C-NMR (100MHz, CDCl3): δ173.915,142.105,129.476,129.400,128.398,125.810,78.691,74.592,71.298,63.237 ,52.756,51.814,42.532,39.033,35.762,33.636,32.118,29.986,29.583,29.538,26.889,26.623,24.847,5.918

[0088] Comparative Example 4

[0089] Synthesis of latanoprostene brood by using compound LB-Br and silver nitrate

[0090] Compound LB-Br (0.5 g, 0.95 mmol) was dissolved in acetonitrile (7.5 mL), silver nitrate (0.29 g, 1.71 mmol) was added, and the mixture was then heated and stirred at about 35 to 40° C. for about 55 hours. The progress of the reaction was observed by HPLC and is shown in Table 1.

[0091] Table 1

[0092]

[0093] As shown in Table 1, after 55 hours of reaction, 0.35% of unreacted compound LB-Br still existed, but 0.77% of 5,6-trans-latanoprostene brood was produced by isomerization of latanoprostene brood. Since 5,6-trans-latanoprostene brood is more difficult to remove by chromatography than compound LB-Br, continuing the reaction does not increase the yield, but only increases the purification cost.

[0094] Example 5

[0095] Synthesis of latanoprostene brood from latanoprost acid-A and 1,4-butanediol dinitrate

[0096] A solution of crude latanoprost acid-A (5-trans isomer>2%) (1.1 g, 2.82 mmol) in DMF (6 mL) was treated with K2CO3 (1.17 g, 8.47 mmol) and 1,4-butanediol dinitrate (7.61 g, 42.25 mmol). The mixture was then stirred at 60 to 65 ° C under a nitrogen atmosphere for 2.5 hours (TLC monitoring), and then cooled to room temperature. The reaction mixture was diluted with ethyl acetate (20 mL), washed with ice water (2×15 mL), dried over magnesium sulfate (3 g) and concentrated under reduced pressure to give 9.8 g of crude latanoprostene bunode and excess 1,4-butanediol dinitrate. HPLC analysis of the crude latanoprostene bronuod composition showed that, in addition to residual solvents and 1,4-butanediol dinitrate, it contained 1.4% of compound LB-dimer, 2.38% of 5,6-trans isomer of latanoprostene bronuod, and 0.05% of 15S-latanoprostene bronuod. Excess 1,4-butanediol dinitrate and compound LB-dimer were removed by column chromatography with 5-fold amount of silica gel, and then concentrated under reduced pressure to provide 1.2 g of purified latanoprostene bronuod (83.9% yield). HPLC analysis of the purified latanoprostene bronuod composition showed that it contained 0.001% of compound LB-dimer, 2.4% of 5,6-trans isomer of latanoprostene bronuod, and 0.06% of 15S-latanoprostene bronuod.

[0097] Latanoprostene Bunode:

[0098] TLC: Rf 0.205 (33% hexane / ethyl acetate); Rf 0.705 (100% ethyl acetate)

[0099] 1H-NMR (400MHz, CDCl3): δ7.245-7.282(m,2H),7.146-7.192(m,3H),5.446- 5.491(m,1H),5.331-5.427(m,1H),4.452(t,2H),4.130(m,1H),4.079(t,2H ),3.927(m,1H),3.639(m,1H),3.042(s,1H),2.610-2.801(m,3H),2.264-2. 343(m,3H),2.059-2.209(m,4H),1.495-1.863(m,14H),1.294-1.393(m,2H)

[0100] 13 C-NMR (100MHz, CDCl3): δ173.870,142.113,129.514,129.331,128.390,125.810,78.683,74.600,72.619,71.298, 63.465,52.740,51.807,42.501,39.025,35.762,33.583,32.103,29.583,26.889,26.600,24.938,24.824,23.625

[0101] Compound LB-Dimer:

[0102] TLC: Rf 0.0 (33% hexane / ethyl acetate); Rf 0.193 (100% ethyl acetate)

[0103] 1 H-NMR (400MHz, CDCl3): δ7.240-7.277(m,2H),7.142-7.190(m,3H),5.421-5.483(m,1H),5.325-5.387(m,1H),4.068-4.117(m,3H),3.91 9(m,1H),3.604-3.663(m,1H),2.611-2.816(m,3H),2.264-2.342(m, 4H),2.030-2.210(m,4H),1.465-1.902(m,12H),1.228-1.381(m,2H)

[0104] 13C-NMR (100MHz, CDCl3): δ174.014,142.151,129.536,129.347,128.390,125.787,78.622,74.463,71.268, 63.921,52.649,51.739,42.524,39.010,35.739,33.629,32.118,29.538,26.858,26.593,25.272,24.839

[0105] Example 6

[0106] Synthesis of latanoprostene brood from latanoprost acid-B and 1,4-butanediol dinitrate

[0107] A solution of crude latanoprost acid-B (35.00 g, 0.09 mol) in DMF (175 mL) was treated with K2CO3 (37.16 g, 0.27 mol) and 1,4-butanediol dinitrate (242.15 g, 1.34 mol). The mixture was then stirred at 60 to 65 ° C under a nitrogen atmosphere for 2.5 hours (TLC monitoring) and then cooled to room temperature. The reaction mixture was diluted with ethyl acetate (600 mL), washed with ice water (2x530 mL), dried over magnesium sulfate (30 g) and concentrated under reduced pressure to give 268 g of crude latanoprostene bunode and excess 1,4-butanediol dinitrate. HPLC analysis of the crude latanoprostene bronuod composition showed that, in addition to residual solvent and 1,4-butanediol dinitrate, it contained 1.4% of compound LB-dimer and 0.02% of 5,6-trans isomer of latanoprostene bronuod, and no 15S-latanoprostene bronuod was detected. Excess 1,4-butanediol dinitrate and compound LB-dimer were removed by column chromatography with 5-fold amount of silica gel, and then concentrated under reduced pressure to provide 40.94g of purified latanoprostene bronuod (90.0% yield). HPLC analysis of the purified latanoprostene bronuod composition showed that it contained 0.0003% of compound LB-dimer and 0.03% of 5,6-trans isomer of latanoprostene bronuod, and no 15S-latanoprostene bronuod was detected. Purity:>99.90%.

[0108] Example 7

[0109] Synthesis of latanoprostene brood via latanoprostene brood-3TES from latanoprost acid-B and 1,4-butanediol dinitrate

[0110] A solution of crude latanoprost acid-B (30.0 g, 76.8 mmol) in DMF (150 mL) was treated with K2CO3 (31.85 g, 0.23 mol) and 1,4-butanediol dinitrate (207 g). The mixture was then stirred at 60 to 65 ° C under a nitrogen atmosphere for 2.5 hours (TLC monitoring). The reaction mixture was cooled to room temperature. The mixture was diluted with ethyl acetate (500 mL), washed with ice water (2×500 mL), dried over magnesium sulfate, and concentrated under reduced pressure to give crude latanoprostene bunode. At room temperature, triethylsilane chloride (47.60 g, 0.32 mol) was added to a solution of crude latanoprostene bunode and imidazole (26.83 g, 0.39 mol) in ethyl acetate (400 mL), and the mixture was stirred for 0.5 hours (TLC monitoring). A saturated aqueous solution of sodium bicarbonate (200 mL) was poured into the reaction mixture, and the mixture was stirred for 5 minutes. The organic layer was separated and extracted with a saturated aqueous solution of sodium bicarbonate. The organic layer was dried over magnesium sulfate, the solid was filtered out, and the filtrate was concentrated under reduced pressure to obtain a crude compound LB-3Si. The crude compound LB-3Si was purified by column chromatography to obtain 65.2 g of compound LB-3Si.

[0111] Compound LB-3Si:

[0112] (Z)-4-(Nitrooxy)butyl 7-((1R,2R,3R,5S)-2-((R)-5-phenyl-((triethylsilyl)oxy)pentyl)-3,5-bis((triethylsilyl)oxy)cyclopentyl)hept-5-enoate

[0113] 1 H-NMR (400MHz, CDCl3): δ7.250-7.286(m,2H),7.147-7.181(m,3H),5.422-5.484(m,1H),5 .308-5.371(m,1H),4.457(t,2H),4.069-4.108(m,3H),3.665-3.758(m,2H),2.566-2.718 (m,2H),2.224-2.314(m,3H),2.061-2.183(m,4H),1.745-1.822(m,8H),1.590-1.697(m,2 H),1.458-1.520(m,2H),1.254-1.412(m,3H),0.930-0.987(m,27H),0.535-0.634(m,18H)

[0114] 13C-NMR (100MHz, CDCl3): δ173.566,142.675,130.295,128.739,128.299,128.269,125.620,76.186,72.566,72.338,71.746,63.199,50.281, 48.103,44.194,39.124,34.471,33.743,31.716,28.065,26.722,25. 864,24.991,24.931,23.625,6.988,6.881,6.866,5.166,4.954,4.923

[0115] Monohydrated p-toluenesulfonic acid (1 g) was added to a stirred solution of compound LB-3Si in methanol (250 mL). The mixture was stirred at room temperature for 2 hours (TLC monitoring). Subsequently, the reaction mixture was quenched with a saturated aqueous sodium bicarbonate solution, and methanol was removed under reduced pressure. The residue was extracted with ethyl acetate. The organic layer was separated. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered and concentrated under reduced pressure to give crude latanoprostene bunode. HPLC (Phenomenex Luna 5 μm silica) analysis of the crude latanoprostene bunode composition showed that it contained 0.8% compound LB-dimer and 0.02% latanoprostene bunode 5,6-trans isomers, and no 15S-latanoprostene bunode was detected. The crude product was further purified by flash column chromatography to obtain 34.8 g of product. HPLC analysis of the purified latanoprostene brood composition showed that it contained 0.0001% of compound LB-dimer and 0.02% of 5,6-trans isomer of latanoprostene brood, and no 15S-latanoprostene brood was detected. Purity: >99.95%.

[0116] Although the present invention has been described with reference to illustrative examples, it should be understood that any modifications or alterations that may be easily accomplished by those skilled in the art will fall within the scope of the disclosure of the specification and the appended claims.

Claims

1. A method for preparing latanoprost bonuode having the structure of the following formula I, comprising reacting latanoprost acid with 1,4-butanediol dinitrate 2. The method of claim 1, further comprising purifying the latanoprostene bunoder by: All hydroxyl groups in the latanoprostene bunoder are silylated with a silanizing agent comprising the residue -SiRaRbRc to form a compound of formula LB-3Si wherein Ra, Rb and Rc are each independently C 1-8 Alkyl, phenyl, benzyl; and The compound of formula LB-3Si is desilylated.

3. The method of claim 1, further comprising forming a compound of formula LB-dimer, LB-dimer.

4. A compound of formula LB-3Si, wherein Ra, Rb and Rc are each independently C 1-8 Alkyl, phenyl, benzyl.

Images